patoloji-ders-notlari

Title

Serdar Balcı

Diseases and Tumors of Exocrine Pancreas

Serdar BALCI, MD

DISEASES OF EXOCRINE PANCREAS

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

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The acinar tissue of the pancreas has been replaced by adipose tissue.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

Pancreatic cysts

Thin-walled, serous, fluid-filled cysts may be found in the pancreas in some patients with autosomal-dominant polycystic kidney disease.

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

TUMORS OF EXOCRINE PANCREAS

Tumors of Pancreas

Pancreatoblastoma
Cystic Neoplasms
- Serous Cystadenoma
- Mucinous Cystic Neoplasm
- **Intraductal Papillary Mucinous Neoplasm **
Pancreatic Ductal Adenocarcinoma
Solid Pseudopapillary Neoplasm
Acinic Cell Carcinoma
Pancreatic Neuroendocrine Tumors

PANCREATOBLASTOMA

Pancreatoblastoma showing a predominantly solid pattern of growth but also small rosette-like glandular formations

Rosai and Ackerman’s Surgical Pathology

PANCREATIC EXOCRINE NEOPLASMS

Pancreatic Exocrine Neoplasms

Cystic
Solid
Benign
Malignant
- most lethal

Cystic Neoplasms

5-15% of all pancreatic cysts are neoplastic

<5% of all pancreatic neoplasms

Serous Cystadenoma

Robbins Basic Pathology

25% of all pancreatic cystic neoplasms

Small cysts containing clear, yellowish fluid

Robbins Basic Pathology

Serous Cystadenoma

Glycogen-rich cuboidal cells

Robbins Basic Pathology

Seventh decade of life
Nonspecific symptoms
- abdominal pain
F:M=2:1
Almost uniformly benign
Surgical resection is curative
Most carry somatic mutations von Hippel-Lindau ( VHL ) tumor suppressor gene

Robbins Basic Pathology

Mucinous Cystic Neoplasm

Robbins Basic Pathology

Mucinous Cystic Neoplasm

95% of mucinous cystic neoplasms arise in women

Usually in the body or tail of the pancreas

Painless, slow-growing masses

Cystic spaces are filled with thick, tenacious mucin

Robbins Basic Pathology

Mucinous Cystic Neoplasm

The cysts are lined by columnar mucinous epithelium, with a densely cellular “ovarian” stroma.

Robbins Basic Pathology

Mucinous Cystic Neoplasm

Degree of cytologic and architectural atypia in the lining epithelium
- low-grade, moderate, or severe dysplasia
1/3 associated with an invasive adenocarcinoma

The cysts are lined by columnar mucinous epithelium, with a densely cellular “ovarian” stroma.

Robbins Basic Pathology

Mucinous Cystic Neoplasm

Distal pancreatectomy for noninvasive cysts typically is curative
- even in the setting of severe dysplasia

Intraductal Papillary Mucinous Neoplasms (IPMNs)

Cross-section through the head of the pancreas showing a prominent papillary neoplasm distending the main pancreatic duct.

Robbins Basic Pathology

Intraductal Papillary Mucinous Neoplasms (IPMNs)

Mucin-producing intraductal neoplasms

More frequently in men than in women

More frequently involve the head of the pancreas

Arise in the main pancreatic ducts, or one of its major branch ducts

Robbins Basic Pathology

Intraductal Papillary Mucinous Neoplasms (IPMNs)

The papillary mucinous neoplasm involved the main pancreatic duct (left) and is extending down into the smaller ducts and ductules (right).

Robbins Basic Pathology

Intraductal Papillary Mucinous Neoplasms (IPMNs)

No cellular stroma seen in mucinous cystic neoplasms

Grades of dysplasia

Associated with an invasive adenocarcinoma component

Up to two thirds of IPMNs harbor oncogenic mutations of GNAS on chromosome 20q13, which encodes the alpha subunit of a stimulatory G-protein

Robbins Basic Pathology

Ankara Atatürk Eğitim ve Araştırma Hastanesi Arşivi

Pancreatic Carcinoma

Infiltrating ductal adenocarcinoma of the pancreas
Fourth leading cause of cancer death
5-year survival rate is less than 5%
80% of cases 60-80 years of age
Smoking, doubles the risk
Chronic pancreatitis and diabetes mellitus are also both associated with an increased risk of pancreatic cancer
- chronic pancreatitis; cause of pancreatic cancer? effect of it?
- diabetes can occur as a consequence?, new-onset diabetes in an elderly patient may be the first sign of this malignancy?
Familial clustering of pancreatic cancer
Germline mutations of the familial breast/ovarian cancer gene BRCA2
- 10% of cases arising in persons of Ashkenazi Jewish heritage

Precursor lesions

Intraductal papillary mucinous neoplasms

Mucinous cystic neoplasms

Pancreatic intraepithelial neoplasias (PanINs)

Accumulation of multiple mutations is more important than their occurrence in a specific order

KRAS

point mutation

most frequently altered oncogene

80-90%

SMAD4 TSG

inactivated 55%

TP53 TSG

50-70%

P16

most frequently inactivated TSG

turned off in 95%

Mutations of VHL or GNAS

Not been described in ductal adenocarcinomas

Robbins Basic Pathology

Pancreatic intraepithelial neoplasia grade 3 (PanIN-3) involving a small pancreatic duct.

Robbins and Cotran Pathologic Basis of Disease

60% of pancreatic cancers arise in the head of the gland

15% in the body, and 5% in the tail

20% diffusely involves the entire organ

Ggray-white, stellate, poorly defined masses

Robbins Basic Pathology

Ductal adenocarcinoma

Highly invasive
- even “early” invasive pancreatic cancers invade peripancreatic tissues extensively
__ Desmoplastic response__
- Intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and extracellular matrix
Obstruct the distal common bile duct
- 50% of such cases, there is marked distention of the biliary tree
- jaundice
Carcinomas of the body and tail of the pancreas do not impinge on the biliary tract and hence remain silent
- quite large and widely disseminated by the time they are discovered
Extend through the retroperitoneal space
Entrap adjacent nerves
- pain
Invade the spleen, adrenals, vertebral column, transverse colon, and stomach
Peripancreatic, gastric, mesenteric, omental, and portahepatic lymph nodes
Liver often is enlarged as a consequence of metastatic deposits
Distant metastases to the lungs and bones

Robbins and Cotran Pathologic Basis of Diseases

Autopsy Pathology: A Manual and Atlas

Moderately to poorly differentiated adenocarcinoma

Abortive tubular structures or cell clusters

Aggressive, deeply infiltrative growth pattern

Dense stromal fibrosis

Perineural invasion within and beyond the organ

Lymphatic invasion also is commonly seen

Robbins Basic Pathology

Ankara Atatürk Eğitim ve Araştırma Hastanesi Arşivi

Less common variants of pancreatic cancer

Adenosquamous carcinomas
- focal squamous differentiation in addition to glandular differentiation
Undifferentiated carcinomas with osteoclast-like giant cells of monocytic lineage intermixed within the neoplasm

Clinical features of pancreas carcinoma

Pain
Obstructive jaundice
Weight loss, anorexia, and generalized malaise and weakness
Migratory thrombophlebitis ( Trousseau syndrome )
- 10% of patients
- elaboration of platelet-aggregating factors
- pro-coagulants from the tumor or its necrotic products
<20% of pancreatic cancers are resectable at the time of diagnosis

SOLID PSEUDOPAPILLARY NEOPLASM

Endocr Pathol. 2014 Mar;25(1):65-79

ACINAR CELL CARCINOMA

Acinar cell carcinoma. The cut surface is solid and has a necrotic center. It lacks the fibrous component usually seen in ductal adenocarcinoma.

Rosai and Ackerman’s Surgical Pathology

A, Acinar cell carcinoma of the pancreas showing a well-differentiated acinar arrangement of the tumor cells

Rosai and Ackerman’s Surgical Pathology