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Tutorial in Human Hepatocarcinogenesis:Premalignant lesions and stem cells
Neil Theise, MDDepartments of Pathology and Medicine (Digestive Diseases)Mount Sinai Beth Israel Medical CenterNew York City
Icahn School of Medicine atMount Sinai
Nodular dysplasias• Hepatocellular adenomas• Dysplastic nodules (only in CLD)
Cellular dysplasias• Small cell change• Large cell change
Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,texture, or degree of bulging from the cut surface…
Dysplastic Nodules
Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,texture, or degree of bulging from the cut surface…
…AND contain portal tracts.
Dysplastic Nodules
Low GradeDysplasticNodules
Features of Low Grade DNs:
Normal cytology or
Large cell change only
No architectural atypia
High GradeDysplasticNodules
Features of High Grade DNs:
Cytologic atypia e.g. small cell change
Clone-like domains e.g. Mallory body clustering, fatty or clear cell change, iron resistance, etc.
Architectural atypia e.g. pseudogland formation
Incidence of DNs in Cirrhotic Livers
Location Source # Cirrhotic Livers
# w/ DNs (%)
Tokushima Autopsy 315 46 (14%)
New York Explant 44 11 (25%)
San Francisco Explant 110 17 (15%)
Kanazawa Autopsy 209 45 (21%)
New York Explant 155 32 (22%)
Bordeaux Explant 41 10 (24%)
Chronic HepatitisHepatitis B and C Autoimmune hepatitis
Metabolic DiseaseGenetic hemochromatosis A-1-AT Deficiency
Chronic Biliary Tract Disease PBC, PSC
Toxic InjuryChronic alcoholic liver injury
Chronic hepatitis
with fibrosis10-50 years
Natural History of Chronic Liver Disease
Cirrhosis
Normal liver
HepatocellularCarcnoma
Increased proliferation
NodularHCC
Low gradedysplastic
nodule
Dysplasticnodule
containing early HCC
Genetic alteration
High gradedysplastic
nodule
Old Model
Chronic hepatitis
with fibrosis10-50 years
Natural History of Chronic Liver Disease
Cirrhosis
Normal liver
HepatocellularCarcnoma
SPREADINGMONOCLONAL
PROLIFERATION
CLONALDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED HSC ACTIVATION
SPREADINGMONOCLONAL
PROLIFERATION
NODULE-IN-NODULELESION
CLONALDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED HSC ACTIVATION
SPREADINGMONOCLONAL
PROLIFERATION
NODULE-IN-NODULELESION
CLONALDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED HSC ACTIVATION
MATUREHEPATOCELLULAR
CARCINOMA
Aihara T, et al.Clonal analysis of regenerative nodules in
hepatitis C virus-induced liver cirrhosis.Gastroenterology 1994; 107: 1805-11.
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I
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SPREADINGMONOCLONAL
PROLIFERATION
NODULE-IN-NODULELESION
CLONALDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED HSC ACTIVATION
MATUREHEPATOCELLULAR
CARCINOMA
NL or INCREASED HSC ACTIVATION
SPREADINGMONOCLONAL
PROLIFERATION
NODULE-IN-NODULELESION
CLONALDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED HSC ACTIVATION
MATUREHEPATOCELLULAR
CARCINOMA
ADJACENT CLONAL CIRRHOTIC NODULES
NL or INCREASED HSC ACTIVATION
SPREADINGMONOCLONAL
PROLIFERATION
NODULE-IN-NODULELESION
CLONALDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED HSC ACTIVATION
MATUREHEPATOCELLULAR
CARCINOMA
ADJACENT CLONAL CIRRHOTIC NODULES
MULTIPLE, ADJACENTOr
DNs w/ INDISTINCT BORDERSMICROSCOPIC HCCs
NL or INCREASED HSC ACTIVATION
Early HCC, vaguely nodular type
Early HCC, distinctly nodular type
Hepatology 2009; 49: 658