patoloji-ders-notlari

Title

Serdar Balcı

Diseases of Exocrine Pancreas

Serdar BALCI, MD

Pancreas

Exocrine organ
- Acinar cells
  - Produce the digestive enzymes
- Ductules and ducts
  - Cuboidal cells lining the smaller ductules secrete bicarbonate-rich fluid
  - Columnar cells lining the larger ducts produce mucin
  - Larger ducts also express the cystic fibrosis transmembrane conductance regulator (CFTR)
    - aberrant function of this membrane protein affects the viscosity of the pancreatic secretions
Endocrine organ
- __ islets of Langerhans__
- secrete insulin, glucagon, and somatostatin

İnhibitors of autodigestion of the pancreas

Pancreatic enzymes are synthesized as inactive proenzymes

Sequestered in membrane-bound zymogen granules

Activation of proenzymes requires conversion of trypsinogen to trypsin by duodenal enteropeptidase (enterokinase)

Trypsin inhibitors (e.g., SPINK1, also known as pancreatic secretory trypsin inhibitor) are secreted by acinar and ductal cells

Trypsin cleaves and inactivates itself

Acinar cells are remarkably resistant to the action of activated enzymes

Cystic Fibrosis

Cystic fibrosis

The acinar tissue of the pancreas has been replaced by adipose tissue.

Autopsy Pathology: A Manual and Atlas

Robbins and Cotran Pathologic Basis of Disease

Pancreas in cystic fibrosis. The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by fibrous tissue.

Robbins and Cotran Pathologic Basis of Disease

CONGENITAL ANOMALIES

Agenesis

Very rarely

totally absent

usually associated with additional severe malformations that are incompatible with life

Pancreatic duodenal homeobox 1 is a homeodomain transcription factor, mutations of the PDX1 gene, located on chromosomal locus 13q12.1

Pancreas Divisum

most common clinically significant congenital pancreatic anomaly

incidence of 3-10% in autopsy series

duct systems of the fetal pancreatic primordia fail to fuse

main pancreatic duct drains only a small portion of the head of the gland

bulk of the pancreas (from the dorsal pancreatic primordium) drains through the minor sphincter, which has a narrow opening

elevated intraductal pressures throughout most of the pancreas

increased risk for chronic pancreatitis

Annular Pancreas

uncommon variant of pancreatic fusion

ring of pancreatic tissue completely encircles the duodenum

manifest with signs and symptoms of duodenal obstruction such as gastric distention and vomiting

Ectopic Pancreas

2% of the population

stomach and duodenum, jejunum, Meckel diverticulum, and ileum

embryologic rests

small (ranging from millimeters to centimeters in diameter)

submucosa

normal pancreatic acini with occasional islets

usually incidental and asymptomatic

can cause pain from localized inflammation, rarely bleeding

2% of pancreatic neuroendocrine tumors arise in ectopic pancreatic tissue

Congenital Cysts

anomalous development of the pancreatic ducts

may be with polycystic diseases

generally unilocular and range from microscopic to 5 cm in diameter

lined by either uniform cuboidal or flattened epithelium

enclosed in a thin, fibrous capsule

contain clear serous fluid

Autopsy Pathology: A Manual and Atlas

PANCREATITIS

Acute Pancreatitis

reversible inflammatory disorder
varies in severity
focal edema and fat necrosis to widespread hemorrhagic parenchymal necrosis
relatively common
- 10-20 per 100,000 people in the Western world
80% of cases are attributable to either biliary tract disease or alcoholism
- 5% of patients with gallstones develop acute pancreatitis
  - gallstones are implicated in 35-60% of cases overall
- Excessive alcohol intake
  - 65% of cases in the United States, 5% or less in the United Kingdom

Robbins Basic Pathology

Other causes of acute pancreatitis

Non–gallstone-related obstruction of the pancreatic ducts
- ampullary region neoplasms, pancreatic cancer, pancreas divisum, biliary “sludge,” or parasites, Ascaris lumbricoides and Clonorchis sinensis
Medications
- **anticonvulsants, cancer chemotherapeutic agents, thiazide diuretics, estrogens, …. **
Infections
- mumps virus or coxsackievirus
Metabolic disorders
- hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states
Ischemia
- vascular thrombosis, embolism, vasculitis, or shock
Trauma
- blunt force and iatrogenic during surgery or endoscopy
Inherited mutations
- genes encoding pancreatic enzymes or their inhibitors (e.g., SPINK1 )
- Hereditary pancreatitis
  - autosomal dominant disease with 80% penetrance
  - recurrent attacks of severe pancreatitis
  - beginning in childhood
  - mutations in the gene PRSS1 , which encodes trypsinogen, the proenzyme of pancreatic trypsin. Trypsin cannot cleave and inactivate itself
**10-20% of acute pancreatitis idiopathic **

Acute Pancreatitis

microvascular leakage causing edema

necrosis of fat by lipases

an acute inflammatory reaction

proteolytic destruction of pancreatic parenchyma

destruction of blood vessels leading to interstitial hemorrhage

The microscopic field shows a region of fat necrosis (right) and focal pancreatic parenchymal necrosis (center).

Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids combine with calcium to form insoluble salts that precipitate in situ

Robbins Basic Pathology

The pancreas has been sectioned longitudinally to reveal dark areas of hemorrhage in the pancreatic substance and a focal area of pale fat necrosis in the peripancreatic fat (upper left).

Robbins Basic Pathology

More severe form → Acute necrotizing pancreatitis
Necrosis of pancreatic tissue affects acinar and ductal tissues as well as the islets of Langerhans
Vascular damage causes hemorrhage into the parenchyma of the pancreas
Macroscopically, the pancreas exhibits red-black hemorrhagic areas interspersed with foci of yellow-white, chalky fat necrosis
Fat necrosis also can occur in extrapancreatic fat, including the omentum and bowel mesentery, and even outside the abdominal cavity (e.g., in subcutaneous fat)
Peritoneum contains a serous, slightly turbid, brown-tinged fluid with globules of fat (derived from enzymatically digested adipose tissue)
Most severe form → hemorrhagic pancreatitis
- extensive parenchymal necrosis, diffuse hemorrhage within the substance of the gland

Acute pancreatitis

Dark red black hemorrhage and chalky white necrosis of interstitial and peripancreatic fat

Autopsy Pathology: A Manual and Atlas

Omentum with fat necrosis

Autopsy Pathology: A Manual and Atlas

Pathogenesis of acute pancreatitis

autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes
activation of trypsin is a critical triggering event in acute pancreatitis
trypsin is inappropriately generated from its proenzyme trypsinogen
- can activate itself and other proenzymes (phospholipases and elastases)
- converts prekallikrein to its activated form, kinin system
- activation of factor XII (Hageman factor), clotting and complement systems

Robbins Basic Pathology

Impaction of a gallstone or biliary sludge

extrinsic compression of the ductal system

blocks ductal flow

increases intraductal pressure

accumulation of an enzyme-rich interstitial fluid

lipase is secreted in an active form, local fat necrosis

Injured tissues, periacinar myofibroblasts, and leukocytes release pro-inflammatory cytokines

local inflammation and interstitial edema through a leaky microvasculature

Edema compromises local blood flow

vascular insufficiency and ischemic injury to acinar cells

Robbins Basic Pathology

Ischemia, viral infections (mumps), drugs, and direct trauma to the pancreas are important in acinar cell injury mechanism

Robbins Basic Pathology

Pancreatic proenzymes and lysosomal hydrolases become packaged together
Proenzyme activation
Lysosomal rupture
- phospholipases
Local release of activated enzymes
The role of this mechanism in human acute pancreatitis is not clear

Robbins Basic Pathology

Alcohol consumption may cause pancreatitis by several mechanisms

transiently increases pancreatic exocrine secretion

contraction of the sphincter of Oddi

direct toxic effects on acinar cells

induction of oxidative stress in acinar cells

membrane damage

secretion of protein-rich pancreatic fluid

deposition of inspissated protein plugs

obstruction of small pancreatic ducts

Complications

disseminated intravascular coagulation
acute respiratory distress syndrome
diffuse fat necrosis
Peripheral vascular collapse (shock)
- increased microvascular permeability
- Hypovolemia
- Endotoxemia
  - breakdown of the barriers between gastrointestinal flora and the bloodstream
- renal failure
  - acute tubular necrosis

Robbins and Cotran Pathologic Basis of Diseases

Pancreatic Pseudocysts

common sequela of acute pancreatitis
- in particular, alcoholic pancreatitis
Liquefied areas of necrotic pancreatic tissue become walled off by fibrous tissue to form a cystic space
No epithelial lining
cyst contents are rich in pancreatic enzymes, and a laboratory assessment of the cyst aspirate can be diagnostic
75% of all pancreatic cysts
Many pseudocysts spontaneously resolve
become secondarily infected
larger pseudocysts can compress or even perforate into adjacent structures
solitary
attached to the surface of the gland
involve peripancreatic tissues
- lesser omental sac
- retroperitoneum between the stomach and transverse colon or liver
2 cm - 30 cm

Autopsy Pathology: A Manual and Atlas

A: Cross-section revealing a poorly defined cyst with a necrotic brownish wall.

Robbins Basic Pathology

B: Histologically, the cyst lacks a true epithelial lining and instead is lined by fibrin and granulation tissue, with typical changes of chronic inflammation.

Robbins Basic Pathology

Chronic Pancreatitis

Long-standing inflammation
Fibrosis
Destruction of the exocrine pancreas
- chronic malabsorption
In its late stages, the endocrine parenchyma also lost
- diabetes mellitus
Recurrent bouts of acute pancreatitis cause chronic pancreatitis

In chronic pancreatitis irreversible impairment in pancreatic function

Robbins and Cotran Pathologic Basis of Diseases

Most common cause is long-term alcohol abuse
- middle-aged men
Long-standing pancreatic duct obstruction
- pseudocysts, calculi, neoplasms, or pancreas divisum
Tropical pancreatitis
- heterogeneous disorder seen in Africa and Asia
- subset of cases having a genetic basis
Hereditary pancreatitis
- mutations in the pancreatic trypsinogen gene ( PRRS1 )
- SPINK1 gene encoding a trypsin inhibitor
Chronic pancreatitis associated with CFTR mutations
- cystic fibrosis → decrease bicarbonate secretion → increase the viscosity of the secretions → promoting protein plugging
40% have no recognizable predisposing factors
- may be associated with unknown inherited mutations

Chronic pancreatitis. The pancreas becomes hard and gray and contains numerous areas of mineralization. Ducts are cystically dilated and contain scattered calculi.

Autopsy Pathology: A Manual and Atlas

Extensive fibrosis and atrophy has left only residual islets (left) and ducts (right), with a sprinkling of chronic inflammatory cells and acinar tissue.

Robbins Basic Pathology

parenchymal fibrosis

reduced number and size of acini

variable dilation of the pancreatic ducts

relative sparing of the islets of Langerhans

Robbins Basic Pathology

Remaining islets of Langerhans become embedded in the sclerotic tissue and may fuse and appear enlarged; eventually they also disappear

Acinar loss, with a chronic inflammatory infiltrate around remaining lobules and ducts

Robbins Basic Pathology

The ductal epithelium may be atrophied or hyperplastic or exhibit squamous metaplasia, and ductal concretions may be noted

Robbins Basic Pathology

Autoimmune pancreatitis (AIP)

Characterized by one of two morphologic patterns
Striking infiltration of the pancreas by lymphoplasmacytic cells
- positive for IgG4
  - multisystem disease and may be one manifestation of IgG4-associated fibrosing disorders
- swirling fibrosis and venulitis (lymphoplasmacytic sclerosing pancreatitis)
a duct-centric mixed infiltrate composed of neutrophils, lymphocytes and plasma cells
- obliterating the ductal epithelium (idiopathic duct centric pancreatitis)
Both can mimic pancreatic cancer
Responds to steroid therapy

Pathogenesis of chronic pancreatitis

Ductal obstruction by concretions
- agents (alcohol) increase the protein concentration of pancreatic secretions
- form ductal plugs
Toxic-metabolic
- direct toxic effect on acinar cells
- lipid accumulation
- acinar cell loss
- parenchymal fibrosis
Oxidative stress
- Alcohol-induced oxidative stress
- free radicals in acinar cells
- membrane damage
- expression of chemokines (IL-8), recruits mononuclear inflammatory cells
Oxidative stress
- promotes the fusion of lysosomes and zymogen granules
- acinar cell necrosis
- inflammation, and fibrosis
Profibrogenic cytokines
- TGF-β, connective tissue growth factor, platelet-derived growth factor
- activation and proliferation of periacinar myofibroblasts (pancreatic stellate cells)
- deposit collagen
- fibrosis