I°Corso AIGO in Epatologia

La cirrosi virale: prevenzione e terapia.La cirrosi virale: prevenzione e terapia.

EpatocarcinomaEpatocarcinoma: algoritmo diagnostico: algoritmo diagnostico

F.FarinatiF.FarinatiGastroenterologiaGastroenterologia, Padova, Padova

Gestione dell’HCC: i problemi

1. Sorveglianza? E come?1. Sorveglianza? E come?2. Prevenzione: si o no?2. Prevenzione: si o no?

3. 3. Radiologia o biopsia?Radiologia o biopsia?44. . StagingStaging : : sTCsTC, RMN o , RMN o lipiodollipiodol --TACTAC oo……....5. Resezione, trapianto o trattamento 5. Resezione, trapianto o trattamento

locoregionalelocoregionale ??6. RFA o PEI ?6. RFA o PEI ?7. La Tace 7. La Tace èè utile ?utile ?8. 8. TamoxifeneTamoxifene , , megestrolomegestrolo ,,

octreotideoctreotide , , ……..?..?

Biopsia. Si o no ?

EASL AISF GENE*

All lesions < 2 cm

Se sCT, RMN, US ed AFP

dubbi

Sempre 50%

All doubtful cases

sTC dubbia 18%

For molecular profile and risk

In caso di ter. aggressive 32%

* GRUPPO collaborativo EPATOCARCINOMA NORD-EST

Surveillance and recall strategy for HCC

> 1cm Normal AFPIncreased AFP**

Spiral CTUS/3m

< 1cm

Surveillance US+AFP/6m

AFP > 400 ng/mLCT-MRI-Angiography

FNAB

No HCC

* Available for curative treatments if diagnosed with HCC ** AFP levels to be defined

*** Pathological confirmation or non-invasive criteria

HCC***

< 2cm > 2cm

No noduleLiver nodule

Cirrhotic patients * US+AFP/6m

Bruix et al. J Hepatol 2001

HCC: vascolarizzazione arteriosa

F.P. ???F.N.???

In calo con le nuove tecnologieMacchina-dipendenti !!!Operatore-dipendenti !!!

AlfaFetoproteinaAlfaFetoproteina nellnell’’HCCHCC

0

10

20

30

40

50

<20 ng 20-200 201-400 >401

AFP ng/ml

Distribuzione di 1158 pazienti con HCC per classi di AFPDistribuzione di 1158 pazienti con HCC per classi di AFP

Italica

%

aFPaFP nellnell’’HCCHCC

0

20

40

60

< 2 cm 2-3 cm 3-5 cm >5 cm

AFP >400 ng/ml

Distribuzione di 1158 pazienti per classe di Distribuzione di 1158 pazienti per classe di ChildChild--PughPughe dimensioni del nodulo principalee dimensioni del nodulo principale(risultati (risultati validativalidati in serie interne)in serie interne)

0

20

40

60

1 nodulo 2-3 noduli >3 noduli diffuso massivo

AFP >400 ng/ml

p<0,0001p<0,0001 p<0,0001p<0,0001

%

aFPaFP e sopravvivenza nelle sopravvivenza nell’’HCCHCC

0 30 60 90 1200,00

0,25

0,50

0,75

1,00

Survivor

Times

1

2

3

4

Pazienti non trattati (p<0,0001)

dd

0 50 100 1500,00

0,25

0,50

0,75

1,00

Survivor

Times

1

2

3

4

Pazienti sottoposti a trattamento p <(0,0001)

AFP MEDIANA0-20 ng/ml 12 mesi21-200 ng/ml 13 mesi201-400 ng/ml 10 mesi> 400 ng/ml 5 mesi

AFP MEDIANA 0-20 ng/ml 33 mesi 21-200 ng/ml 26 mesi 201-400 ng/ml 20 mesi > 400 ng/ml 9,2 mesi

Seeding ???

Seeding and biopsy

The risk of seeding appears limited according to the currentl y availableepidemiological data; this should be considered. The be st accuracyin the sampling of hepatocellular carcinoma nodules is o btained bycombining smear cytology and microhistology…… .Seeding………… against the risk of false-positive diagnosis of malignancy based on imaging studies alone.

GUT 2004

Fine-needle biopsy in focal liver lesions: the usefulness of a screening programme and

the role of cytology and microhistology.

When both cytological and microhistological examinations were performed, the positive correlation between the two techniques was 80%, with a slightlyhigher sensitivity for microhistology (93%)

Ital J Gastroenterol. 1995

HCC diagnosis and staging in the 2000s

��Tumor Tumor yesyes //notnot��Tumor Tumor burdenburden��LiverLiver functionfunction��Tumor Tumor biologybiology ??????

New staging systems for HCC: any role for tumor biology ?

0

20

40

60

80

100

12 24 36 48 60

p53 - p53 < 10 p53 > 10

p53 overexpression

Months

%

JIM, 2004

New staging systems for HCC: any role for tumor biology ?

�� CoxCox multiple multiple regressionregression analysisanalysisTNMTNMOkudaOkudaChildChildCD44CD44MIB1 (Ki67)MIB1 (Ki67)GradingGrading

�� p53 single p53 single independentindependent predictorpredictor of of survivalsurvival (p=0.0048)(p=0.0048)

New staging systems for HCC: any role for tumor biology ?

Parameters n Overall survival rates %

1-year 3-year 5-year

P53 expres. - 110 88.8 66.3 60.6

+ 86 83.5 57.3 42.9

++ 13 60.0 46.7

+++ 13 38.5 12.3

Qin LX, W.J.Gastroenterol. 2002

New staging systems for HCC: any role for tumor biology ?

0

20

40

60

80

100

12 24 36 48 60

G1 G2 G3

Grading

Months

%

JIM, 2004

��VascularVascular invasioninvasion and grading and grading determinedetermine outcomeoutcome after after OLTxOLTx forforHCC HCC ……((NeuhausNeuhaus, , HepatologyHepatology2001)2001)

��OLTxOLTx forfor the treatment of the treatment of moderatelymoderately or or wellwell differentiateddifferentiatedHCCHCC…… ((CilloCillo, , AnnAnn SurgerySurgery, 2004), 2004)

Tumor grading ?

Gestione dell’HCC: i problemi1. Sorveglianza? E come?1. Sorveglianza? E come?2. Prevenzione: si o no?2. Prevenzione: si o no?3. 3. Quando Quando biopsiarebiopsiare ..

4. 4. StagingStaging : : sTCsTC, RMN o , RMN o lipiodollipiodol --TACTACoo…….., come esprimerlo?.., come esprimerlo?

5. Resezione, 5. Resezione, OLTxOLTx , , locoregionalelocoregionale ??6. RFA o PEI ?6. RFA o PEI ?7. La Tace 7. La Tace èè utile ?utile ?8. 8. TamoxifeneTamoxifene , , megestrolomegestrolo ,,

octreotideoctreotide , , ……..?..?

Staging

EASL AISF GENEUS + sCT sCT

RMN dinamica(contr.paramagn)

sCT/dRMN 32%Solo sCT 50%

Dynamic MRI>< sCT

USdoppler/colorD

power D/levovist

13% lipiodol CT

No angiography or lipiodol-CT

No angiografia,arterioTC,portoTC

or lipiodol-CT

5% laparoscopia

Classificazione di Barcellona (BCLC)

IPerformance status

Liver Transplantation (CLT / LDLT)

Symptomatic treatment

Okuda 3, PS >2, Child-Pugh C

Terminal stage (D)

Okuda 1-2, PS 0-2, Child-Pugh A-BSTAGES A - C STAGE D

Normal

Locoreg

Curative Treatments50% - 75% at 5 years

Single 3 nodules <3cm

Portal pressure/ bilirubinAssociated

diseasesIncreased

No Yes

Early stage ( A)Single or 3 nodules < 3cm, PS 0

Intermediate stage (B)Multinodular, PS 0

Chemoemb.New

Agents

Advanced stage (C)Extrahep. HCC, PS 1-2

Extrahepatic disease

No Yes

Randomized controlled trials40% - 50% at 3 yr vs 10% at 3yr

Resection PEI/RF

HCC

BCLC Staging and Treatment Strategy

Semin Liver Dis 1999, Hepatology 2002

Survival in untreated HCC

patients

Llovet, Lancet 2003

Life expectancy in untreated earlyHCC

Llovet, Lancet 2003

Intermediate stage HCC ?

14%14%28%28%47%47%J.I.MJ.I.MITALICAITALICA

17%17%27%27%63%63%BCLC IIBCLC II

50%50%65%65%80%80%BCLC IBCLC I

III III yearyearsurvivalsurvival

II II yearyearsurvivalsurvival

I I yearyear

survivalsurvival

CLIP scoring systemScore

Variable 0 1 2

Child-Pugh A B C

Tumormorphology

Uninodular< 50%

Multinodular< 50%

Massive or> 50%

AFP (ng/dL) < 400 ng/dL > 400 ng/dL

Portalthrombosis

No Yes

Add each individual value, score 0 to 6

CLIP score: a new prognostic system

Median Range

CLIP 0 43 37-48 CLIP 1 32 25 – 38 CLIP 2 17 14 - 19 CLIP 3 5 4 – 5 CLIP 4 3 1.5 – 4

CLIP 5-6 1 1 – 1

CLIP group, Hepatology 1998

Survival curves by CLIP staging

0

20

40

60

80

100

12 24 36 48 60

CLIP O CLIP I CLIP 2CLIP 3 CLIP 4 CLIP 5

Farinati, Cancer, 2000

Months

%

BCLC o CLIP?

++--20052005GUTGUTTateishiTateishi

====20032003EJGHEJGHRabeRabe

--++20042004J.HepatJ.HepatCilloCillo

====20042004JIMJIMGianniniGiannini

====20042004DMWDMWCaselitzCaselitz

--++20052005GUTGUTGriecoGrieco

CLIPCLIPBCLCBCLCYearYearJournalJournalAuthorAuthor

TNM forOLTxPTS TNM

15 I

19 II

11 IIIa

13 IVa

2 recurrences, 1 in stage I end1 in stage 3a

Llovet, Hepatology 1998

1)bilobarity2) size of the greatest tumor (2 to 5 cm and > 5 cm)3) vascular invasion(micro/macroscopic). Prognostic risk score (PRS) was calculated

from the relative risks of multivariateanalysis.

Tumor recurrence risk:

grade 1: PRS = 0 to < 7.5;

grade 2: PRS = 7.5 to < or = 11.0;

grade 3: PRS > 11.0 to 15.0;

grade 4: PRS > or = 15.0; and

grade 5: positive node, metastasis, or margin.

Iwatsuki, J.Am.Coll.Surg, 2000

Staging

New staging systems for HCC

�� GroupeGroupe EtudeEtude et et TraitmentTraitment CarcinomeCarcinomeHepatocellulaireHepatocellulaire ::

KarnovskyKarnovsky

BilirubinBilirubinAlkalineAlkaline phosphatasephosphatase 3 3 riskrisk --groupsgroupsAFPAFPPortalPortal thrombosisthrombosis

J. Hepatol, 1999

New staging systems for HCC: the surgical patients

Stage DescriptionStage 1 Single, no vascular invasion

Stage 2 Solitary or multiple,segmental portal thrombosis

Stage 3 Major vessel involved,LN +

Stage 4 Distant metastasis

Izumi, Gastroenterology, 1994Staudacher, Tumori, 2000 ?

Gestione dell’HCC: i problemi

1. Sorveglianza? E come?1. Sorveglianza? E come?2. Prevenzione: si o no?2. Prevenzione: si o no?

3. 3. Quando Quando biopsiarebiopsiare ? Sempre (?)? Sempre (?)4. 4. StagingStaging : : sTCsTC, RMN , RMN CLIP e/o BCLCCLIP e/o BCLC5. Resezione, trapianto o trattamento 5. Resezione, trapianto o trattamento

locoregionalelocoregionale ??6. RFA o PEI ?6. RFA o PEI ?7. La Tace 7. La Tace èè utile ?utile ?8. 8. TamoxifeneTamoxifene , , megestrolomegestrolo ,,

octreotideoctreotide , , ……..?..?

Surveillance and recall strategy for HCC

> 1cm Normal AFPIncreased AFP**

Spiral CTUS/3m

< 1cm

Surveillance US+AFP/6m

AFP > 400 ng/mLCT-MRI-Angiography

FNAB

No HCC

* Available for curative treatments if diagnosed with HCC ** AFP levels to be defined

*** Pathological confirmation or non-invasive criteria

HCC***

< 2cm > 2cm

No noduleLiver nodule

Cirrhotic patients * US+AFP/6m

Bruix et al. J Hepatol 2001

Surveillance and recall strategy for HCC

Any size, any aFP

Treatable Normal AFPIncreased AFP**

Spiral CTCT scan

Large size, untreatable, aFP> 400

Surveillance US+AFP/6m

CT-MRI

FNAB

TREATMENT

Contra for FNAB

No noduleLiver nodule

Cirrhotic patients * US+AFP/6m

Modified from Bruix et al. J Hepatol 2001

HCC

STOP

What about tomorrow ?

Diagnosi-staging-(trattamento)

HCC diagnosis and staging in the 2000s

��Tumor Tumor burdenburden��LiverLiver functionfunction��Tumor Tumor biologybiology

www.gastropadova.itwww.hcc-infohelp.org