Pathology of the

hepatobiliary system
and pancreas

Normal liver

smooth brown surface

topographic division: the right, left, caudate, and quadrate lobes
functional organization of the liver into eight segments I to VIII

Microarchitecture - Kiernans lobule

Portal tract (PT) contains branches of the hepatic artery, portal vein,
and interlobular bile duct. The liver cell plates converge to the
terminal hepatic venule (THV).

Function
Maintaining body metabolic homeostasis:
Lipid and carbohydrate metabolism:
production and secretion of glucose
Protein synthesis: albumin, coagulation
factors
Detoxification and drug metabolism
Conjugation and excretion of bilirubin
Synthesis and excretion of bile salts

Diseases of the Liver

Hepatitis (acute/chronic)
Fatty liver (Alcoholic Liver Disease)
Cirrhosis
Vascular disorders (portal
hypertension)
Tumors (benign/malignant)

Clinical consequences of liver disease

(life-threatening complications are in blue)

Hepatic dysfunction:
Decrease synthesis capacity leading to :
Hypoalbuminemia: edema, ascitis, muscle wasting, weight loss
Hypoglycemia: weakness and syncope
Coagulation factor deficiency: bleeding

Decrease detoxification capacity leading to:

Hyper-ammonemia and increase toxic metabolites:
Encephalopathy (altered behavior and disturbances in
consciousness that may lead to deep coma and death)
Injury to other organs by active toxins

Hepatorenal syndrome:
Renal failure without intrinsic or functional causes of renal
failure. ? Altered blood flow to the kidney.

Clinical consequences of liver disease,

continued

Jaundice: yellow discoloration of skin and sclera

due to accumulation of bilirubin
Cholestasis: systemic accumulation of bilirubin in
addition to bile salts and cholesterol (usually
secondary to obstruction)
Portal hypertension in cirrhosis: increased
resistance to portal blood flow

Esophageal varices
Ascitis
Splenomegaly
Hemorrhoids

Malignancy on top of cirrhosis

Jaundice
Accumulation of bilirubin in tissue leading to yellow
discoloration of skin and sclera (icterus)
Normal serum level: 0.3-1.2 mg/dl; jaundice
appears with levels above 2.0-2.5 mg/dl
Source of bilirubin: the breakdown of senescent red
blood cells in the spleen releases heme that
changes into bilirubin by specific enzymes.

Bilirubin
Metabolism

Bilirubin
Conjugation is a function of the liver
by adding glucuronic acid to bilirubin

Unconjugated
- Albumin bound
- Insoluble in
water, toxic

Conjugated
- Loosely bound
to albumin
- Water soluble,
non-toxic,
excreted in
urine

Patterns of hepatic injury

Degeneration
ballooning degeneration
feathery degeneration

Intracellular accumulation
Iron
Copper
Triglyceride fat droplets steatosis

Necrosis and Apoptosis

ischemic coagulative necrosis - "mummified" cells
lytic necrosis - cellular debris
zonal distribution centrilobular, midzonal and periportal
necrosis
extension: focal or spotty, interface hepatitis, bridging necrosis
submassive and massive necrosis

Inflammation
Regeneration
Fibrosis Cirrhosis

Laboratory evaluation of liver disease

Searching for etiology:
Hepatitis viral antigens and antibodies
Autoimmune antibodies: for autoimmune
hepatitis
Tissue iron and copper: for hemochromatosis
and Wilson disease

Hepatitis
Inflammation
+
Hepatocyte Apoptosis/Necrosis
Time Course: Acute / Chronic
Causes: Virus / Drugs

Acute Hepatitis
Causes:
Viruses: A, B, C, D, E
Drugs
Alchool

Clinical syndromes:
Acute asymptomatic infection with recovery: serologic
evidence only
Acute symptomatic hepatitis with recovery: anicteric
or icteric
Fulminant hepatitis: with massive to submassive
hepatic necrosis

Hepatitis A virus
RNA virus
Mode of transmission: fecal-oral (contaminated
water and food)
Incubation period: 2-6 weeks
Virus shedding: 2-3 weeks before and 1 week after
appearance of jaundice
50% of population above age 50 are seropositive in
USA, no carrier state
No increase risk for chronic hepatitis, or carcinoma
Because viremia is transient, no need to screen
donated blood

Hepatitis E

RNA virus
Mode of transmission: waterborne
Incubation period: 2-8 weeks
Endemic in certain populations; 40% in Indian
population
Self-limited infection but with higher mortality in
pregnant females

Morphology
Enlarged, reddened liver; greenish if cholestatic
Parenchymal changes:
Hepatocyte injury:

Swelling (ballooning degeneration)

Hepatocyte necrosis: isolated cells or clusters
Cytolysis (rupture) or apoptosis (shrinkage) - Councilman bodies
If severe: bridging necrosis

Lobular disarray: loss of normal architecture

Cholestasis: canalicular bile plugs
Regenerative changes: hepatocyte proliferation
Sinusoidal cell reactive changes:
cellular debris in Kupffer cells
Influx of mononuclear cells into sinusoids

Portal tracts:
Inflammation: mixture of inflammatory cells
interface hepatitis

 Hepatocytes swollen
and vacuolated
(ballooning
degeneration) (B)
Focal necrosis of
hepatocytes (N),
most severely
affecting centrilobular
areas of (Zone 3)
Cells dying by
apoptosis -shrunken,
eosinophilic
Councilman bodies
(C)

Centrilobular necrosis

Councilman bodies

Chronic Hepatitis
Def.: Inflammation of the liver continuing without improvement for 6 months or
longer
Etiology is the single most important indicator of likelihood to progress to
cirrhosis
Classification:

 Morphological definition
Portal inflammation (lympho plasma cells)
Interface activity lobular activity
Fibrosis

Lesions may range from mild to severe

Hepatitis B virus
DNA virus
Mode of transmission: parenteral and body fluids
(including saliva)
Incubation period: 4-26 weeks
Virus essentially non-cytopathic
Liver damage = immunological attempt to eradicate
virus
Successful acute hepatitis ( antiHBs)
Failure (perinatal transmission, immunodeficiency,
idiopathic) carrier state with minimal changes or
chronic hepatitis with variable activity and fibrosis

Hepatitis B infection: Possible outcomes

Possible outcomes of infection:
Subclinical or acute hepatitis with recovery and
clearance (85%); 1% of those may develop
fulminant hepatitis and death
Healthy carriers (10%)
Persistent infection (5%): 80% recover and 20%
develop chronic hepatitis
20% of chronic hepatitis patients develop
cirrhosis and 10% of those develop
hepatocellular carcinoma

Hepatitis B virus
Mode of chronic infection
Replicative (permissive)
Full replication of genome / formation of
complete virion HBV DNA, HBeAg in serum
high infectivity
Non-replicative (non-permissive)
HBs particles only HBV DNA-ve, anti-HBe+ve
little or no infectivity

HBV : vertical transmission

HBc tissue expression ++
Mild inflammation

HBc - sanded nuclei

HBc - immunostaining

HBs carrier :
HBV DNA -ve, high HBs
in serum and liver

Ground-glass
inclusions

HBs - immuno

Hepatitis C
RNA virus
Mode of transmission: parenteral, sexual and
vertical, 40% unknown source. It is present in
the saliva.
Incubation period: 2-26 weeks
Important public health issue: HCV accounts for
40% cases end-stage liver disease
60% new cases of HCC
30% liver transplants

Possible outcomes

HCV is the
leading cause for
chronic liver
disease

 common findings
lymphoid aggregates
bile duct damage
focally mild to moderate macrovesicular
steatosis

Hepatitis D
Defective RNA virus that needs Hep B capsule
to replicate
Mode of transmission: Parenteral
Coinfection of B and D: mild disease with
recovery in most cases, <5% chronic hepatitis
Superinfection by D after B: accelerated more
severe hepatitis; 80% chronic hepatitis

The points to remember

Hepatitis A Hepatitis B

Hepatitis C

Transmission Oral-fecal Parenteral

Parenteral

Carrier state

None

Present

Present

Chronic
hepatitis

None

5-10%

>70%

Fulminant
hepatitis

0.1%

0.1-1.0%

Rare

Carcinoma

No

Yes

Yes

Diagnostic confirmation
Histological activity
Pathologists role
Histological stage

PMN, piecemeal necrosis

Portal
Inflammation
Interface
activity

Alternative grading of fibrosis (0 to 4)

2 = early septa

1 = mild portal fibrosis

3 = bridging septa

4 = cirrhosis

Drug-induced hepatitis
Predictable or unpredictable (idiosyncrasy)
Mechanisms: direct toxicity, conversion of drug
to an active toxin, immune-mediated
A long list of drugs can cause different forms of
injury: hepatitis, fibrosis, granulomas, necrosis,
cholestasis, vascular disorders and neoplasia
Example: Acetaminophen overdose induces
centrilobular necrosis

Autoimmune hepatitis
More in females (70%)
Elevated serum IgG levels
High titers of autoantibodies (antinuclear, anti-smooth
muscle, and anti-microsomal)
Increased frequency of HLA-B8 and DRw3
Associated with other forms of autoimmune disorders
such as rheumatoid arthritis and ulcerative colitis
Respond to immunosuppressive drugs

Morphology
Marked interface
activity
Lymphocytes /
plasma cells

morphologic features of acute and chronic hepatitis

Liver cirrhosis
Among the top 10 causes of death in the Western
world.
Def.: 3 components:
bridging fibrous septae
regenerative nodules
disruption of the architecture of the entire liver

The parenchymal injury and consequent fibrosis

are diffuse
reorganization of the vascular microarchitecture
Multi-factorial etiology
Gross types:
Micronodular (< 3mm)
Macronodular (>3 mm)

Causes

Alcoholic liver disease 60-70%

Viral hepatitis 10%
Biliary diseases 5-10%
Primary hemochromatosis 5%
Cryptogenic cirrhosis 10-15%
Once cirrhosis is established, it is usually impossible to
establish an etiologic diagnosis on morphologic grounds
alone.

Complications:
portal HT
liver cell failure
HCC

Macronodular and
micronodular
cirrhosis

thickened liver-cell plates

(regenerative hyperplasi

Activated stellate (Ito) cells in

cirrhosis: SMA
immunostain

Alcoholic liver disease

100,000 death annually related to alcohol; 20,000
are related directly to end-stage liver cirrhosis; the
rest is related to car accidents
Effects on liver:
80% fatty liver (steatosis)
10% alcoholic hepatitis
10% cirrhosis
they do not necessarily represent a continuum
of changes

Fatty Liver
Intake of alcohol

oxidative stress
Accumulation of vacuoles of TG
initially centrilobular

Fibrosis
around CLV and extends
to sinusoids

microvesicular

stellate cell ( ITO) activation to

myofibroblasts

macrovesicular

continued alcohol

The fatty change is completely reversible if there is abstention

from further intake of alcohol

large (up to 4 to 6 kg), soft

organ that is yellow and
greasy.

Alcoholic Hepatitis
Hepatocyte swelling (ballooning) and necrosis
Mallory bodies - eosinophilic cytoplasmic inclusions
(accumulation of cytokeratin intermediate filaments and
other proteins)
Neutrophilic reaction around degenerating hepatocytes,
particularly those having Mallory bodies
Fibrosis
Steatotic hepatocytes are present, interspersed with the
inflammatory cells and activated stellate cells
Macroscopic liver is mottled red with bile-stained areas

Mallory bodies

Alcoholic Cirrhosis
"Laennec cirrhosis"
The final and irreversible form of alcoholic liver
disease
It evolves slowly and insidiously
At first, the cirrhotic liver is yellow-tan, fatty, and
enlarged
After years brown, shrunken, nonfatty organ
Fibrous septae are delicate and extend through
sinusoids from central to portal regions bridges
nodular fibrosis
Regenerative nodules: initial micronudules
macronodules
The end-stage comes to resemble, both
macroscopically and microscopically, the cirrhosis
developing from viral hepatitis and other causes.

Tumors of the Liver

Benign tumor
Adenoma
Malignant tumor
Hepatocellular carcinoma
Cholangiocarcinoma
Metastatic tumors

Hepatocellular carcinoma
The most frequent primitive tumor
In occidental countries
80 to 85% of HCC associated with cirrhosis
Normal

10-15% of HCC in a liver non-cirrhotic

Chronic
hepatitis
Cirrhosis = pre-cancerous state with an annual incidence of HCC
3-6%
SURVEILLANCE echography and AFP +++
All the tumors developed in a liver cirrhotic are priori a HCC

Aetiology

Viral hepatitis: B, C
Aflatoxin B1
Alcohol
Metabolic disease
Genetic
haemochromatosis
Other

Metabolic syndrome
Anabolic steroids
El-Serag and Rudolph Gastroenterol 2007;132:2557

HCC in cirrhosis

1cm

2cm

Modified from Hitiroglou Sem Liv Dis 2004; 24(1):65

Precursor lesions
Adenomatous hyperplasia (dysplastic
nodules)
Focal liver cell dysplasia - Small cell
dysplasia
Hepatocellular adenoma catenin mutated

Liver Cell Adenoma

Mass is composed of cords of hepatocytes without portal tracts.

 Polychrome tumour, unique or

multifocal
Usually paler than the surrounding
liver substance
strong propensity for invasion of
vascular channels intrahepatic
Small HCC
unique nodule < 2 cm
Well demarcated and encapsulated
or Indistinct limits

Satellite nodule
Nodule < 2cm, located < 2cm of
principal tumor

grossly

Unic large tumor

Satellite nodule

Multifocal

 HCCs consist of tumour cells that resemble hepatocytes

Variable degree of atypia

Rare mitosis
Thick cords > 3 cells
Abnormal reticulin network

The stroma is composed of sinusoid-like blood spaces

lined by a single layer of endothelial cells CD34 +
sinusoid capillarization
Cytological variants
Clear cell, fusiforme (sarcomatous), giant (pleomorphic), oncocitic

Architectural variants

Trabecular (plate-like). ++
Pseudoglandular and acinar
Compact
Scirrhous

HCC patterns
Pseudoglandular
Trabecular
Solid

Fibrolamellar HCC

Cytological variants

reticulin

CD34

Grading
WHO 3 grades
Well differentiated HCC.
cells with minimal atypia
thin trabecular pattern, rare pseudoglands
common fatty change

Moderately differentiated HCC

trabeculae of three or more cells in thickness
pseudoglandular pattern is frequent

Poorly differentiated HCC

solid pattern
pleomorphism, including bizarre giant cells
Edmonson : 4 grades

III

Biliary tumours
Cholangiocarcinoma
Intrahepatic (peripheral)
Hilar (Klatskin)
Extrahepatic (hilum-ampulla of Vater)

Hepatobiliary cystadenocarcinoma
Usually in a pre-existing biliary cystadenoma

Cholangiocarcinoma

The 2nd tumor primitive in the liver (HCC/CC : 9/1)

In a non-cirrhotic liver
Tardif symptoms: fiver, jaundice, mass
ACE and Ca 19-9 seric increased, AFP N
Hematogenous metastases to the lungs, bones
(mainly vertebrae), adrenals, brain, regional lymph
nodes ~ 50% of cases
Poor pronostic : 40% at 5 years

Risk conditions:
Chronic inflammation of the biliary tree
Primary sclerosing cholangitis
Recurrent pyogenic cholangitis (Japan, Korea)
Parasites: C. Sinensis, O. Viverrini (SE Asia)

Ductal plate malformation (Caroli disease)

Cirrhosis
Deposition of Thorotrast

Clonorchiase

Opisthorchiase

Pre-malignant lesions
Intraductal papillary
neoplasm of the biliary
tree (IPN-B)

Biliary intraepithelial
neoplasia, BilIN or
biliary dysplasia (flat,
micropapillary)

Clinical-histological aspects
Intrahepatic

Hilar or extrahepatic

Mass lesion

Stricture

Fever, night sweats,

weight loss, pain
Differential diagnosis:
Metastatic adenocarcinoma
Hepatocellular carcinoma
Epithelioid
haemangioendothelioma

Biliary obstruction, pain

Differential diagnosis:
Inflammatory stricture

lymphoma
Metastatic ADK

Grossly
variably sized nodules,
usually coalescent
gray to gray-white, firm
and solid
some intraductal
growth, with polyp
formation.
central necrosis or
scarring are common,
mucin may be visible
on the cut surfaces.

Microscopically
resemble ADK arising in other parts of the body
the full range of morphologic variation
Most are well to moderately differentiated
sclerosing ADK
glandular and tubular structures
lined by cuboidal-to-low columnar epithelial cells
markedly desmoplastic, with dense collagenous
stroma

No bile production

Gallbladder
Clinically important organ but
not essential for life
Stores bile
No muscularis mucosa or
submucosa
Histology:
Mucosal lining: single layer
of columnar cells
Fibromuscular layer
Serosa: fats, blood vessels

Diseases of the Gallbladder

Cholelithiasis (cholesterol/pigment stones)

Cholecystitis (acute/chronic)
Cholesterolosis (strawberry gallbladder)
Tumors (adenocarcinoma)

 Cholelithiasis
Afflict 10% of adult
population in Western
countries
Gallstones made of
cholesterol, bilirubin and
calcium salts with different
concentrations
Complications:

empyema,
perforation,
fistula,
inflammation,
obstruction,
pancreatitis

Gallstones
Cholesterol

Pigmented

Asian > Western

Western > others
Hemolytic anemia
Advancing age >40y
Biliary infection
Female sex
Obesity
Hyperlipidemia and bile stasis

Acute cholecystitis
Calculous:
acute inflammation of a gallbladder that has
stones.
It may represent a medical emergency
no associated infection initially

Acalculous:
no stones
impaired blood supply to gallbladder:

multi-organ failure
severe burns / severe trauma
post-operative state / post-partum state
prolonged hyper-alimentation

gangrene & perforation more common

-gallbladder is enlarged
and tense,
-subserosal
hemorrhages bright
red or violaceous to
green-black discoloration
- the wall is thickened,
edematous, and
hyperemic
-In severe cases
gangrenous cholecystitis

 The inflammatory reactions consist of the usual

patterns of acute inflammation

Edema
leukocytic infiltration
vascular congestion
frank abscess formation or gangrenous necrosis

Chronic cholecystitis:

With or without preceding episodes of acute cholecystitis

Almost always associated with gallstones
Obstruction of outflow is not necessary
Thickened, fibrotic gallbladder wall
Degree of inflammation variable
Dystrophic calcification (Porcelain GB)
Hydrops gallbladder

Chronic cholecystitis with

cholesterolosis

Chronic cholecystitis with

cholesterol stones
The gallbladder wall is thickened
and gray-white,
owing to fibrosis and
inflammation. The mucosa is
effaced

The Pancreas

Weight of pancreas: 50 100 g

Pancreatic
parenchyma

INS

CK 7

GLU

Pancreatic diseases
85% exocrine: enzymes
for digestion
Acute and chronic
pancreatitis
Cystic fibrosis
Tumors

15% endocrine: insulin,

glucagon and others
Diabetes
Tumors

Pancreatic exocrine enzymes

Acute Pancreatitis
Autodigestion and inflammation of the pancreas
Most common causes:
Gallstones, alcoholism, shock, hypercalcemia

Possible mechanisms:
Duct obstruction
Acinar cell injury
Defective intracellular transport

Abdominal pain radiating to the back, elevated

serum amylase and lipase, hypocalcemia
Mortality is high: 20-40%, from shock, sepsis or
acute respiratory failure

Acute pancreatitis

Pathology
Mild cases
Edema (microvascular leakage)
Fat necrosis and saponification (release of
lipolytic enzymes)
Severe cases (necrotizing pancreatitis)
Necrosis of acinar cells, ducts, islets (release
of proteolytic enzymes)
Fat necrosis (within and outside of abdomen)
Interstitial hemorrhage (necrosis of blood
vessels of blood vessel walls)

Normal
Pancreatic
parenchyma

Peripancreatic fat

Chalky fat necrosis

Acute pancreatitis

Parenchymal necrosis

autodigestion

fat necrosis

Norm
al

Acute Necrotizing Pancreatitis

Sequels
Systemic complications
Shock
Organ failure

DIC
Pancreatic abscesses
Pseudocysts
Duodenal obstruction

Chronic Pancreatitis
Recurrent bouts of inflammation progressive
destruction of pancreatic parenchyma and its
replacement by fibrosis
Primary causes:

Alcohol abuse
Hypercalcemia / hyperlipoproteinemia
Pancreas divisum
Hereditary pancreatitis
idiopathic

30% of idiopathic cases have been found to have

mutation in CFTR gene
Diagnosis: abdominal pain, malabsorption,
calcifications on X-ray

Pathology
Reduced size of pancreas
Loss of lobular appearance of pancreas
Loss of exocrine tissue (typically not islets)

Irregularly distributed fibrosis

Inflammation
Destruction of ducts ductal dilatation
Pseudocysts (25% of cases)

Normal

Norm
al

Sequels

Duct obstruction
Pseudocysts
Malabsorption
Secondary diabetes

Pancreatic Pseudocysts
Localized collections of pancreatic
secretions (within or adjacent to pancreas)
Lack a true epithelial lining
Lined by macrophages, fibrosis

Different from sterile pancreatic

abscesses
Collections of neutrophils following liquefactive
necrosis of pancreatic parenchyma

Pancreatic Pseudocyst - Gross

Pancreatic Pseudocyst

vs. congenital
cyst

Tumors of the Exocrine Pancreas

Ductal Adenocarcinoma
Intraductal Papillary Mucinous Neoplasm (IPMN)
Mucinous Cystic Neoplasm
Microcystic Adenoma
Solid-pseudopapillary Neoplasm
Acinar Cell Carcinoma
Pancreatoblastoma

Ductal Adenocarcinoma
Most common neoplasm of the pancreas
The 5th most frequent cause of death
from cancer
Most common between 60 & 80 years
Slight male predominance (1.6:1)
Prognosis is poor: 5% survive for 5 years

Risk Factors

Cigarette smoking
High fat diets
Chronic pancreatitis
Diabetes mellitus
Chemical (carcinogen) exposure
Genetic Risk Factors:
Hereditary breast and ovarian cancer
BRCA2 families

Hereditary pancreatitis (50X!)

Peutz-Jeghers Syndrome
HNPCC

Clinical Features

Painless jaundice
Abdominal pain
Weight loss
Migratory thrombophlebitis

TROUSSEAU
SIGN

Molecular Genetics
K-RAS point mutations
(present in >90% of pancreatic cancers)

Tumor suppressor gene mutations

P53 (present in 60-80%)
p16

HER/2-neu overexpression
(present in ~70%)

Gross Pathology
Most occur in the head of the pancreas
(60%)
15% in the body
5% in the tail
20% diffuse

Poorly circumscribed, grey-white, firm

masses
Can infiltrate outside the pancreas into other
organs

Histopathology
Arise from ductal (glandular) epithelium
Typically moderately to poorly differentiated
adenocarcinoma
Perineural and angiolymphatic invasion
common
Almost always associated with chronic
pancreatitis
Histologic variants
Adenosquamous Carcinoma
Anaplastic Carcinoma
Undifferentiated carcinoma with osteoclast-like giant
cells

Moderately differentiated

Well differntiated

Poorly differentiated

Perineural
invasion

NE

E
V
R

Extension of pancreatic ductal

adenocarcinoma

- peripancreatic extension
- lymph node metastasis
- hematogenous metastasis
- duodenal-bile duct extension
- intrapancreatic extension

Intraductal Papillary Mucinous

Neoplasm (IPMN)
Mucinous neoplasm that arises in and
causes cystic dilatation of the main (large)
pancreatic ducts
Can progress to invasive adenocarcinoma

IPMN

Mucinous Cystic Neoplasm

Form unilocular or multilocular cysts

Often within the tail of the pancreas
No connection to the ductal system
Usually occurs in women
Can progress to invasive adenocarcinoma

Mucinous Cystic Neoplasm

Acinar Cell Carcinoma

Tumor of the
pancreatic acinar
cells
Not ductal-derived
Norm
al