Hepatocarcinogenesis - Kuwait

Dysplastic Nodules &

Hepatocarcinogenesis

Dysplastic Nodules &

Hepatocarcinogenesis

Differential Diagnosis of:“Distinctive nodules” in cirrhosis

Low grade dysplastic nodules High grade dysplastic nodules

Hepatocellular carcinoma (Focal nodular hyperplasia)

(Adenoma)

Differential Diagnosis of:“Distinctive nodules” in cirrhosis

Low grade dysplastic nodules High grade dysplastic nodules

Hepatocellular carcinoma (Focal nodular hyperplasia)

(Adenoma)

Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of

Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of

Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:

size,


size,


size,color,


size,color,


size,color,texture,


size,color,texture,


size,color,texture,or degree of bulging from the cut surface


size,color,texture,or degree of bulging from the cut surface


color,size,texture,or degree of bulging from the cut surface AND contain portal tracts (….?)


color,size,texture,or degree of bulging from the cut surface AND contain portal tracts (….?)

Low GradeDysplasticNodules

Low GradeDysplasticNodules

Features of Low Grade DNs:Features of Low Grade DNs:

Normal cytology or

Large cell change only

Normal cytology or

Large cell change only

No architectural atypiaNo architectural atypia

High GradeDysplasticNodules

High GradeDysplasticNodules

Features of High Grade DNs:Features of High Grade DNs:

Cytologic atypia, e.g. small cell changeCytologic atypia, e.g. small cell change

Clone-like domains e.g. Mallory body clustering, iron resistance, fatty or clear cell change, etc.

Clone-like domains e.g. Mallory body clustering, iron resistance, fatty or clear cell change, etc.

Architectural atypia, e.g. pseudogland formation Architectural atypia, e.g. pseudogland formation

Incidence of DNs in Cirrhotic LiversIncidence of DNs in Cirrhotic Livers

LocationLocation SourceSource

# Cirrhotic # Cirrhotic LiversLivers

# Livers with# Livers with

DNs (%)DNs (%)

TokushimaTokushima AutopsyAutopsy 315315 46 (14%)46 (14%)

New YorkNew York ExplantExplant 4444 11 (25%)11 (25%)

San FranciscoSan Francisco ExplantExplant 110110 17 (15%)17 (15%)

KanazawaKanazawa AutopsyAutopsy 209209 45 (21%)45 (21%)

New YorkNew York ExplantExplant 155155 32 (22%)32 (22%)

BordeauxBordeaux ExplantExplant 4141 10 (24%)10 (24%)

Chronic HepatitisHepatitis B and C Autoimmune hepatitis

Chronic HepatitisHepatitis B and C Autoimmune hepatitis

Metabolic DiseaseGenetic hemochromatosis A-1-AT Deficiency

Metabolic DiseaseGenetic hemochromatosis A-1-AT Deficiency

Chronic Biliary Tract Disease PBC, PSC Chronic Biliary Tract Disease PBC, PSC

Toxic InjuryChronic alcoholic liver injury

Toxic InjuryChronic alcoholic liver injury

Dysplastic Nodule Development:Dysplastic Nodule Development:

The Old Model The Old Model

Increased proliferation

NodularHCC

Low gradedysplastic

nodule

Dysplasticnodule

containing early HCC

Genetic alteration

High gradedysplastic

nodule

Old Model

Problems for the Old ModelProblems for the Old Model

Problem 1Problem 1

DNs nearly always contain portal tractsDNs nearly always contain portal tracts

Problem 2Problem 2

DNs have been identified in non-cirrhotic DNs have been identified in non-cirrhotic livers.livers.

Problem 3Problem 3

DNs are clonal lesions.DNs are clonal lesions.

An Alternate ModelAn Alternate Model

DN predictions based on our alternate DN predictions based on our alternate hypothesis:hypothesis:

1.1. Diminished proliferationDiminished proliferation



Terasaki et al, Am J Clinical Path 1991Terasaki et al, Am J Clinical Path 1991

Le Bail et al, Human Pathology 1995Le Bail et al, Human Pathology 1995

Theise et al, Liver 1996Theise et al, Liver 1996



2.2. Diminished HSC activationDiminished HSC activation

Park YN et al, Liver 1997







3.3. Diminished apoptosisDiminished apoptosis


1.1. Diminished proliferationDiminished proliferation2.2. Diminished HSC activationDiminished HSC activation

3.3. Diminished apoptosisDiminished apoptosisPark YN et al, Cancer 2001Park YN et al, Cancer 2001

SPREADINGSPREADINGMONOCLONALMONOCLONAL

PROLIFERATIONPROLIFERATION

CLONALCLONALDYSPLASTIC NODULEDYSPLASTIC NODULE

DEVELOPING CIRRHOSIS

DIMINISHED DIMINISHED HSC ACTIVATIONHSC ACTIVATION



NODULE-IN-NODULENODULE-IN-NODULELESIONLESION






MATUREHEPATOCELLULAR

CARCINOMA


CARCINOMA





Aihara T, et al.Clonal analysis of regenerative nodules in hepatitis C virus-induced liver cirrhosis.Gastroenterology 1994; 107: 1805-11.

XX

XX X

X

X

X

X

X

X

XX

XX I

I

I

I

I

I

X

IIII

IIII I

I

I

I

I

I

II

IIII

IIII I

I

I

I

I

I

II




CARCINOMA


CARCINOMA



ADJACENT CLONAL ADJACENT CLONAL CIRRHOTIC NODULESCIRRHOTIC NODULES



NL or INCREASED NL or INCREASED HSC ACTIVATIONHSC ACTIVATION




CARCINOMA


CARCINOMA







MULTIPLE, ADJACENTMULTIPLE, ADJACENTOrOr

DNs w/ INDISTINCT BORDERSDNs w/ INDISTINCT BORDERSMICROSCOPIC HCCsMICROSCOPIC HCCs




CARCINOMA


CARCINOMA

NODULE-IN-NODULENODULE-IN-NODULELESIONSLESIONS



MULTIPLE, ADJACENTMULTIPLE, ADJACENTOrOr

DNs w/ INDISTINCT BORDERSDNs w/ INDISTINCT BORDERSMICROSCOPIC HCCsMICROSCOPIC HCCs




Two Variants ofTwo Variants ofEarly HCCEarly HCC

Early Hepatocellular Carcinoma

Vaguelynodular type

Distinctly nodular type

Diagnostic Re-capDiagnostic Re-cap& &

CasesCases

LGDN HGDN eHCC

Diffuse hemosiderosis X

Diffuse (or zonal) fatty change X

Angiogenesis (“unpaired arteries”) X

Scirrhous change X

Large cell change X

Features found in dysplastic nodules

LN LGDN HGDN eHCC

Diffuse hemosiderosis X rare rare

Diffuse (or zonal) fatty change X X X

Angiogenesis (“unpaired arteries”) X XX XXX

Scirrhous change X X X

Large cell change X X X


Case 1

43 year old woman with hepatitis C cirrhosis. Well defined, distinctive nodule measuring 1.9 cm in

explanted liver.

Case 6B, 2x, H&E

Case 6B, 10x, Trichrome

Case 6B, 10x, H&E

Case 6B, 10x, H&E

Case 1

Low grade dysplastic nodule

LGDN HGDN eHCC






Small cell change X X

Pseudoacinar growth X XX

Iron resistence in otherwise siderotic nodule X X

Mallory body clustering (with/without steatosis, PMNs) X X

Nodule-in-nodule expansile growth (with steatosis or other changes above)

X X


LGDN HGDN eHCC






Small cell change X X

Pseudoacinar growth X XX

Iron resistence in otherwise siderotic nodule X X

Mallory body clustering (with/without steatosis, PMNs) X X

Nodule-in-nodule expansile growth (with steatosis or other changes above)

X X

Stromal invasion X


Falkowski O, et alJ Hepatol 2003

Case 2

54 year old man with hepatitis C cirrhosis. Ill defined, 1.0 cm, distinctive nodule identified in

explanted liver.

Case 6A, 2x, H&E

Case 6A, 2x, H&E

Case 6A, 2x, H&E

Case 6A, 2x, H&E

Case 6A, 4x, H&E

Case 6A, 4x, H&E

Case 6A, 10x, H&E

Case 6A, 10x, H&E

Case 6A, 10x, H&E

Biliary cytokeratins (AE1/AE3)

Case 2

Hepatocellular carcinoma arising in high grade dysplastic nodule.

The Future…

Glypican-3?Immuno. distinguishesHCC from non-HCC

HCC HCC

HCC HCC

HGDN w/ HCC focus

CK19 in histologically “pure” HCC?CK19 positive by immunoindicates prognosisIntermediate between HCC and ChC

??

Health & Medicine

Hepatocarcinogenesis - Kuwait