Pathology of the biliary tract

• Gallstones
• Inflammation
• Tumors
• Atresia
GALLSTONES (CHOLELITHIASIS)

Afflict 10% to 20% of adult populations in developed

countries

Types
• Cholesterol stones 90 %
• Pigment stones 10%
Cholesterol stones

• Develop in the gallbladder; composed of cholesterol

+ Ca++-salts + bilirubin
• Multiple; from black to yellowish brown
• Small stones tend to enter the cystic duct and the
common bile duct
 Cholesterol stones: from black to yellowish brown;
multiple; faceted surface owing to tight apposition

Hepatic duct
Common bile duct

Gallbladder
Cystic duct
Yellowish-brownish cholesterol stones
Pathogenesis

• Excess cholesterol is eliminated via the bile only

• The cholesterol is made water soluble
by aggregation with bile salts and lecithins
 Pathogenesis
Crystallization of cholesterol (nucleation) can be
induced by
• Bile supersaturated with cholesterol
• Gallbladder hypomotility and/or defective
gallbladder emptying
• Hypersecretion of gallbladder mucus

Cholesterol can no longer remain dispersed and

nucleates into cholesterol monohydrate crystals
 Cholesterol monohydrate crystals

Precipitation of Ca++-salts

Cholesterol stone
Risk factors of gallbladder stones
• More common in females
• Age - peak in fourties
• Excess biliary secretion of cholesterol, e.g., obesity,
high calory food intake
•  gallbladder motility, e.g., multiple pregnancies,
rapid weight loss
Pigment (Ca-bilirubinate) stones

• Arise anywhere in the biliary tree

• Black, small, hard, multiple

Pathogenesis
Crystallization of unconjugated bilirubin occurs in
• chronic hemolytic anemias (e.g., sickle cell anemia,
thalassaemia)
• biliary tract infections (deconjugate bilirubin!) +
prolonged biliary stasis
Consequences of stones
• Inflammation: cholecystitis, cholangitis
• Migration of stone causes intense right upper
quadrant pain (“biliary colic”)
• Obstruction:
Cystic duct: empyema of gallbladder; hydrops of
gallbladder
Hepatic duct, common bile duct, ampulla of Vater:
jaundice + acute pancreatitis
• Perforation of gallbladder  peritonitis
CHOLECYSTITIS

Types
• Acute calculous
• Chronic calculous
• Hydrops of gallbladder
Acute calculous cholecystitis

Pathogenesis

• Stone in the cystic duct and/or gallbladder  bile

outflow obstruction

• Chemical and mechanical irritation of mucosa 

ulcerations

• Sec. colonization of bacteria

Morphology: variants

• Ulcerophlegmonous: hyperemic mucosa covered

with multiple ulcers; the wall is edematous

• Gangrenous: infrequent; green-black necroses of

mucosa and tunica muscularis; high risk of
perforation

• Empyema of gallbladder: enlarged gallbladder filled

with pus
Ulcerophlegmonous cholecystitis: hyperemic
mucosa covered with multiple ulcers; the wall is
edematous
Clinical features

• Right upper quadrant pain (mild  severe); hours

after a meal
• Distended, tender gallbladder; ultrasonography:
stone + gall bladder wall thickening greater than 4
mm
• Fever, nausea, vomiting, granulocytosis
Outcome

• Mild – moderate attacks: subside spontaneously

over 1 to 10 days
• Severe attacks: require emergency
cholecystectomy
• Relapses  chronic cholecystitis
Chronic calculous cholecystitis

Pathogenic factors
• Supersaturated bile with cholesterol
• Cholelithiasis
• Bacterial infection (usually E. coli) in 30% of cases
Gross changes

• Gallbladder may be contracted or normal in size or

enlarged

• Stone(s) in the lumen

• Mucosal atrophy

• Thickened, fibrous wall

Thinned mucosa, thickened gallbladder wall, cholesterol stones
LM
• Lymphocytic and mononuclear cell infiltrates in the
mucosa and the tunica muscularis
• Subepithelial and intramural fibrosis
• + dysplastic epithelium (precancerous)
 Chronic cholecystitis: high grade dysplasia

Lumen Wall
Clinical features
• Recurrent attacks of steady or colicky pain
• Often intolerance of fatty foods

Complications
• Risk of malignant transformation
• Fibrous adhesions between the gallbladder,
duodenum, stomach, and large bowel
• Perforation  cholecystoduodenal fistula +
gallstone ileus (rare nowadays)
Cholecystoduodenal fistula
Hydrops (mucocele) of gallbladder

• Stone in the cystic duct

• Atrophic, chronically obstructed gallbladder
containing only clear secretions
• The gallbladder is markedly enlarged, the
muscular wall is thinned
Hydrops: the gallbladder is markedly enlarged, the
muscular wall is thinned
CARCINOMA OF THE GALLBLADDER

Peak: 7th decade; predisposing factor: chronic

calculous cholecystitis

Gross
2 patterns of growth
• Infiltrating: thickening and induration of the
gallbladder wall
• Exophytic: fungating mass grows into the lumen

LM
Moderately or poorly differentiated adenocarcinoma;
mainly desmoplastic
Carcinoma developed in chronic calculous
cholecystitis. Note infiltrating growth pattern
LM: moderately differentiated desmoplastic
adenocarcinoma

Lumen

Tunica muscularis
Invasion of the liver by gallbladder carcinoma

Liver
 Clinical features

• Symptoms are those of chronic cholecystitis

• By the time of the dg most have spread locally and

invaded the liver, the cystic duct and adjacent bile
ducts, and the peritoneum

• Metastases in portal lymph nodes, in liver

• 5-yr-survival rate is a mere 1%

 Carcinoma of the gallbladder.
Hematogeneous metastases in the liver.
DISORDERS OF THE EXTRAHEPATIC BILE
DUCTS

• Biliary atresia
• Choledocholithiasis
• Cholangitis
• Carcinoma
BILIARY ATRESIA

Pathogenesis: obscure

• Blockade of bile flow owing to post-natal

inflammatory destruction or
• aberrant intrauterine development of the
extrahepatic bile ducts

 obstructive jaundice of neonates

Outcome
• At 3 mo of age: periportal fibrosis
• At 6 mo: biliary cirrhosis
• At age 2 yr: death
CHOLEDOCHOLITHIASIS

• Cholesterol stones derive from the gallbladder

• Pigment stones form de novo in the common bile
duct

Consequences
• Obstructive jaundice, bile stasis above the site of
obstruction
• + Acute pancreatitis
• Bacterial superinfection  ascending purulent
cholangitis  cholangiohepatitis
Clinical features

• Painful jaundice; serum ALP

• Endoscopic retrograde cholangiopancreatography
(ERCP): cannulation of the ampulla; contrast material
is injected into the common bile duct and the
pancreatic duct and the patient is screened
radiologically; excellent method to verify the stone; if
necessary, papillotomy facilitates the passage of
stone into the duodenum
• Small stones pass through the ampulla of Vater; if
the stone gets wedged in the ampulla of Vater,
papillotomy is performed to help to pass the stone
cessation of inflammation and jaundice
• Repeated episodes of choledocholithiasis for years
sec. biliary cirrhosis
ASCENDING ACUTE CHOLANGITIS AND
CHOLANGIOHEPATITIS

• Acute purulent inflammation of the wall of bile

ducts due to bacterial infection

• Agents: the patient’s own enteric flora, most often

E. coli

• Results from obstruction of the extrahepatic bile

ducts: choledocholithiasis, tumors, strictures, etc.
 Morphology
Gross
• Extrahepatic bile duct obstruction
• Pus fills the distended large intrahepatic bile ducts
• Swollen, yellow-green liver + multiple liver
abscesses
Muliple liver abscesses; the obstruction was
managed by stenting the common bile duct
Green liver in obstructive jaundice

The patient had carcinoma of the head of pancreas; the tumor

infiltrated and obstructed the common bile duct;
liver metastases
Morphology
Gross
• Extrahepatic bile duct obstruction
• Pus fills the distended large intrahepatic bile ducts
• Swollen, yellow-green liver + multiple liver
abscesses

LM
• Bile ductules: distension, bile plugs and ng-s in
the lumina
• Portal tracts infiltrated with neutrophils and
mononuclears
• + abscesses
Clinical features

Jaundice, liver pain, fever, chills,  sepsis  death

CARCINOMA OF THE EXTRAHEPATIC BILE
DUCTS

In elderly people; no significant association between

previous history choledocholithiasis and cancer

Predisposing factors
• Primary sclerosing cholangitis
• Idiopathic inflammatory bowel disease
• Clonorchis sinensis (fluke) infection in Asia
Morphology
• Localization:
at the bifurcation of the right and left hepatic duct
or in the common bile duct
or in the ampulla of Vater

• Gross: small; diffusely infiltrative or exophytic

polypoid lesion

• LM: desmoplastic adenocarcinoma

Carcinoma of the cystic duct, the hepatoduodenal
ligament and the hepatic duct (probe)
Carcinoma of ampulla of Vater
 Clinical features

• Insidiously developing, painless obstructive

jaundice
• Usual situation at the time of the exploration: the
hepatoduodenal ligament is infiltrated, and
metastases are in the portal lymph nodes, and in
the liver
• Poor prognosis: mean survival 12 mo
 PATHOLOGY OF THE PANCREAS

• Inflammations
• Tumors
• 1st semester: diabetes, cystic fibrosis
 ACUTE PANCREATITIS

Pathogenesis

• Normally, trypsinogen is converted to active trypsin in

the duodenum

• Premature, intrapancreatic activation of trypsinogen

occurs In acute pancreatitis
Majority of cases: associated with pancreatic duct
obstruction and/or alcohol abuse

• Gallstone in the common bile duct or ampulla of Vater

 blockade of ductal flow + bile reflux  acinar cell
injury (ACI)

• Alcohol consumption  ACI

• ACI: the zymogen granules coalesce with lysosomes;

trypsinogen is converted to active trypsin activates
the digestive enzymes within the acini and ductules
 proteolytic (autodigestive) necrosis, hemorrhage
and inflammation of pancreas + peripancreatic fat
tissue
Minority of cases:
• Mutations in cationic trypsinogen (PRSS1) gene
or trypsin inhibitor (SPINK1) gene  trypsin is
more active than it should be

• Acinar injury can be induced by trauma, mumps

virus infection, shock
To the interested student (does not belong to the
topic of the exam)

Promoters of Inflammatory injury

• Premature intrapancreatic activation of trypsinogen is
promoted by PRSS1 mutations, active trypsin, and
high calcium. Calcium signaling is a regulator for
acinar cell function, and alcohol interferes with this
signaling.

• Cystic fibrosis transmembrane conductance regulator

(CFTR) controls duct cells to secrete a bicarbonate-
rich fluid that flushes the trypsin out of the pancreas
into the duodenum. CFTR mutations lead to
decreased fluid secretion and reduced trypsin wash
To the interested student

Defenders of inflammatory injury

• Trypsin degradation is facilitated by
chymotrypsinogen C gene (CTRC); protects
pancreas from trypsin-related injury.

• More active trypsin within pancreas leads to

pancreatic injury which triggers acute inflammatory
response. Inflammation up-regulates serin protease
(SPINK1) expression. SPINK1 blocks active trypsin
and blocks further activation of trypsinogen, thereby
limiting pancreatic injury.
Genetic and environmental factors that affect acinar cells or ducts
Modified from Muniraj et al. Disease-a-Month 60:530-550, 2014

Stimulation
Acinus
Calcium regulation
• Hypercalcemia
• Alcohol

Trypsin related mutations

• PRSS1+: activation of Duct
trypsinogen Duct cell secretion
• CTRC+: ineffective • CFTR
trypsin degradation
• SPINK1+: ineffective Duct obstruction
blockade of active • Gallstone
trypsin • Duct stones
• Tumor
• Mucus
Secretion to the duodenum
Normal site of trypsinogen activation
 Classification according to the severity of
acute pancreatitis
Clinically
• mild - morphologically acute interstitial pancreatitis:
interstitial (IS) edema + foci of enzymatic necrosis
in the acini by LM
• moderately severe - morphologically acute
necrotizing pancreatitis: IS edema and gross foci of
enzymatic necrosis
• severe - morphologically acute necrotizing-
hemorrhagic pancreatitis: the entire pancreas is
involved; confluent foci of necrosis and
hemorrhage; foci of enzymatic fat necrosis in the
extrapancreatic collections of fat, such as the
mesentery of the bowel and the omentum
Moderately severe - acute necrotizing pancreatitis
IS edema and gross foci of enzymatic necrosis
Severe - acute necrotizing-hemorrhagic pancreatitis.
The entire pancreas is involved; confluent foci of
necrosis and hemorrhage
Acute necrotizing-hemorrhagic pancreatitis
Severe pancreatitis. Foci of enzymatic fat necrosis in the mesentery of
bowels
 Complications in severe pancreatitis

• SIRS (systemic inflammatory response sy)-induced

shock
• Bacterial superinfection of necrotic pancreatic
tissue  abscess(es)  sepsis
• Disruption of large ducts  can result in unilateral
pleural effusion, enlarging peripancreatic fluid
collection, or pancreatic ascites
• > 4 weeks: pseudocyst formation (1 to 15 cm):
massive liquefactive necrosis enclosed by
granulation tissue; + infection of pseudocysts 
pancreatic abscesses
 Clinical features

After a heavy meal + alcohol consumption intense

epigastric pain radiating to the back

Abdominal echo: enlarged pancreas; diagnostic

laboratory data:  serum amylase and lipase; fatty
acids bind calcium  hypocalcemia
+ sy of acute abdomen in severe pancreatitis
• intense pain
• involuntary spasm of the abdominal wall called
abdominal guarding
• absence of bowel sounds
 Outcome

Mild: heals completely

Moderate: necrotic foci heal with fibrosis; pancreatic

function remains preserved

Severe:
• Shock, ARDS, acute renal failure (ischemic AKI);
bacterial superinfection of necrotic tissue: sepsis
 high mortality rate
• In survivors: pseudocysts + abscesses;
pancreatic insufficiency: malabsorption,
steatorrhoea, diabetes
 CHRONIC PANCREATITIS

Irreversible condition characterized by

• chronic progressive pancreatic inflammation,
• fibrosis, and scarring
• resulting in loss of both exocrine and endocrine
tissue
 Pathogenesis
Still not understood; TIGARO classification of risk
factors
• Toxic-metabolic: chronic alcohol abuse (mostly in
middle-aged men), hypercalcemia, chronic renal
failure, etc.
• Idiopathic
• Genetic-induced: SPINK1 gene mutation or PRSS1
gene mutation or CFTR gene mutation (no
extrapancreatic manifestations of cystic fibrosis)
• Autoimmune
• Recurrent acute pancreatitis
• Obstruction of pancreatic duct by stone or tumor or
congenital abnormality (pancreas divisum [1 papilla
minor + 1 accesory duct])
 Alcoholic chronic pancreatitis

Gross: atrophied, markedly fibrotic pancreas,

irregularly dilated ducts obstructed with Ca-carbonate
stones + pseudocysts

LM: loss of exocrine glands, replaced by scar tissue;

dilated interlobular ducts plugged by protein
concretions; periductal infiltrates composed of ly-s and
mononuclears; disappearance of islets: relatively lately
Alcoholic chronic pancreatitis: atrophied, markedly fibrotic
pancreas, irregularly dilated ducts obstructed with Ca-
carbonate stones + pseudocysts (not present in this patient)
 Clinical features

• Repeated attacks of mild/moderate pancreatic

inflammation, recurrent pain or persistent pain

• Pancreatic insufficiency (malabsorption,

steatorrhoea) + diabetes

• If fibrosis involves the common bile duct or the

ampulla of Vater: mild obstructive jaundice
 Autoimmune chronic pancreatitis

• Duct-centric mixed inflammatory cell infiltrate with

increased numbers of IgG4-producing plasma cells

• Periductal dense fibrosis

• Responds to steroid therapy

 TUMORS OF THE PANCREAS

• Carcinoma
• Cystic tumors
• Islet cell (endocrine) tumors
 CARCINOMA OF THE PANCREAS

• Arises from ductal epithelium of exocrine pancreas,

termed invasive ductal adenocc

• More frequent in smokers

• Peak: between 60-70 ys

• Precursor lesion: ductal dysplasia - Pancreatic

Intraepithelial Neoplasm (PanIN)
 Molecular pathogenesis

Driver mutations in the epithelial cells of small ducts

and ductules
• Mutation of the oncogene K-RAS
• Inactivation of the tumor suppressor genes SMAD4,
p16, TP53
 Localization

• 60% in the head: infiltrates the ampulla of Vater 

obstructive jaundice
• 15% in the body
• 5% in the tail
• 20% diffuse involvement in the entire gland
 Morphology

• Hard, poor-defined mass; difficult to distinguish

from chronic pancreatitis
• LM: desmoplastic adenocarcinoma (perineural
spread is common – pain)
 Spread
Highly invasive
• Continuous: peritoneum ( carcinosis of
peritoneum), stomach, lesser omentum
• Lymphatic: peripancreatic lymph nodes
• Hematogeneous: liver, bones, lungs
 Carcinoma (cc) in the pancreatic head, infiltrating the papilla of Vater and the
common bile duct (cbd). Distal to the tumor, obstructive pancreatitis developed.
The Wirsungian duct is markedly dilated and tortuous

cc

cbd
W

W
 Cc of the pancreas: hard, poor-defined
mass; difficult to distinguish from chronic pancreatitis
Desmoplastic adenocarcinoma (perineural
spread is common - pain)
Hematogeneous metastases in the liver
 Clinical features

• Usually remain silent until impinge upon adjacent

organs
• Cc of the head: painless jaundice
• Cc of the tail: + migratory superficial thrombophlebitis
(Trousseau’s sign)
• If pain - by the time it appears the cancer is usually
beyond cure
• Poor prognosis: 5-y survival rate 5%
 CYSTIC TUMORS
• Rare
• Mucinous cystadenomas or cystadenocarcinomas:
mostly in women older than age 65; painless, slow-
growing masses
• Serous cystadenomas - no malignant counterpart; In
7th decade in life; also in men; cause abdominal pain
Cystadenoma of pancreas
Cystadenocarcinoma of pancreas
 ISLET CELL TUMORS
• Rare lesions arising from the pancreas or from the
peripancreatic tissue
• Most tumors produce pancreatic hormones, some
are nonfunctional

INSULINOMA
• Solitary, < 20 mm, encapsulated
• 90% adenoma; 10% adenocarcinoma
• Hypoglycemic attacks precipitated by fasting or
exercise
 GASTRINOMA

• Locations: pancreas, peripancreatic region, wall of

duodenum

• More than half of the tumors are locally invasive or

have already metastasized

• Hypergastrinemia  extreme gastric acid secretion

 multiple peptic ulcers in the stomach and
duodenum

• May be part of multiple endocrin neoplasia (MEN I)

Gastrinoma in the duodenal wall. Gastrin immunostaining