Tumeurs bénignes du foie€¦ · Tumeurs bénignes du foie •Angiomes •Hyperplasies nodulaires...
Transcript of Tumeurs bénignes du foie€¦ · Tumeurs bénignes du foie •Angiomes •Hyperplasies nodulaires...
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Tumeurs bénignes du foie
• Angiomes• Hyperplasies nodulaires focales• Adénomes• Tumeurs rares• Pseudo-tumeurs (stéatoses focales,
perturbations hémodynamiques)
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Application à la (ponction-) biopsie
• HNF– critères
• disparition de l’architecture hépatique normale• présence de cloisons fibreuses• vaisseaux dystrophiques• néoductules et inflammation• remaniements sinusoïdaux
– proposition d’un score histologique
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Application à la (ponction-) biopsie
• HNF
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• Adénome– disparition de l’architecture hépatique
normale– pas de cloison fibreuse– travées épaisses formées de «grands»
hépatocytes éosinophiles ou stéatosiques– nombreuses artérioles
Application à la (ponction-) biopsie
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HNF: données nouvelles
• Physiopathologie– hypothèse vasculaire: données cliniques
• forme primitive: lésion malformative due à un hyperdébit artériel localisé
• tumeurs HNF-like: secondaires à des pathologies vasculaires
– hypothèse vasculaire: données moléculaires• anomalies d’expression des facteurs angiogéniques
(angiopoïétines 1 et 2)
– rapports avec les oestroprogestatifs
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•4% of all new cancer cases in the world
•Third most common cause of cancer-related deathamong men and the sixth among women
•85-90% = Hepatocellular carcinoma
Primary liver cancers
Nordenstedt Dig Liver Dis 2010
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Inheritedmetabolic diseases
Etiological Factors of Hepatocellular Carcinoma
HBV350 million
carriers
chronic hepatitis
HCV170 million
carriers
cirrhosis (90% of cases)
hepatocellular carcinoma
Aflatoxin B1Ethanol consumption
• ß-tyrosinemia• hemochromatosisa1-antitrysin deficiency
• glycogen storage disease• Wilson’s disease•PFIC2
othercarcinogens
Male genderDiabetesObesity
Metabolic syndrome
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Hepatocellular carcinoma
IN WESTERN COUNTRIES
90% of HCC on cirrhotic livers
Chronic liver disease 10% of HCC on non cirrhotic livers
Cirrhosis = pre-cancerous state with an annual incidence of 2- 5% for HCC
Normal liver
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Hepatocellular carcinoma: Gross aspect
Expansive uninodular Expansive multinodular
Mixed DiffuseSatellite nodules
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Diffuse cirrhosis-like HCC
Jakate Am J Surg Pathol 2010
Biopsy +
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Hepatocellular carcinomaClassical type
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Histological types of Hepatocellular Carcinoma (WHO)
Architecture•Trabecular•Pseudoglandular•Compact•Squirrhous
Cytology (variants)•Pleomorphic•Clear cells•Oncocytic•Sarcomatoid
Other aspects•Bile•Glycogen•Steatosis•Nuclear inclusions •Hyaline cytoplasmic globules•Mallory’s bodies•Pale bodies
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Hepatocellular Carcinoma: Architecture
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Hepatocellular Carcinoma: Cytological aspects
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Steatohepatitic hepatocellular carcinoma
Salomao Am J Surg Pathol 2010
22 steatohepatitic HCC (35.5%)/62 HCC on explant livers with HCV cirrhosis
SteatosisMallory bodies Inflammatory infiltratesPericellular or trabecular fibrosis
Risk factors for NALFD/NASH: 63.6%Steatosis/Steatohepatitis: 63.6% in the non neoplastic liver
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HCC ON CIRRHOTIC LIVERSMOST OFTEN AN EASY DIAGNOSIS
BY IMAGING TECHNIQUES
No need for an histological proof
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Diagnosis of HCC on cirrhotic livers:MOST OFTEN AN EASY DIAGNOSIS
Nodule on cirrhotic liver > 2cmDiagnosis of HCC by non invasive imaging and laboratorycriteria� Hypervascular arterial supply/portal wash-out� High serum AFP� Pathological confirmation is not mandatory. It could be
necessary if the imaging data are not typical
Nodule 1-2 cm
Nodule < 1cm
� One or two imaging techniques � If inconclusive : Biopsy
� Repeat US
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Hemorrhagic risk
Tumor cell seeding on biopsy track (2.7%) –biological glue
Usefulness of an associated biopsy in non tumor liver +++
Higher opportunity of immunostaining
Ultra-sound guided core biopsy – 16-18G
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Small Nodules resulting from screening on cirrhotic livers
« Macronodules » : detected by US screening
Macroregenerative nodules
Low grade dysplastic nodules
High grade dysplastic nodules
Small HCC ≤ 2 cm�Early HCC�Progressed HCC
International working party Hepatology 1995;22:983-993International Consensus Group for Hepatocellular Neoplasia Hepatology 2009
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Macronodule
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Hepatocellular carcinoma: Multistep carcinogenesis
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MACROGENERATIVE NODULESHyperplastic - Polyclonal - Benign
DYSPLASTIC NODULESLow grade High grade Well differentiated HCC
Thickness of liver cell platesExpansive growingPseudo-glands/ bileNuclear densitySmall cell dysplasiaNuclear atypiaIron load resistanceReticulin lossUnpaired artery density (actin) Sinusoid capillarization CD34
Macronodules on cirrhotic liver
Stromal invasion
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Risk of transformation of dysplastic nodule into HCC
� LGDN: 20%
� HGDN: 20 – 80%
Dysplastic nodules and Hepatocellular carcinoma
Nault Hepatology 2014
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Macroregenerative nodules
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Dysplastic nodule
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Normal
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CD34
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Low grade High grade Well differentiated
HCCPlate thickness 1 to 2 cells 2 to 3 cells > 3 cellsPseudoglands 0 0 ou + 0 ou +Nodule in the nodule 0 ou + + ou 0 + ou 0Portal tractsStromal invasion
+0
+ ou 00
0+
Reticulin + +/- -Unpaired arteries quelques + ++Atypia mild +, focal +Mitosis (1à 5/ 10 HPF) - rares variableDysplasia Large cell Large or small cell -Clonality Mono or poly Mono or poly mono
Dysplastic Nodules
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� Reticulin stainingDecreased framework in HCC
� ImmunostainingSMA (smooth muscle actin): unpaired arteriesCD34: sinusoid capillarization
Glypican3: Fetal oncoproteinHSP70: Heat shock proteinGlutamine synthetase: Glutamine synthesis
International Group recommendations:2 positive markers/3
Specificity 100% Sensitivity 60% for nodules of 0,5 to 2cm
Additional diagnostic tools
International Consensus Group for Hepatocellular Neoplasia Hepatology 2009
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MRN HCC
G3
HSP
GS
Tremosini Gut 2012Conventional histology
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Nodule > 2cm ÎImaging diagnosis (typical features on one imaging technique)If atypical features ÎGuided biopsy
Nodule < 1cm Î Repetition of imaging
Nodule 1cm to 2cm Î Imaging diagnosis (typical features on 2* imaging techniques)If not ÎGuided biopsy
MRN / Dysplastic nodule / HCC ?
Limits +++In the nodule?In the nodule within the nodule?Low sensitivity for the diagnosis of early HCC?
EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma 2012
Small Nodules resulting from screening on cirrhotic livers
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DIAGNOSIS OF HCC ON NON CIRRHOTIC LIVER
Pathological diagnosis of HCC is recommended for all nodules occurring in non-cirrhotic livers.
EASL–EORTC 2012
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Hepatocellular carcinoma on non cirrhotic liver
• 10 to 15% of HCC in Western countries• Large tumors
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Paradis Hepatology 2009
Metabolic syndrome and HCC
� Non cirrhotic liver 65%
� Larger tumors� Well differentiated HCC
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Differential diagnosis of hepatocellular tumor ( adenoma/ well differentiated HCC)
Fibrous variant of HCC: cholangiocarcinoma, metastasis?
Other rare differential diagnoses: metastasis of Neuroendocrine carcinoma, epithelioid angiomyolipoma
Hepatocellular carcinoma on non cirrhotic liver
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Cellular densityThickness of liver platesPseudoglandular structuresReticulin staining ++Cytonuclear atypia, Mitoses CD34 ??b-cateninGlypican 3
Clinical background +++Evolution
Hepatocellular carcinoma/ Adenoma
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HCC/ Adenoma
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B-catenin mutated adenoma
bb-catenin
Glutamine synthetase
Risk of transformation++
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Wang Arch Pathol Lab Med 2008
GLYPICAN 3
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• Abondant fibrous stroma• Differential diagnosis Immunohistochemistry
Hepatocellular carcinoma with fibrous stromaSclerosing HCC???
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CC KL1 + Vimentin +CK7, CK8, CK18,CK19 +CK20 - or + focalEMA +CEAp + apical or cytopl
Colorectal : CK7 -, CK20 +Pancreas/Stomach : CK7 +, CK 20+/-
Meta
Immunophenotype of liver tumors
HCC Hep Par 1 + 73%/ poorly ≠ 63%Glypican 3 76-79%/ poorly ≠ 89%AFP + 17% à 62%CEAp +canalicular 45% à 80%/ CD10CK8, CK18 +CK7*, CK19, CK20 -EMA -
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CEAp
Immunophenotype of HCC
CK19Hep-Par1 Glypican 3
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Epithelioid angiomyolipoma
Exclusive monophasic component : epithelioid cellsÕ perivascular cells PEC / PECOMA
HMB45
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Fibrolamellar carcinoma
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� Rare (<2% of HCC)� Yound adults and children� Non cirrhotic liver� Normal AFP level� Better prognosis?
Fibrolamellar carcinoma
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Fibrolamellar carcinoma
HepPar1+, CK8 et 18 + / CK7 +, EMA+
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PATHOLOGICAL PROGNOSTIC INDICATORS IN HCC
A résumer (et à regrouper resection/transplantation)
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Identification of pathological parameters with predictive efficiency (survival or recurrence)
from resection specimens
•Uninodular > multinodular > massive tumor •Tumor size • Capsule• Satellite nodules• Macrovascular invasion ++• Necrosis• Curative resection
Gross parameters
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•Edmonson grading*•Nuclear grade*•Mitotic index•Capsular invasion•Microvascular invasion*•Intratumoral inflammation•Activity and fibrosis in non tumoral liver
Histological parameters
Identification of pathological parameters with predictive efficiency (survival or recurrence)
from resection specimens
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Nuclear grade
Am J Surg Pathol 2002; 26: 25-34
425 curative resections
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Microvascular invasion
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WHOWell differentiatedModerately differentiatedPoorly differentiated
EDMONSONGrade I: Benign appearance - no or slight atypia -Adenoma? Dysplastic nodule? – Associated with higher grades
Grade II: Well differentiated – Trabecular or pseudoacinar architecture - Moderate atypia - Bile +
Grade III: Compact architecture - Marked atypia - Syncytial cells
Grade IV: Poorly differentiated - Marked atypia - Small cell or sarcomatoid features
Histological grading
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I II
III IV
Edmonson’s grading
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Post-chemoembolization changes
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Post-chemoembolization changes
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-High-throughput molecular studies: cDNA arrays, CGH arrays, microRNAs, proteome analysis
-Molecular classifications of HCC :Molecular signature with predictive efficiency IHC markers
-Characterization of signalisation pathways leading to new targeted therapies
The close future
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EpCAM
o Epithelial cell adhesion molecule CD326
o Tumor-associated calcium signal transducer 1 gene
o Liver: oAdult liver: bile ducts, ductulesoFetal liver: hepatoblasts
o HCC: 35% + for EpCAM
Schmelzer JEM 2007Yamashita Cancer Res 2008
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Bipotent progenitor cell of adult liver
hepatocytes
Portal tractAdult stem cell
Progenitor cell of adult liver
Ductular reaction
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EpCAM positive HCC
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Seok Hepatology 2012
The spectrum of liver cell tumors
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Cholangiolocellular carcinoma30 cholangiolocellular carcinoma
Komuta Hepatology 2008
-Progenitor cells= target of liver carcinogenesis
CK19+
CLC = phenotypic homology with ductular reaction( = non tumoral HPCs)
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Lineage of primary liver cancers
EMT
Komuta Hepatology 2008
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Classical HCC
Progenitor-like HCC
Cholangiocarcinoma
Primary tumors on cirrhotic livers
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Early HCCa/HCC of small size (≤ 2cm), well differentiated (G1), vaguely nodular
Progressed HCCa/HCC of small size (≤ 2cm), usually moderatelydifferentiated (G2), distinctly nodular type
HCC of not small size (>2cm) single or multiple
b/ HCC with stem/progenitor cell immunophenotype
c/ Mixed hepatobiliary carcinoma, classical type
d/Mixed hepatobiliary carcinomawith stem/progenitor cell phenotype and immunophenotype
PROPOSAL OF A NEW PATHOLOGICAL CLASSIFICATION
Roncalli Dig Liver Dis 2010
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Akiba Am J Surg Pathol 2013
Classification relying upon the major component >50%
Combined Hepatocellular-CholangiocarcinomasClassification WHO 2010
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Akiba Am J Surg Pathol 2013
� Two distinct components, hepatocellular carcinoma and cholangiocarcinoma
� Most often observed on chronic liver diseases (HCV, HBV, hemochromatosis)
HepPar1
CK19
Combined Hepatocellular-CholangiocarcinomasClassical type
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Akiba Am J Surg Pathol 2013
� Nests of mature hepatocytes
� Peripheral clusters of small stem/progenitor cellsCK7+ CK19+ CD56+ c-kit+ EpCAM+
� Fibrous stroma
� Rare
Combined Hepatocellular-CholangiocarcinomaWith Stem cell features – typical type
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Akiba Am J Surg Pathol 2013
� Cells intermediate betweenhepatocyte and cholangiocyte
� Strands, solids nests or trabeculae
� HepPar1+, AFP+, CK19+, c-kit+
� Minor components: HCC, CC,cholangiolocellular carcinoma
Combined Hepatocellular-CholangiocarcinomaWith Stem cell features – intermediate type
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Akiba Am J Surg Pathol 2013
� Small anastomozing glands with fibrous stroma
� Cuboidal cells
� Coexpression of biliary and progenitor cell markers
� CK19, cKit, NCAM, EpCAM
� Minor components: HCC, CC
Combined Hepatocellular-CholangiocarcinomaWith Stem cell features – cholangiolocellular type
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� Sorafenib
� Tivantinib: c-met receptor?
Targeted therapies in HCC?
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Conclusion
Cirrhotic liver:Diagnosis of small tumors (1 -2 cm)?Prognostic factors: Tumor differentiation
Vascular invasionStem/progenitor cell markers
New prognosis markers from molecular studiesA continuous spectrum of liver cell tumors
Non cirrhotic liver:Biopsy for differential diagnosis? New prognosis markers from molecular studies
New therapies?