View
645
Download
0
Category
Tags:
Preview:
Citation preview
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,
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,texture,
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,texture,
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,texture,or degree of bulging from the cut surface
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
size,color,texture,or degree of bulging from the cut surface
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
color,size,texture,or degree of bulging from the cut surface AND contain portal tracts (….?)
Dysplastic nodules are defined as:Distinctive nodules which differ from the surrounding parenchyma in terms of:
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
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
DN predictions based on our alternate DN predictions based on our alternate hypothesis:hypothesis:
1.1. Diminished proliferationDiminished proliferation
2.2. Diminished HSC activationDiminished HSC activation
Park YN et al, Liver 1997
DN predictions based on our alternate DN predictions based on our alternate hypothesis:hypothesis:
1.1. Diminished proliferationDiminished proliferation
2.2. Diminished HSC activationDiminished HSC activation
DN predictions based on our alternate DN predictions based on our alternate hypothesis:hypothesis:
1.1. Diminished proliferationDiminished proliferation
2.2. Diminished HSC activationDiminished HSC activation
3.3. Diminished apoptosisDiminished apoptosis
DN predictions based on our alternate DN predictions based on our alternate hypothesis:hypothesis:
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
SPREADINGSPREADINGMONOCLONALMONOCLONAL
PROLIFERATIONPROLIFERATION
NODULE-IN-NODULENODULE-IN-NODULELESIONLESION
CLONALCLONALDYSPLASTIC NODULEDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED DIMINISHED HSC ACTIVATIONHSC ACTIVATION
SPREADINGSPREADINGMONOCLONALMONOCLONAL
PROLIFERATIONPROLIFERATION
MATUREHEPATOCELLULAR
CARCINOMA
MATUREHEPATOCELLULAR
CARCINOMA
NODULE-IN-NODULENODULE-IN-NODULELESIONLESION
CLONALCLONALDYSPLASTIC NODULEDYSPLASTIC NODULE
DEVELOPING CIRRHOSIS
DIMINISHED DIMINISHED HSC ACTIVATIONHSC ACTIVATION
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
SPREADINGSPREADINGMONOCLONALMONOCLONAL
PROLIFERATIONPROLIFERATION
MATUREHEPATOCELLULAR
CARCINOMA
MATUREHEPATOCELLULAR
CARCINOMA
NODULE-IN-NODULENODULE-IN-NODULELESIONLESION
CLONALCLONALDYSPLASTIC NODULEDYSPLASTIC NODULE
ADJACENT CLONAL ADJACENT CLONAL CIRRHOTIC NODULESCIRRHOTIC NODULES
DEVELOPING CIRRHOSIS
DIMINISHED DIMINISHED HSC ACTIVATIONHSC ACTIVATION
NL or INCREASED NL or INCREASED HSC ACTIVATIONHSC ACTIVATION
SPREADINGSPREADINGMONOCLONALMONOCLONAL
PROLIFERATIONPROLIFERATION
MATUREHEPATOCELLULAR
CARCINOMA
MATUREHEPATOCELLULAR
CARCINOMA
NODULE-IN-NODULENODULE-IN-NODULELESIONLESION
CLONALCLONALDYSPLASTIC NODULEDYSPLASTIC NODULE
ADJACENT CLONAL ADJACENT CLONAL CIRRHOTIC NODULESCIRRHOTIC NODULES
DEVELOPING CIRRHOSIS
DIMINISHED DIMINISHED HSC ACTIVATIONHSC ACTIVATION
NL or INCREASED NL or INCREASED HSC ACTIVATIONHSC ACTIVATION
MULTIPLE, ADJACENTMULTIPLE, ADJACENTOrOr
DNs w/ INDISTINCT BORDERSDNs w/ INDISTINCT BORDERSMICROSCOPIC HCCsMICROSCOPIC HCCs
SPREADINGSPREADINGMONOCLONALMONOCLONAL
PROLIFERATIONPROLIFERATION
MATUREHEPATOCELLULAR
CARCINOMA
MATUREHEPATOCELLULAR
CARCINOMA
NODULE-IN-NODULENODULE-IN-NODULELESIONSLESIONS
CLONALCLONALDYSPLASTIC NODULEDYSPLASTIC NODULE
ADJACENT CLONAL ADJACENT CLONAL CIRRHOTIC NODULESCIRRHOTIC NODULES
MULTIPLE, ADJACENTMULTIPLE, ADJACENTOrOr
DNs w/ INDISTINCT BORDERSDNs w/ INDISTINCT BORDERSMICROSCOPIC HCCsMICROSCOPIC HCCs
DEVELOPING CIRRHOSIS
DIMINISHED DIMINISHED HSC ACTIVATIONHSC ACTIVATION
NL or INCREASED NL or INCREASED HSC ACTIVATIONHSC ACTIVATION
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
Features found in dysplastic nodules
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
Diffuse hemosiderosis X rare rare
Diffuse (or zonal) fatty change X
Angiogenesis (“unpaired arteries”) X XX XXX
Scirrhous change X X X
Large cell change X X X
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
Features found in dysplastic nodules
LGDN HGDN eHCC
Diffuse hemosiderosis X rare rare
Diffuse (or zonal) fatty change X
Angiogenesis (“unpaired arteries”) X XX XXX
Scirrhous change X X X
Large cell change X X X
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
Features found in dysplastic nodules
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
??
Recommended