LIVER PATHOLOGY

ARNEL G. BAYOTAS, RMT, MD, FPSP, ASCPI, MHA

Anatomic and Clinical Pathologist
Learning Objectives: At the end of the
laboratory session, the students can:

◼ Recognize the histomorphologic features of

conditions affecting the liver and biliary tract.
◼ Describe the pathogenesis of the disease process.
◼ Correlate the morphologic changes with the
clinical presentation of the disease.
◼ Apply basic concepts learned given a case
involving disorder of the liver and biliary tract.
◼ Enumerate important diagnostic procedures
needed to evaluate conditions involving the liver
and biliary tract.
◼ Interpret results of basic laboratory tests used to
evaluate disorders of the liver and biliary tract.
Pathologic Findings

◼ Acute injury: ◼ Subacute or chronic

▪ widespread edema injury
▪ acute and chronic ▪ mononuclear
inflammation inflammatory cells
▪ necrosis ▪ necrosis or degeneration
Most common patterns of injury

◼ Hepatocellular compartment
▪ Portal inflammation
▪ Interface activity (periportal hepatitis, piecemeal
necrosis)
▪ Lobular inflammation
▪ Vacuolar degeneration (balloon cell change)
▪ Acidophilic bodies
▪ Fibrosis
Most common patterns of injury

◼ Hepatocellular compartment
▪ Steatosis
▪ Steatohepatitis
▪ Mallory’s hyaline (Mallory bodies)
▪ Megamitochondria
▪ Iron accumulation
Most common patterns of injury

Portal inflammation Steatohepatitis

Most common patterns of injury

Mallory’s hyaline
 Most common patterns of injury
◼ Biliary compartment ◼ Vascular compartment
▪ Cholestasis ▪ Venulitis (endothelitis)
▪ Bile duct proliferation ▪ Extramedullary hematopoiesis
▪ Bile duct injury
▪ Ductopenia
 Most common patterns of injury

3. loss of
ductules
1. acute
inflammation

2. poorly
formed bile
ductules

Bile stasis
CLINICAL SYNDROMES
Hepatic failure Portal Hypertension Cholestasis Cirrhosis
Associated with
Cirrhosis
1. Jaundice 1. Ascites 1. Jaundice 1. Anorexia
2. Hypoalbuminemia 2. Splenomegaly 2. Pruritus 2. Weight loss
3. Hyperammonemia 3. Esophageal varices 3. Skin xanthomas 3. Weakness
4. Palmar erythema
4. Hemorrhoids 4. Inc. Alkaline 4. frank debilitation
5. Spider angioma
6. Hypogonadism & 5. Caput phosphatase 5. Progressive liver
gynecomastia in men medusae-abdomin 5. Intestinal failure
7. Coagulopathy al skin malabsorption of 6. Portal HPN
8. Hepatic fat soluble vit. 7. Hepatocellular CA
encephalopathy
9. Hepatorenal
syndrome
CHOLESTASIS

◼ Bile stagnation due to: ◼ Other causes:

▪ hepatocellular ▪ Pregnancy
dysfunction ▪ benign familial recurrent
▪ intra- or extrahepatic cholestasis
biliary obstruction ▪ Medications –
amiodarone
▪ Sepsis
▪ Rarely malaria
falciparum
CHOLESTASIS

◼ Symptoms: ◼ Laboratory
▪ Jaundice ▪ Elevated serum bilirubin
▪ Pruritus ▪ Elevated serum alkaline
▪ Skin xanthomas phosphatase
▪ Fat soluble vitamin
deficiency - ADEK
CHOLESTASIS
Neonatal cholestasis
▪ 1 in 2500 live birth ◼ Clinical features:
◼ Major causes: ▪ Jaundice
▪ Biliary atresia ▪ dark urine
▪ Neonatal hepatitis ▪ light or acholic stools,
▪ Hepatomegaly
▪ hypoprothrombinemia
Neonatal cholestasis

◼ Morphologic features
▪ Lobular disarray
▪ Giant cell transformation of
hepatocytes (unique
feature)
▪ Hepatocellular and
canalicular cholestasis
▪ Mononuclear infiltration of
portal areas
▪ Reactive changes in
Kupffer cells
▪ Extramedullary
hematopoiesis
Liver neoplasms
FOCAL NODULAR
HYPERPLASIA (FNH)
◼ Non-neoplastic mass ◼ Clinical manifestation:
lesion caused by ▪ 80% asymptomatic
nodular overgrowth of ▪ 70-80% solitary
hepatocytes in region of ▪ 80-90-occurs in women
altered hepatic blood of reproductive age
flow
FNH- Clinical features

◼ Usually incidental finding

◼ Associated with oral contraceptive use in 50%
to 60% of cases
◼ Rarely associated with abdominal pain,
hepatomegaly, or tenderness
◼ Associated with extrahepatic vascular lesions
 FNH - Pathologic features

◼ Gross findings
▪ Single subcapsular lesion in
right lobe
▪ Average size less than 5 cm
to 10 cm
▪ Central stellate scar with
radiating septa

sharply circumscribed nodular

mass often appearing lighter than
the surrounding liver.
FNH - Pathologic features

◼ Microscopic findings
▪ Nodular overgrowth of
normal-appearing
hepatocytes
▪ Large caliber vessels in
central stellate scar
▪ Bile ductular
proliferation in scar
LIVER CELL ADENOMA
◼ Arises in normal or nearly normal liver in
patients with abnormal hormonal or metabolic
condition
◼ 95% women, usually child-bearing age
◼ history of 5+ years of OCP in 85%
◼ Regresses with discontinued use
◼ Spontaneous
◼ 2-4% of hepatic tumors in children
LIVER CELL ADENOMA
◼ Associated with:
▪ Glycogen storage disease types Ia and III
▪ Fanconi’s anemia
▪ Familial adenomatous polyposis
▪ Familial DM
▪ Hurler’s disease or Tyrosinemia
◼ Associated with anabolic steroids (in men),
anti-estrogens, Klinefelter’s syndrome or other
abnormal secretion of sex steroids
LIVER CELL ADENOMA
◼ Associated with:
▪ Glycogen storage disease types Ia and III
▪ Fanconi’s anemia
▪ Familial adenomatous polyposis
▪ Familial DM
▪ Hurler’s disease or Tyrosinemia
◼ Associated with anabolic steroids (in men),
anti-estrogens, Klinefelter’s syndrome or other
abnormal secretion of sex steroids
HEPATIC ADENOMA - Gross findings

◼ Yellow, tan, or red-brown

solitary nodule in
noncirrhotic liver
◼ Most measure 5 to 15 cm
◼ May be hemorrhagic

Hepatic adenomas are sharply

circumscribed lesions. Intrahepatic
hemorrhage is common in resected
specimens.
HEPATIC ADENOMA - Microscopic
findings

◼ Benign hepatocytes
without acinar
architecture or portal
tracts
◼ Tumor cells often contain
glycogen or fat
◼ Thin-walled vascular
channels scattered
throughout tumor Normal portal structures are lacking,
and there is no biliary epithelium. The
hepatocytes are bland. Haphazardly
◼ No biliary epithelium arranged parenchymal vessels are
characteristic
HEPATOCELLULAR CA
◼ Also called LIVER CELL CARCINOMA,
HEPATOMA
◼ 85% of hepatic malignancies (30% in
children)
◼ Major cause of cancer death worldwide
(20-40% in China, Japan, sub-Saharan
African), although not in North America
◼ Primary carcinomas are rare in North
America, but more common in countries
bordering Mediterranean Sea endemic for viral
hepatitis
CAUSES OF HCC:

◼ The most common cause of HCC is the

scarring of the liver due to:
▪ Alcohol abuse
▪ Hepatitis B
▪ Hemochromatosis or iron overload
▪ Autoimmune diseases
▪ Diseases that causes inflammation of the liver
HCC: Risk factors/causes
◼ HBV-infant carriers have 200x risk
◼ Cirrhosis
◼ Hepatitis C virus (HCV)
◼ Aflatoxins
◼ Genetic variation
◼ Thorotrast exposure
◼ Androgenic steroids
◼ Tyrosinemia
HCC
Aflatoxins:
◼ Aflatoxin B1, a metabolite of the fungus Aspergillus
flavus, is a potent carcinogen in some areas endemic
for HCC
◼ is activated by hepatocytes, products intercalate into
DNA to form mutagenic adducts with guanosine
HCC:
GROSS

◼ Unifocal, multifocal or diffusely infiltrative soft tumor,

paler than normal tissue, may be green due to bile
◼ Extensive intrahepatic metastases are common
◼ Snakelike masses of tumor - involve the:
▪ portal vein (35-80%)
▪ hepatic vein (20%)
▪ inferior vena cava
◼ Hemorrhage and necrosis
◼ Occasionally tumor is pedunculated
◼ Liver usually cirrhotic, often enlarged
HEPATOCELLULAR CARCINOMA

- Arise in the setting of cirrhosis

- Worldwide, viral hepatitis is the most common cause, but in the U.S.,
chronic alcoholism is the most common cause.
- large and bulky and has a greenish cast because it contains bile
- To the right of the main mass are smaller satellite nodules.
HCC

◼ Laboratory:
▪ Elevated serum AFP
▪ 70% sensitive
▪ Reduced sensitivity in alcohol-related cirrhosis (65%)
▪ Tumors arising in non-cirrhotic liver (33%)
▪ Tumors 2 cm or less (25%)
HCC
◼ 5 year survival:
▪ 10% normally to 50% in tumors 5 cm or less with resection
▪ Death usually within 1 year from cachexia
▪ GI bleed
▪ Liver failure
▪ Rupture of tumor (10%)
◼ Metastases:
▪ Initially within liver
▪ Distant metastases late to:
▪ Lungs
▪ Bone
▪ adrenal gland
▪ porta hepatis lymph nodes
HCC: GROSS
◼ Soft yellow-green or reddish
masses of varying sizes:
3 basic patterns
▪ Multinodular
▪ Solitary
▪ Massive or diffuse
◼ For symptomatic individuals- most common is a
large mass surrounded by several satellite nodules,
multinodular appearance may be difficult to
distinguish from cirrhosis.
◼ Diffuse pattern – rare
◼ Tumor thrombi in veins are common as is
spontaneous rupture of larger masses
HCC: MICRO
Patterns:
▪ Trabecular (most common) with 4+ cells surrounded by
layer of flattened endothelial cells
▪ Solid (compact)
▪ Pseudoglandular (acinar with proteinaceous material or
bile in lumina, may resemble thyroid follicles),
▪ Pelioid
▪ Giant cell
▪ Sarcomatoid
▪ Clear cell patterns
◼ Sinusoidal vessels surrounding tumor cells is important
diagnostic feature
◼ Scanty stroma, from well differentiated to bizarre
(often within same tumor)
HCC: MICRO

Cells
▪ Polygonal with distinct cell membranes
▪ Higher N/C ratio
▪ Abundant granular eosinophilic cytoplasm
▪ Round nuclei with coarse chromatin and
thickened nuclear membrane
▪ Prominent nucleoli
HCC
Cells:

▪ Also intranuclear pseudoinclusions

▪ Mallory’s hyaline (2-25%)
▪ Bile (5-33%) and bile canaliculi
▪ Vascular invasion and portal vein thrombosis are
common
▪ Mitotic figures are common
▪ Minimal desmoplasia
▪ Occasionally fibrous variants, vascular lakes (pelioid
pattern), abundant fat, no central veins
CHOLANGIOCA (INTRAHEPATIC)

◼ Called BILE DUCT CARCINOMA

◼ 10% of primary liver cancers
◼ Adenoca arising from intrahepatic bile duct
epithelial cells
◼ High prevalence in southeast and eastern Asia,
incl: Korea
CHOLANGIOCARCINOMA

10-20% are associated with :

◼ Chronic bile stasis or cholangitis due to
autosomal dominant polycystic disease
◼ Congenitally dilated hepatic ducts (Caroli’s
disease)
◼ Congenital hepatic fibrosis
CHOLANGIOCARCINOMA

◼ Infection by liver flukes Clonorchis sinensis or

Opisthorchis viverrini
◼ Thorotrast, anabolic steroids, intrahepatic
lithiasis (5-10% of these patients)
◼ Primary sclerosing cholangitis (7-42% of these
patients)
◼ Choledochal cysts
CHOLANGIOCA
(INTRAHEPATIC)
◼ Rarely associated with
neoplastic transformation of von Meyenburg
complexes
◼ Not associated with cirrhosis
◼ Diagnosis of exclusion (must rule out
metastatic adenocarcinoma)
◼ Usually age 60+ years; no gender preference;
but mean age 40 years in those with primary
sclerosing cholangitis or chronic inflammatory
bowel disease
CHOLANGIOCARCINOMA
◼ Klatskin tumor [American internist]: hilar tumor arising
at confluence of left and right hepatic ducts
Laboratory:
Normal AFP, occasional hypercalcemia
Poor prognosis
Death w/in 6 mos; 5 yr survival in resectable cases is 30%
◼ 50-75% metastasize to regional lymph nodes, lungs,
vertebrae, adrenals, brain, elsewhere at autopsy
◼ 50% are metastatic to perihilar, peripancreatic and
para-aortic nodes
Poor prognostic factors:
Lymphatic or intrahepatic metastases
Reduced keratin 903 expression may be a favorable prognostic
factor
CHOLANGIOCA
Gross:
◼ Solitary, 7-10 cm,
◼ multinodular or diffuse small nodules < 1 cm;
gray-white and firm;
◼ Often hepatomegaly and satellite nodules
◼ No peripheral hyperemic zone seen in metastatic
disease
◼ Rarely cirrhosis
◼ Rarely bile stained, although may see bile in
periphery
◼ May invade portal vein
CHOLANGIOCA
Micro:
◼ Mod to well diff adenoca with glandular and tubular structures,
mucin production and dense desmoplasia
◼ Epithelial cells are anaplastic, cuboidal to columnar with
eosinophilic cytoplasm and round central nuclei, tumor cells are
heterogeneous even within the same gland but resemble bile duct
cells, not hepatocytes
◼ Spread along hepatic plates, duct walls, via nerves (81%
perineural), but not sinusoidal
▪ Stroma may be circumferential
around glands
▪ Associated with neutrophils
▪ Variable vascular invasion
▪ NO bile production
 CHOLANGIOCA
Positive stains:
◼ Mucin (almost always)
◼ CEA (cytoplasmic and luminal, not canalicular)
◼ CAM 5.2, AE1-AE3, keratin 903 (74%), CK7
(90-96%), CK19 (84%), CK20 (30-70%, more
often positive in non-peripheral tumors), EMA,
amylase, PTH-related peptide, p53 (10-94%),
Negative stains: AFP
Molecular: Kras mutations
 CHOLANGIOCARCINOMA

- has a glandular appearance

- A liver CA may have both HCC & cholangiolar differentiation
- DO NOT MAKE BILE, but the cells do make mucin, and they can be
almost impossible to distinguish from mets Adenoca on biopsy or FNA.
METASTASES TO THE LIVER

Note the numerous mass lesions that are of variable size. Some of the larger ones
demonstrate central necrosis. The masses are metastases to the liver.
The obstruction from such masses generally elevates alkaline phos, but not all bile
ducts are obstructed, so hyperbilirubinemia is typically not present. Also, the
transaminases are usually not greatly elevated.
METASTATIC CARCINOMA

Microscopically, metastatic infiltrating ductal carcinoma from breast is

seen on the right, with normal liver parenchyma on the left.
ACUTE ALLOGRAFT
REJECTION
Hepatic Allograft Rejection: this is
an injury to the transplanted liver
cased by IMMUNOLOGIC
REACTIONS of the HOST.
3 Types of Rejection:
1. Humoral Rejection
(Hyperacute/Antibody Mediated)
- Rare
- Common in ABO Incompatible
Donor
- C4d Immunostains help for the
diagnosis
2. Acute Rejection (Cellular)
Most common form
Occurs usually at 1st - 3rd weeks after transplantation (7-10days)
CELL MEDIATED IMMUNE REACTION directed to Bile Duct
Epithelium and Endothelium of Portal and Centrilobular Veins.
Microscopic: Triad of portal infiltration, bile duct damage, and
endotheliitis. (2 features may satisfy the diagnosis)
Inflammation: Predominantly Lymphocytes
CHRONIC REJECTION
(Ductopenic Rejection)
- This is an immunologic injury to the allograft that is
severe or persistent acute rejection that may lead to
IRREVERSIBLE DAMAGE of the bile ducts, arteries,
and terminal hepatic veins. (CENTRILOBULAR &
PORTAL TRACTS AFFECTED)
Clinical History: History of Acute Cellular rejection with
Progressive Cholestasis.
Microscopic Features:
1. Bile duct atrophy/pynknosis
2. Foam Cell Obliterative Arteriopathy
3. Bile Duct Loss >50% of the portal tracts
GALL BLADDER
1. Cholelithiasis
2. Cholesterosis
3. Acute Cholecystitis
4. Chronic Cholecystitis
5. Carcinoma of the Gall Bladder
CHOLELITHIASIS
- This is one of the most common GIT
Diseases worldwide affecting F>M.
Formation and Risk of Gallstones are
due to:
1. Body Weight
2. Childbearing
3. Estrogens
Other Conditions that Cholelithiasis are
also involved:
1. Hemolysis
2. Crohn Disease
3. Congenital Anomalies in Biliary Tree
CHOLELITHIASIS
Gallstones (Stones) – formed based on
the amount of Cholesterol.
a. Cholesterol (Mixed Type) (>80%
Stones) – Cholesterol, Bile Salts, &
Phospholipids
b. Pigment (Medical Condition Related
DUE TO HYPERBILIRUBINEMIA) –
Calcium Bilirubinate, Phosphate, &
Carbonate
Key for the Development Stones:
(Cholesterol Crystal Aggregates &
Mucin Proteins)
1. Bile Supersaturation & Destabilization
2. Gallbladder Hypomotility
CHOLELITHIASIS
Other Types of Stones:
1. Brown Stone – Calcium Salts of
Bilirubin and Palmitate.
2. Calcium Carbonate & Phospahate
Stones
3. Brown-Green Stones – Associated
with Infections (E-Coli and Biliary Flukes)
Choledocholithiasis – can occur with or
with out obstruction but are secondary to
Cholelithiasis.
Hydrops – Caused by impaction
gallstone to cystic duct.
Obstruction at Common Bile Duct or
Ampulla – Can cause severe colicky
pain and Obstructive Jaundice.
 MIRRIZI SYNDROME

Mirrizi Syndrome – Impacted cystic duct

stone causes edema and compression and
obstruction of common hepatic duct.
Internal Biliary Fistulas – 90% occur at
the area: (Due to the Inflammatory
Adhesions between Affected Billiary Tree
and Adjacent Organ)
1. DUODENUM & GALLBLADDER
2. GALLBLADDER & COLON
3. CYSTIC BILE DUCT & DUODENUM
ACUTE
CHOLELITHIASIS
Clinical
GROSS: Symptoms: Pain in the RIGHT
UPPER QUADRANT, NAUSEA &
1. Angry Red Color, Large and Distended,
VOMITING, FEVER.
Hemorrhagic External Surface.
Three Types of Acute Cholecystitis:
2. Foci of gangrene perforation.
1. Calculous (90%) – due to
3. Edema and fibrin within the gallbladder
chemical/ischemic and or due to
wall (MUCOSAL ULCERATION &
impacted stone in the cystic duct.
FIBRINOINFLAMMATORY EXUDATE)
2. Acalculous (10%) – Serious medical
MICROSCOPIC: Mucosal lining is reddish
condition such cardiac surgery , TPN,
Sepsis
3. Emphysematous (Acute gaseous
Cholecystitis) – Common in diabetics
infecting gas-forming types.
 CHRONIC
-CHOLECYSTITIS
May or may not suffered pain.
GROSS: Enlarged, Shrunken, of Normal
Size and Adhesions are seen. STONE are
present 95% cases.
MICROSCOPIC:
1. MONONUCLEAR INFILTRATION
(Lymphocytes and Plasma Cells)
2. FIBROSIS
3. ROKITANSKY-ASCHOF SINUSES –
lined by columnar or cuboidal
epithelium and may contain bile stones.
 CHOLESTEROSIS
-Accumulation of LIPDS WITHIN THE
MACROPHAGES IN THE LAMINA
PROPRIA.
GROSS: Linear Yellow Streaks in the
MUSCOSAL RIDGES (STRAWBERRY
BLADDER)
Associated Findings:
1. Cholesterol Stones
2. Cholesterol Polyps
 ADENOCARCINOMA OF
THE
GROSS:
Molecular
polypoid,
BILIARY
GALLBLADDER
This isDiffuse
the most
(70%)
common
Aberration:
MICROSCOPIC:
or papillary
CANCERS.
growing
80-95%
or nodular,
of
mass (30%). Some
1. KRAS mutation (60%)(90%) –
ADENOCARCINOMA
are PANCREATOBILIARY
not so apparent in gross
TYPEspecimens
Affects F>M(3-4:1) and occurs >50%
andTP53
2. Mutation (50%)
MICROSCOPIC – High Grade
EXAMINATION Tumor
IS
2. in at
Types age 50 years.
MICROPAPILLARY TYPE – Aggressive
IMPORTANT.
Behavior. cases risk to develop this
Associated
3. Loss of Histidine (EARLY SIGNS)
LOCATION:
cancer:
3. ADENOSQUAMOUS TYPE (Squamous
Fundus (70-80%)
1. component should beFistula
25-99%)
1. Cholescystoenteric
4.SPREAD
2. &
Body (1/3
PURE METASTASIS: (ALL HALF THE
or 10%) CARCINOMA
SQUAMMOUS
Porcelein
2.PATIENTS Gallbladder
ALREADY HAVECarcinoma
THIS AT THE
3. Neck
5.TIME (10%)ADENOCARCINOMA – 50%
SURGEY)
MUCINOUS
Segmental Adenomyosis
3. Extracellular Mucin
PORCELEIN GALLBLADDER
1. LIVERStones
Calculi: INVASION
mayDIRECTLY
be present(COMMON)
(80-90%)
4. Gardner Syndrome
6. SIGNET RING CELLS (Advanced
2.
WITHSTOMACH
MARKED
Presentation)& DUODENUM
FIBROSIS OF INVASION
THE
5. Anomalous connection Common Bile
WALL
3. (PREEXISTING
OVARIAN METASTASISCHRONIC
with SIMULATE
7. Duct
CLEAR and Pancreatic
CELL VARIANT Duct
CHOLECYSTITIS).
OF PRIMARY OVARIAN IS RISK
CLINICAL SIGN: Elevated Alkaline
Phosphatase
ADENOCARCINOMA OF THE GALLBLADDER