This document provides an overview of liver pathology, covering topics such as normal liver anatomy and histology, biopsy techniques, viral hepatitis, cirrhosis, tumors, and other disorders. It begins with a basic introduction and table of contents, then discusses the liver's structure and function at both the gross and microscopic level. Specific pathological conditions are described in detail, with information on etiology, gross and microscopic appearance, important histological stains, and differential diagnosis when relevant. These include fatty liver disease, viral hepatitis, cirrhosis, vascular and pigmentary disorders, as well as benign and malignant epithelial and mesenchymal tumors.

1. LIVER PATHOLOGY

2. Contents
•Introdution
•Normal anatomy & Histology
•Biopsy
•Viral hepatitis
•Steatosis and steatohepatitis
•Cirrhosis
•Vascular disorders
•Pigmentary disorders
•Drug/ toxin mediated injury
•Benign Epithelial tumors
•Malignant Epithelial tumors
•Mesenchymal tumors
•Metastatic tumors

3. LIVER
⚫Largest internal organ
⚫1.4–1.6 kg (3.1–3.5 lb)
⚫Reddish brown soft organ with four lobes of unequal
size and shape

4. Histologically units LOBULES
Center of the lobule - CV
Periphery of the lobule - PT
Functionally, Divided into :
3 ZONES, based upon
oxygen supply
Zone 1- Encircles the PT
where the oxygenated blood
from hepatic arteries enters.
Zone 3 is located around CV,
where oxygenation is poor.
Zone 2 is located in between.
LIVER HISTOLOGY
CV
PT

7. Liver Biopsy
•Liver histopathology remains a mainstay in the
diagnostic work-up of most liver diseases
•Biopsy remains the gold standard for the diagnosis
of cellular rejection
•Adequacy of biopsy,
•Site of biopsy (is it from liver?),
•Architecture on low power;
•Assess inflammation (degree, type),
•Necrosis, fibrosis, tumor cells

8. Pattern Recognition
• Acute Hepatitis
• Chronic hepatitis
• Fatty liver disease
• Biliary Pathology
• Vascular Pathology
• Metabolic liver disease
• Architecture and fibrosis

9. STEATOSIS

10. ⚫This liver is slightly
enlarged
⚫Tense capsule
⚫Pale yellow seen
both on external
and cut surface
FATTY CHANGE: GROSS

11. Initial microvesicular
Macrovesicular droplets
Fat cysts - coalescence and
rupture
Less often - lipogranulomas
(Lymphocytes, macrophages and
multinucleate giant
Cells)
FATTY CHANGE: MICRO

12. VIRAL HEPATITIS

13. Microscopy :
Ballooning degeneration
Spotty necrosis
Predominantly sinusoidal and
lobular mononuclear cell infiltrate
(occasional neutrophils and
eosinophils)
Kupffer cell hyperplasia
Scattered apoptotic bodies
Canalicular cholestasis
Hepatocellular regeneration

14. Microscopy of CVH
• Predominantly portal tract inflammation
• Interface hepatitis
• Lobular acidophil bodies
•Mononuclear inflammatory cells, +/-plasma
cells
•Portal-based lymphoid aggregates and
lymphoid follicle formation
• Bile ductular proliferation
• Progressive fibrosis with eventual cirrhosis

16. VIRAL HEPATITIS: TRICHROME
This trichrome stain demonstrates the collapse of the liver parenchyma with
viral hepatitis. The blue-staining areas are the connective tissue of many portal
tracts that have collapsed together.

17. Hepatitis A - mononuclear infiltrate
rich in plasma cells
Hepatitis B - “ground-glass”
hepatocytes - cells with
endoplasmic
reticulum swollen by HBsAg
Hepatitis C - shows lymphoid
aggregates or fully formed
lymphoid follicles

18. ALCOHOLIC
HEPATITIS
- Mallory's hyaline, neutrophils, necrosis of hepatocytes,
collagen deposition, and fatty change

19. MALLORY'S HYALINE
- Rope like red hyaline material within hepatocytes
- also known as "alcoholic" hyaline, Mallory- Denk Bodies - chronic
alcoholism
- aggregates of intermediate filaments in the cytoplasm resulting from
hepatocyte injury.

20. CIRRHOSIS

21. CIRRHOSIS
⚫Diffuse nodulation of liver due to fibrous bands
subdividing liver into regenerative nodules
⚫Nodules : >3 mm - macronodular
< less than 3 mm - Micronodular

22. MICRONODULAR CIRRHOSIS
The regenerative nodules - quite small, averaging
< 3 mm in size
CAUSES: Chronic Alcoholism – Most Common
Wilson's disease
Primary biliary cirrhosis
Hemochromatosis.

23. MACRONODULAR
CIRRHOSIS
CAUSES: Viral hepatitis (B or C) - most common cause
Wilson's disease
Alpha-1-antitrypsin deficiency

24. CIRRHOSIS: micro
Regenerative nodules of hepatocytes are surrounded by fibrous
connective tissue that bridges between portal tracts.
Within this collagenous tissue are scattered lymphocytes as well as a
proliferation of bile ducts.

25. PRIMARY BILIARY CIRRHOSIS
A rare autoimmune disease
(mostly of middle-aged women)
Characterized by destruction of
bile ductules within the triads of the
liver.
Intense chronic inflammatory
infiltrate
Loss of bile ductules.
Micronodular cirrhosis

26. PIGMENTARY DISORDERS
OF THE LIVER

27. HEMOSIDEROSIS
Hemosiderosis - accumulation of iron.
The hepatocytes and Kupffer cells here
are full of granular brown deposits of
hemosiderin from accumulation of
excess iron in the liver.
Hemochromatosis - used when organ
dysfunction occurs.
The iron accumulation may lead to a
micronodular cirrhosis - "pigment"
cirrhosis).

28. Iron stain highlights the periportal predominance of iron
deposition seen in hemochromatosis.
There are larger dark blue granules in the hepatocytes closer
to the portal tracts.

29. HEREDITARY HEMOCHROMATOSIS (HHC):
GROSS
- Dark brown - liver, the pancreas and lymph nodes -due to
extensive iron deposition
- HHC results from a mutation involving the hemochromatosis gene (HFE)
that leads to increased iron absorption from the gut.

30. LIPOFUSCIN PIGMENT
-Pale golden brown finely granular pigment in nearly all hepatocytes is
lipochrome (lipofuscin).
-This is a "wear and tear" pigment from the accumulation of
autophagolysosomes over time.
- This pigment is of no real pathologic importance

31. CHOLESTASIS: MICRO
- accumulations of pigment - bile
- often this is due to extrahepatic biliary tract obstruction
- Bile may also accumulate in liver (called cholestasis) when there is
hepatocyte injury.

32. INTRAHEPATIC LITHIASIS
- Small stone in an intrahepatic bile duct
- Produce a localized cholestasis, but the serum bilirubin is NOT
increased, because there is plenty of non-obstructed liver to
clear the bilirubin from the blood
- Serum Alkaline Phos is increased with biliary tract obstruction at any
level

33. VASCULAR
DISORDERS

34. CHRONIC PASSIVE CONGESTION
"nutmeg" liver - chronic passive congestion of the liver.
the dark red congested regions that represent accumulation of
RBC's in centrilobular regions.
This is usually due to a "RIGHT SIDED" heart failure.

35. CENTRILOBULAR NECROSIS
If the passive congestion is pronounced, then there can be centrilobular
necrosis, because the oxygenation in zone 3 of the hepatic lobule is
decreased.
The light brown pigment in the necrotic hepatocytes around the central vein is
lipochrome.

36. CPC - CARDIAC CIRRHOSIS
"cardiac cirrhosis" - fibrosis bridging between central zonal regions,
The portal tracts appear to be in the center of the reorganized lobule.
Unlike a true cirrhosis, there is minimal nodular regeneration.

37. INFARCTION OF THE LIVER
Infarcts are uncommon because the liver has two blood supplies-portal
venous system and hepatic arterial system.
The infarcts seen here are yellow, with geographic borders and surrounding
hyperemia.
About half of liver infarcts occur with arteritis, and the remaining half are due
to a variety of causes.

38. ACETAMINOPHEN OVERDOSE
There is extensive hepatocyte necrosis
This pattern can be seen with a variety of hepatotoxins.

39. POLYCYSTIC KIDNEY DISEASE
(PCKD) - POLYCYSTIC LIVER
- Manifest with renal failure beginning in
middle age
- Sometimes the liver can be affected as
well by polycystic change.
- Less commonly the pancreas is involved.
- These patients with DPKD can also have
berry aneurysms in the cerebral arteries.

40. EXTRAHEPATIC BILIARY ATRESIA
•Inflammation with stricture of
hepatic or common bile ducts.
•This leads to marked cholestasis with
intrahepatic bile duct proliferation,
fibrosis, and cirrhosis.
•The liver is rock hard.
•The dark green color comes from
formalin acting on bile pigments in the
liver from marked cholestasis, turning
bilrubin to biliverdin.

41. EXTRAHEPATIC BILIARY ATRESIA
Microscopy:
•Numerous brown-green bile plugs,
•Bile duct proliferation
•Extensive fibrosis.

42. α-1-ANTITRYPSIN DEFICIENCY
AAT deficiency - chronic obstructive
pulmonary disease with panlobular
emphysema.
The periportal red hyaline globules seen
with periodic acid-Schiff (PAS) stain
The globules are collections of alpha-1-
antitrypsin not being excreted from
hepatocytes.
This may eventually lead to chronic
hepatitis and cirrhosis.

43. TUMORS OF THE
LIVER &
INTRAHEPATIC DUCTS

44. BENIGN EPITHELIAL
TUMORS

46. FOCAL NODULAR HYPERPLASIA
(FNH)
⚫Benign nonneoplastic hepatic lesion,
⚫Arising in a noncirrhotic liver parenchyma
⚫Most common in young adults
⚫May represent hyperplastic response to arterial
malformation or other vascular anomaly

47. Gross :
•Well demarcated,
•Unencapsulated
•Solitary lesion
•Lighter in color than the surrounding liver parenchyma
•Subcapsular region
•Measure < 5 cm
•Cut surface :
•Central scar
•Radiating fibrous septa

48. Micro :
•Bland hepatocytes
•Surrounded by fibrous septa
•Artery branches
•Bile ductular reaction
•Variable amount of mixed
inflammatory infiltrate
•Portal tracts are absent except
at periphery

49. •Hepatocytes - similar to
those in the surrounding
liver
•1 - 2 cells thick
•Supported by an intact
reticulin framework

50. FNH
⚫Positive stains: alpha-1-antitrypsin
⚫Negative stains: p53, CD143 (angiotensin I-converting
enzyme: reduced expression
⚫DD:
⚫ Budd-Chiari syndrome or cirrhosis (adjacent liver is not
normal)
⚫ Fibrolamellar hepatocellular carcinoma (marked atypia of
hepatocytes)
⚫ Hepatocellular adenoma (encapsulated, monoclonal)
⚫ Peritumoral hyperplasia
⚫ Mesenchymal hamartoma

51. GROSS: LIVER CELL ADENOMA
⚫Solitary (70 %), pale, yellow-tan
⚫bile-stained nodules,
⚫Often subcapsular, 10-30 cm,
⚫Sharply demarcated
⚫Usually right lobe,
⚫Adjacent liver is noncirrhotic

52. LIVER CELL ADENOMA: MICRO
⚫Sheets and cords 1-3 cells thick of normal appearing hepatocytes
with variable glycogen
⚫Prominent “free floating” arterial vessels and draining veins
throughout the tumor
⚫Intact reticulin framework
⚫No/rare mitotic figures
⚫No portal tracts, no central
veins or connection with biliary
system

53. LIVER CELL ADENOMA
⚫Positive stains: ER, PR
⚫Negative stains: p53
⚫DD:
⚫HEPATOCELLULAR CARCINOMA (mitotic activity,
atypia, trabecular growth, cell plates > 2 cells thick,
vascular invasion, infiltrative, often different clinical
features)
⚫ FOCAL NODULAR HYPERPLASIA (central stellate
scar and radiating fibrous septa)

54. BILE DUCT ADENOMA (Cholangioma)
⚫30% - incidental finding
⚫GROSS:
Small, well-circumscribed but unencapsulated,
firm, gray-white/ tan,
subcapsular nodule;
85% solitary;
usually 5 mm or less

55. BDA: MICRO:
⚫Small tubules set in a fibrous
stroma with lymphocytes
⚫Single layer of cuboidal cells;
⚫possible mucin secretion;
⚫no bile in the lumen
⚫Normal portal tracts often included

56. Biliary Hamartoma
⚫ Within cirrhotic livers, most commonly
seen chronic hepatitis C and alcohol-
related liver disease
⚫ single or multiple
Micro :
•composed of bile duct
structures that grow in an
irregular inter-anastomosing
fashion.
•duct structures have open
lumens, associated with either a
myxoid or fibrotic stroma

57. Intraductal
papillary
neoplasm of the
bile ducts
GROSS:
⚫Inner surface of ducts has velvety friable papillary
growths / excrescences with masses filling dilated major
bile ducts
⚫Masses are soft, friable, white-red-tan

58. Micro:
⚫Multiple papillary tumors
composed of fibrovascular
cores
⚫Lined by columnar,
pseudostratified, biliary-type
cells with numerous
cytoplasmic mucin vacuoles
⚫Ovarian stroma is absent
⚫Varying cytologic atypia and
mitotic activity
⚫May have associated tubular
adenocarcinoma with invasion

59. Differential diagnosis
Mucinous cystic neoplasm
Also a cystic hepatic lesion
Lined by biliary type epithelium
Has ovarian type stroma and
Does not communicate with biliary lumen
Cholangiocarcinoma
May show areas of cystic degeneration
Does not communicate with biliary lumen
Simple cyst, simple hepatic cyst, Simple biliary cyst, bile
duct cyst
Lacks papillary projections

60. MALIGNANT TUMORS

61. Hepatocellular Carcinoma
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 may involve the portal
vein (35-80%), hepatic vein (20%) or inferior vena
cava
⚫Hemorrhage and necrosis are common
⚫Occasionally tumor is pedunculated
⚫Liver usually cirrhotic, often enlarged

62. HEPATOCELLULAR CARCINOMA

63. HCC: MICRO
Patterns:
⚫ Trabecular (most common) - 4+ cells surrounded by
layer of flattened endothelial cells
⚫ Pseudoglandular (acinar with proteinaceous material or bile in
lumina)
⚫ Solid and macrotrabecular
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

64. ⚫Sinusoidal vessels surrounding tumor cells is important
diagnostic feature
⚫Scanty stroma, from well differentiated to bizarre (often
within same tumor)

65. HEPATOCELLULAR CARCINOMA

66. Differential diagnosis
1. Hepatocellular adenoma:
Neoplastic hepatocytes are not expanded on reticulin stain (no loss)
Noncirrhotic background
2. Intrahepatic cholangiocarcinoma:
Discrete gland formation surrounded by desmoplastic stroma
Negative for hepatocellular markers; positive for CK7
3. Dysplastic nodule in cirrhosis:
~ 1 cm lesion
Preserved portal tracts
4. Metastatic neuroendocrine neoplasms:
Positive staining for neuroendocrine markers while negative for hepatocellular markers
5. Metastatic carcinomas
Possible clinical history of prior malignancy
Differing immunohistochemical profile

67. CLEAR CELL VARIANT - HCC
⚫Predominant appearance in
5-16% of cases, but some
clear cells present in 20-40%
of cases
⚫Tumor cells have prominent
clear cytoplasm due to
cytoplasmic fat or glycogen
⚫May need to hunt for
typical HCC to rule out
metastatic tumor
⚫Similar prognosis to classic
tumor

68. FIBROLAMELLAR VARIANT- HCC
GROSS:
⚫Single (75%)
⚫Large (mean 13 cm)
⚫Hard
⚫Scirrhous
⚫Well-circumscribed
⚫Bulging
⚫White-brown tumor with fibrous bands throughout and
central stellate scar
⚫Most cases involve left lobe, but may involve both lobes
⚫Variable bile staining, hemorrhage and necrosis

69. FIBROLAMELLAR VARIANT - HCC
Micro:
⚫ Nests, sheets or cords of well
differentiated oncocytic cells in
⚫ Background of dense, acellular
collagen bundles
⚫ That may contain small, thick-
walled vessels
⚫ Fibrotic tissue coalesces into
central scar

70. Differential diagnosis
1. Cholangiocarcinoma:
Truly glandular, often conspicuous pleomorphism
2. Focal nodular hyperplasia:
Ductular reaction around central scar
Lesional cells are not characteristically oncocytic
Does not have the nuclear features of fibrolamellar carcinoma
3. Hepatocellular carcinoma, sclerosing variant:
No oncocytes, smaller tumor cells, pseudoglandular pattern common
4. Metastatic carcinoma with sclerotic stroma:
Conspicuous pleomorphism
5. Neuroendocrine tumors:
Nuclear features are often not typical of fibrolamellar carcinoma
Positive for neuroendocrine marker

71. ONCOCYTIC VARIANT -HCC
⚫Oncocytes are present in fibrolamellar variant and
⚫Occasionally in classic hepatocellular carcinoma
⚫Rarely these cells predominate without fibrous
stroma of fibrolamellar variant
⚫Cytoplasm is intensely eosinophilic with coarse
granules

72. PLEOMORPHIC (GIANT CELL) VARIANT
⚫<1% of all hepatocellular
carcinomas,
⚫Although 15% have some
tumor giant cells
⚫Multinucleated tumor giant
cells predominate,
⚫marked loss of cell cohesion

73. SARCOMATOID VARIANT - HCC
⚫1-9% of all HCC have prominent
sarcomatoid pattern
⚫Diffuse collection of spindle cells
resembling fibrosarcoma
⚫Classic HCC is also present;
⚫May have pleomorphic and
osteoclast-like giant cells

74. Differential diagnosis
1. Undifferentiated pleomorphic sarcoma and fibrosarcoma
No area of classic HCC
Immunohistochemistry (entirely negative for pancytokeratin)
2. Metastatic sarcomatoid carcinoma:
Will not have area of classic HCC
Usually multiple nodules
Immunohistochemistry (pancytokeratin+)
Negative for hepatocellular markers,

75. SCLEROSING: HCC
Micro:
⚫Fibrous septa separate trabecular cell plates but no
lamellar fibrosis
⚫Cell plates 3 or more cells thick
⚫Tumor cells may have pseudoglandular (acinar)
features compared to fibrolamellar variant
⚫Tumor cells are smaller
⚫Lack vesicular nuclei and prominent nucleoli
⚫Have less abundant and granular cytoplasm
⚫No apparent endothelial sinusoidal cells

76. CHOLANGIOCARCINOMA
Gross:
Large, nonencapsulated, well
demarcated,
Firm, white-tan to gray
Nodular intrahepatic mass
More frequent in the right lobe of the
liver
Satellite nodules in 30%
Noncirrhotic background liver in
most cases

77. Grossly - 3 growth patterns
1. Mass forming: hepatic parenchymal solid mass
2. Periductal infiltrating: infiltrates along the portal
tracts, causing bile duct strictures
3. Intraductal growth: papillary or polypoid growth
inside a dilated bile duct

78. Micro:
⚫Moderate to well differentiated adeno
ca
⚫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
⚫Multicentricity and perineural
invasion are common

79. HEPATOBLASTOMA
•Malignant primary hepatic blastomatous tumor
•Most frequent liver tumor in children
•1 - 1.5 cases per million
•80 - 90% between 5 months to 6 years old
•Slight male predominance

80. Gross :
•Single or multinodular
•Well defined boundaries
•Tan-brown cut surface
•Undifferentiated subtypes have a variegated appearance
•Necrosis and hemorrhage are present in posttreatment
specimens
•Osteoid may be present- firm and gritty

82. Fetal pattern
•Small to medium sized cells
•Thin trabeculae or nests
•Resembling hepatocytes of
fetal liver
•Clear or finely granular
cytoplasm
•Small round nucleus with
indistinct nucleolus
•Foci of extramedullary
hematopoiesis are usually
present
•Low mitotic activity,
•Referred to as well
differentiated hepatoblastoma

83. Embryonal pattern
•Resembles liver at 6 - 8 weeks of gestation
•Solid nests or glandular / acinar morphology
•Papillae and pseudorosettes
•Dark and granular cytoplasm without glycogen or lipids
•Enlarged nuclei with coarse chromatin,
•Resembling blastemal cells
•Extramedullary hematopoiesis- absent
•Increased mitotic activity

84. Small cell undifferentiated
pattern
•Small, round blue tumor
•Solid sheets of
discohesive small cells
•Abundant mitoses,
apoptosis and necrosis

85. Cholangioblastic pattern
Small ducts within or around hepatocellular components
Mesenchymal pattern
•Mature and immature fibrous tissue
•Osteoid or osteoid-like tissue
•Hyaline cartilage
•Small subset may exhibit teratoid features:
endodermal, neuroectodermal (neuronal cells, glial
tissue, melanin producing cells) and complex
tissue (striated muscle)

86. MESENCHYMAL
TUMORS

87. HEMANGIOMA: GROSS
Gross:
⚫solitary (70-90%), usually 2-
4 cm, although tumors up to
20 cm are overrepresented
in studies of excisions
⚫Soft, red-purple, well
circumscribed
⚫Subcapsular or deep
⚫Collapse when sectioned as
blood oozes out

88. HEMANGIOMA: MICRO
Micro:
⚫Variably sized vascular
spaces
⚫Lined by flat endothelial
cells and
⚫Fibrous stroma

89. Epithelioid hemangioendothelioma
Low grade Malignant endothelial neoplasm
GROSS :
Poorly circumscribed, firm, white-tan mass
Variable size, up to 18 cm

90. MICROSCOPY
oCords, strands or small nests of large endothelial cells with
abundant eosinophilic cytoplasm
oEmbedded in a myxohyaline stroma
oTumor cells have vesicular, round to oval, sometimes indented
nuclei
oIntracytoplasmic, round,
clear vacuoles representing
small vascular lumina,
oMay contain erythrocytes

91. Peliosis Hepatis
Peliosis hepatis represents blood-fi lled cysts
in the hepatic parenchyma
certain drugs,particularly anabolic steroids,
high-dose oral contraceptive,
or azathioprine in patients with solid organ
transplants,TB,IMMUNO COMPRO MISED
Most cases ofpeliosis are detected
incidentally,
but rupture,intraperitoneal hemorrhage,and
death
have been reported.Peliosis may regress on
stopping hormone
or drug causing the lesion.
M/E blood-filled cystic spaces,separated by
cords of normal or compressed hepatocytes,
distributed randomly in liver parenchyma

92. METASTASES TO THE LIVER
Numerous mass lesions that are of variable size
Larger ones demonstrate central necrosis

94. METASTATIC CARCINOMA
Microscopically, metastatic infiltrating ductal carcinoma from breast is seen
on the right, with normal liver parenchyma on the left.

95. REFERNCES :
1. Mills SE , Carter D ,Sternberg diagnostic pathology , 4th
edition , Lipincott Williams and wilkins.
2. Rosai J,Rosai and Ackerman surgical pathology, 9th edition
3. Differential diagnosis in surgicalpathology ,3rd edition
4. Robbins and cotran, Pathologic basis of disease.
5. Internet sources

96. THANK YOU