Acute pancreatitis and Carcinoma pancreas

By Naulo pokhrelLMC, Palpa, Nepal

Acute PancreatitisPancreatitis: inflammation in the pancreas associated with injury to exocrine parenchyma

Acute pancreatitis Chronic pancreatitis

Acute PancreatitisReversible pancreatic

parenchymal injury associated with inflammation

Relatively commonCAUSE : Alcoholism, Gall bladder

disease accounts for 80%Gall stones are present in about

35 to 60 % of cases and 5% of patients with gall stones develop pancreatitis

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Male : female ratio – 1:3 for gall bladder disease and 6:1 for alcoholism

OTHER CAUSES : Obstruction in pancreatic duct

system : periampullary neoplasm, biliary sludge , parasites esp. ascaris

Medication : Furosemide , azathioprine , Estrogen, sulphonamides

Infection including mumps Trauma : Blunt injury to the abdomen

Ischemic injury from shock, embolism, vasculitis

Metabolic disorders- hypertriglyceridaemia, hyperparathyoidism

Germline mutation in cationic trypsinogen and trypsin inhibitor genes

Hereditary PancreatitisCharacterized by recurrent attack

of severe pancreatitis esp. beginning in childhood

Germline (inherited) mutation in cationic trypsinogen gene

Trypsin becomes resistance to cleavage

It can activate other digestive enzymes giving rise to pancreatitis

Autosomal dominant mode of inheritance

Serine protease inhibitor kazal type I (SPINK1) gene codes for Pancreatic secretory trypsin inhibitor

Leads to increased trypsin levelAnd pancreatitisThis mode is autosomal recessive

Pathogenesis

Autodigestion of pancreatic substance by inappropriately activated pancreatic enzymes

inappropriately activated pancreatic enzymes activates other proenzymes prophospholipase(degrade fat cells) , proelastase (damage elastic fibres of blood vessels)

Activates kinin system and by activation fo Hagmen factor; clotting system as well

Leads to inflammation and thromboses

Mechanism of inappropriate activation of pancreatic enzymes

Pancreatic duct obstruction : gall stones, biliary sludge in ampulla of vatar obstruction

Accumulation of enzyme rich fluid in the interstitium including activated lipase

Fat necrosisInjury to tissuesRelease of inf. Cytokines IL-1B, IL-6, TNF,

PAF

Initiation of inflammationEdemaVascular compromiseIschemic injury to acinar cells

Primary acinar injuryBY viruses(mumps)DrugsDirect traumaIschemiashock

Defective intracellular transport proenzymes within the acinar cells

Pancreatic proenzymes and lysosomal hydrolases packed together

Alcohol consumptionIncreased release of protein rich

pancreatic fluidDeposition of inspissated protein

plugObstruction of small pancreatic

ductsMay result in transient

contraction of sphincter of oddi (direct toxic effect on acinar cells)

Morphology of acute pancreatitis

Region of fat necrosis on the right and focal pancreatic parenchymal necosis centre

Morphology of acute pancreatitisBasic alterations are:Microvascular likage causing

edemaNecrosis of fat by lipolytic

enzymesAcute inflammationProteolytic destruction of

pancreatic parenchymaDestruction of blood vessels and

haemorrhage

In milder formEdemaFocal areas of fat necrosisMild inflammation

In more severe form (Acute necrotizing pancreatitis)Necrosis of Acinar tissues,

Ductal tissues, Islet of langerhans and Haemorrhage

MICROSCOPICALLY - pancreatitis shows red black haemorrhage interspersed with yello white chalky fat necrosis

In most severe haemorrhagic pancreatitis : extensive parenchymal necrosis with haemorrhage

Clinical featureAbdominal pain referred to upper

back and sometimes to left shoulder accompained by anorexia , nausea , vomitting

Lab findings : increased serum amylase, glycosuria, hypocalcaemia(d/t precepatation of Ca soaps in necrotic fat),

Direct visualisation of inflamed pancres by radiography

Key management is resting of pancreas by total restriction of oral intake and supportive therapy by iv fluids and analgesia

5% of patients of severe acute pancreatitis die from shock in first week of illness

Complications : Acute respiratory distress syndrome , aute renal failure.

Carcinoma of pancreas4th leading cause of death (lung,

colon, breast)Infiltrating ductal adenocarcinoma of

pancreasProgression from non neoplastic

epithelium to histologically well-defined non invasive leisons in ducts and ductules to invasive carcinoma

Precursor leisons : Pancreatic Intraepithelial Neoplasias (PanINs)

Location in pancreas60% in head15% in body5% in tail20% diffuseMost commonly seen in elder

patients (>60 years)Highly invasive carcinoma5 year survival rate is less than

5%

PathogenesisFrom inherited and acquired

mutationsProgressive accumulation of

genetic changesPrecursor leisons are Pancreatic

Intraepithelial Neoplasias (PanINs)

Molecular alterations in pancreatic carcinogenesis – KRAS, p16, SMAD4,and P53

K-RAS gene(chromosome 12p) is most frequently altered;point mutation leads to activation: in 80 to 90% of cases

P 16 tumor supressor gene inactivated 90% cases

SMAD4 tumor supressor gene inactivated in 55% of pancreatic cancers

P 53 tumor supressor gene inactivated in 50 to 70% of cases

Carcinomaa of pancreas more common in black than in white

Smoking doubles the riskChronic pancreatitis and dibetes

mellitus are also risk factors

Morphology

MorphologySite: 60% in head ,15% in body ,5% in

tail ,20% diffuse carcinomas are hard , stellate, gray white,

poorely defined massesMajority are ductal adeno-carcinoma2 charactreistic feature : highly invasive,

and elicts intense non-neoplastic host reaction composed of fibroblasts , lymphocytes and extracellular matrix(desmoplastic response)

Carcinomas in head of pancreas obstruct the distal common bile duct leads to jaundice

Often extend through retroperitonial space

May invade adrenals, spleen, transverse colon, stomach

Liver is often enlarged because of metastatic deposits

Distant metastasis to LUNGS and BONES

Microscopically

Moderately to poorely differentiated adenocarcinoma forming abortive tubular structures or cell clusters and exhibiting an aggressive , deeply infiltrative growth pattern

Deep stromal fibrosisLess comm varients includes acinar cell

carcinomas showing prominent acinar cells with zymogen granules and enzyme production

Adenosquamous carcinomaUndifferentiated carcinomas with osteoclast

like giant cell

Clinical featuresPainObstructive jaundiceWeight loss, anorexiaMigratory thrombophlebitis

(Trousseau syndrome) in 1o% of patients; elaboration of PAF and procoagulants from tumors or its necrotic contents

Elevated serum level of carcinoembryonic and CA19 antigens