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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XX X

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X

X

X

X

XX

XX I

I

I

I

I

I

X

IIII

IIII I

I

I

I

I

I

II

IIII

II

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