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Gian Ludovico Rapaccini
Master di II livello in “Diagnostica Ecografica e Terapie Ecoguidate”
Corso SIGE-AISF
Test non invasivi in Gastroenterologia ed Epatologia
Roma, 22-24 settembre 2017
“Le nuove sfide nella diagnosi non invasiva dell’Epatocarcinoma“
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HCC ( HepatoCellular Carcinoma): EPIDEMIOLOGIA
Incidenza mondiale: più di 300.000 nuovi casi ogni anno(in Italia 10.000-15.000)
più frequente nei maschi picco di incidenza intorno ai 60 anni (nelle aree ad alta
incidenza terzo-quarto decennio di vita) Elevata incidenza: Africa subsahariana e Sud-Est
asiatico Moderata incidenza: Paesi mediterranei (Italia, Spagna,
Grecia, Nord-Africa) Bassa incidenza: Europa continentale, Nord-America
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Hepatocellular Carcinoma (HCC) incidence / 100.000 )
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EPATOCARCINOMA Il 70-80% degli HCC insorge su fegato cirrotico
(worldwide!!) L’incidenza annuale di HCC in Italia nei pazienti affetti da
cirrosi epatica si calcola tra il 3 e il 5.1% La cirrosi epatica è una “lesione” pre-neoplastica:
elevata attività rigenerativa conseguente alla necrosiepatocitaria e potenziale rischio di rimaneggiamentocasuale delle sequenze di DNA dei cromosomiepatocitari
HCV, HBV, alcool, malattie autoimmunitarie emetaboliche, fattori ambientali, cirrosi biliare primitiva edemocromatosi
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HCC : storia naturale
pre – US post – US
raro frequentediagnosi tardiva diagnosi precoce
sintomatico asintomaticobreve sopravvivenza lunga sopravvivenza
incurabile curabile
guaribile OLT !
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EPATOCARCINOMA Le linee guida AASLD raccomandano un programma di
sorveglianza nei pazienti a rischio ogni 6-(12) mesi cirrosi epatica da HBV e HCV, cirrosi alcolica, cirrosi biliare
primitiva, emocromatosi, epatopatia autoimmune, steatoepatitenon alcolica e deficit di alfa-1-antitripsina
Diagnosi precoce migliori risultati terapeutici Esecuzione periodica di un esame ecografico
convenzionale e il monitoraggio sericodell’alfafetoproteina
Management of HCC: An update. J Bruix and M Sherman 2010
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• HCC incidence: 1-6%/year• Known risk factors:
• Age > 60 yrs• Male sex • AFP > 10-20 ng/ml• HBV-HCV co-infection• Mixed etiology (HBV or HCV + alcohol)• Large cell dysplasia • High proliferating liver cell indexes (PCNA, AgNOR)• Child-Pugh B-C class
The screening is recommended in HBV- or HCV-related, alcoholic, hemocromatosic, and biliary
cirrhosis
Bruix J, Hepatology 2005
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0
0,5
1
1,5
2
2,5
3
3,5
4
1987-1991 1992-1996 1997-2001
cm
Mean diameter of HCC diagnosed by screening during three successive 5-year periods (417 cirrhotics)
3,7
2,2
3,0
Sangiovanni A, Gastroenterology 2004
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HCC: US La sensibilità dell’ecografia di identificare lesioni focali in
un fegato cirrotico dipende da numerosi fattori: la sede le dimensioni pattern ecografico del nodulo l’esperienza dell’operatore e l’apparecchiatura utilizzata le caratteristiche somatiche del paziente e sua compliance
respiratoria
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HCC: US maggiore difficoltà
nell’individuare lesioni localizzate nei segmenti epatici posteriori ed in sede sottodiaframmatica
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HCC: US La sensibilità dell’US
per HCC è influenzata dalle dimensioni della lesione < 1 cm 13-37%
< 2 cm 46-95 %
2-3 cm 82-93 %
> 3 cm > 95%
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HCC: US
Pattern ecografico influenza lasensibilità della metodicaMargini ben definiti, pattern ipoecogeno o
evidenza di alone ipoecogeno perifericoQuadro infiltrativo, pattern isoecogeno
Ecostruttura del parenchima epaticocircostante
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HCC:USSmall HCC: < 2 cm
Pattern ipoecogeno: 75% dei casi
Pattern iperecogeno: 17-22.5%
< 65 aa, cirrosi epatica HCV relata, bassi valori di AFP
Pattern isoecogeno: difficile individuazione
Pattern nodulo in nodulo e a mosaico
(presenza nel nodulo di differenti popolazioni cellulari)
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Pattern ipoecogeno
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Pattern iperecogeno
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Pattern isoecogeno
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Alone ipoecogeno periferico e coni d’ombra laterali (presenza di pseudocapsula)
Rinforzo distale degli echi (ricca vascolarizzazione endotumorale
HCC:US
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Pattern nodulo in nodulo
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• Small HCC < 2 cm: the hypoechoic pattern is the most common; the hyperechoic pattern is found in 17% of the cases and in 25% of the tumors diagnosed in patients younger than 65 years • The US pattern is not related to the tumor histological grading• The hyperechoic pattern seems to be related to AFP lower levels and to hepatitis C virus etiology of cirrhosis
( Rapaccini GL, Liver Int, 2004 )
Small HCC : echo-pattern
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HCC: USHCC > 2 cm pattern disomogeneo per la presenza di aree
ipoecogene alternate ad aree iperecogene e azone di colliquazione
Nelle forme infiltrative i margini della lesione sono irregolari e non differenziabili dal restante parenchima.
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EPATOCARCINOGENESI Nel fegato cirrotico il processo di
carcinogenesi epatica avviene attraverso unasequenza di eventi
Macronodulo rigenerativo, nodulo displasticoa basso grado, nodulo displastico ad altogrado ed epatocarcinoma stadio precoce(early HCC)
I noduli displastici (DN) devono essereconsiderati lesioni pre-neoplastiche
L’evoluzione neoplastica è più frequente neinoduli displastici ad alto grado
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HCC/DN Lesioni focali < 2 cm Lesione ipoecogenaPattern iperecogeno non
è infrequenteDD tra DN e piccolo HCC
: è possibile mediante latipizzazione istologicadella lesione
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HCC/DN Tipizzazione nodulo (dd tra DN e
HCC) Esame istologico necessario per la
corretta stadiazione Dimostrazione di foci displastici e
valutazione della severità della displasia
Dimostrazione di foci neoplastici Disponibilità di un frustolo ottenuto
dal parenchima cirrotico extranodulare
Pompili M, Gastroenterol Intern 1991
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Neoangiogenesis is essential to tumour growth
Folkman, Nature Rev Cancer 2002
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VEGF HGF MCP-1PlGF IGF HIF-1FGF Eritropoietin SDF-1alphaAngiopoietin-1 GM-CSFAngiopoietin-2Angiogenin
Angiogenic Factors
Blood vessel
Endothelial cells
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DN: VASCULARIZATION• Dysplastic nodule contains
multiple portal elements and produces almost the same volume of portal flow and arterial flow as does the sorrounding parenchyma of cirrhotic livers.
Koito K, AJR 1998
• HCC seems to have a dominant arterial blood supply compared with DN. Doppler sonography revealed arterial pulsating flow in HCC, but not in DN
Arterial vessels
Portal vessels
DYSPLASTIC NODULE
HEPATOCELLULAR CARCINOMA
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Early arterial phase Vascular mapping
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Introduction ( Sonovue ®, Bracco, Italy )
The microbubbles are flexible, endowed with outstanding stability and resistance to pressure. Their nonlinear
oscillation results in harmonic frequencies with low-mechanical-
index (<0.09).
New US equipment is tuned to the signal generated by the bubble vibration,
which is greater in amplitude than that
generated by tissues.Serra C. Eur Radiol 2007
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HCC : dinamic behaviour at contrast enhanced imaging techniques
Arterial phase hyper (-echoic, -intense )
Portal phase iso ( -echoic, -intense )
Late phase hypo ( -echoic, -intense )
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HCC: CEUS L’ecografia con mdc (CEUS) è in grado di evidenziare il
comportamento contrastografico tipico dell’HCC con buona concordanza con le altre tecniche di imaging,la TC e la RMN con mdc; in tal modo consente una migliore caratterizzazione delle lesioni focali insorte in fegato cirrotico. Alla CEUS il nodulo di HCC presenta enhancement in fase arteriosa con wash out in fase portale e tardiva
Bolondi L, Hepatology 2005; Giorgio A, AJR 2004 Pompili M, Liver Int 2005;Gaiani S, J Hepatol 2004
La sensibilità dell’ecografia con contrasto è del 97% per le lesioni>3 cm; 92% per le lesioni tra 2 e 3 cm, 87% per le lesioni tra 1 e 2 cm, del 67% per le lesioni inferiori al cm.
Gaiani S., J Hepatol 2004
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HCCFASE ARTERIOSA
Enhancement omogeneo o disomogeneo in presenza di aree di necrosi
FASE PORTALE
Isointensità rispetto al fegato
Rapido wash-out con ipointensità rispetto al fegato circostante
FASE TARDIVA
Completo wash-out con ipointensità rispetto al fegato circostante
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10/20 - 25/35 sec 30/45 - 120 sec 120 - 360 sec
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FLL
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CURATIVE TREATMENTS FOR HCC
Liver transplantation Liver resection
Ablation treatmentsPercutaneous ethanol injection (PEI)
Radiofrequency ablation (RFA)
Laser therapy
Microwave
Cryotherapy
Transarterial chemoembolization (TACE)
Systemic treatments for advanced HCC : Sorafenib, TARE
Bruix J et al, J Hepatol 2001, Hepatology 2005, 2010
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All the ablative procedures cause the same pathological changes of the targeted HCC
Coagulative necrosis
Cell apoptosis
Granulation tissue
Disruption of tumor vascularity
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• 56 hypervascular HCC nodules (range 1,0 – 7,5 cm) in 47 patients treated by PEI, RFA, TACE or combined treatment
• Efficacy evaluation at 4 weeks from treatment completion blindly assessed by multiphasic CT and CEUS with SF6 (Sonovue) as contrast agent
• Complete necrosis diagnosed if no intralesional enhancement could be demonstrated during the arterial phase of the imaging studies
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PARTIAL NECROSIS ON HELICAL CT: 26 HCCs
CEUS AGREEMENT: 23/26
TOTAL NECROSIS ON HELICAL CT: 30 HCCs
CEUS AGREEMENT: 30/30
Pompili M, Liver Int 2005
• Helical CT – CEUS overall agreement: 53/56 (95%)
• In the detection of post-ablation persistence of HCC viability CEUS showed sensitivity of 87% and specificity of 98% (no false positive cases)
• CEUS was very promising in the efficacy evaluation of ablation treatment for HCC. Nodules still vascularized in the arterial phase should be considered still viable and addressed to additional treatment without further assessment
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TOTAL NECROSIS (patient treated by TACE)
CEUS Arterial phase
Basal Helical CT
Helical CT Arterial phase
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PARTIAL NECROSIS (pt treated with multisession PEI)
Helical CT Arterial phase
US with CE
CEUS Arterial phase
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Post RF
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Post TACE
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EARLY PREDICTION OF RESPONSE TO SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR
CARCINOMA:THE ROLE OF DYNAMIC CONTRAST ENHANCED
ULTRASOUND
Zocco MA, Lupascu A, Di Stasio E, Ainora ME, Garcovich M, Roccarina D, Annicchiarico BE, Caracciolo
G, Ponziani F, D’Aversa F, Tortora A, Riccardi L, Siciliano M, Rapaccini GL, Pompili M, Gasbarrini A
Internal Medicine and GastroenterologyCatholic University of Sacred Heart, Rome (Italy)
J Hepatol, 59, 1014-1021, 2013
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Asia-Pacific Study Phase III Results
OVERALL SURVIVAL (OS)Sorafenib: 6.5 months (95% Cl: 5.6-7.6)Placebo: 4.2 months (95% Cl: 3.7-5.5)
TIME TO PROGRESSION (TTP)Sorafenib: 2.8 months (95% Cl: 2.6-3.6) Placebo: 1.4 months (95% Cl: 1.3-1.5)
Cheng AL et al. Lancet Oncol 2009; 10: 25–34
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Contrast Enhanced UltraSound- Analysis and placement of ROIs -
Wash-in
Wash-out
Time
AUC
TP
t0
PI
Con
tras
t Int
ensi
ty (d
B)
PI (peak intensity) in AU TP (time to peak intensity) in sec AUC (area under the curve) in AU TP (slope coefficient of wash-in) in AU/sec MTT (mean transit time) in sec
Perfusion parameters extracted from time-intensity curves
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Results- Contrast-uptake time intensity curves -
Clinical example of RESPONDER
Increase in tumor necrosis with drastic reduction in tumor perfusion
Baseline
After 15 days
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Results- Contrast-uptake time intensity curves -
Clinical example of RESPONDER
Reduced maximum enhancement with lower area under the enhancement curve early after treatment (T1)
T0
T2
T1
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Results- Contrast-uptake time intensity curves -
Clinical example of non-RESPONDER
Persistance of intralesional flow signals with no significant changes in contrast enhancement
BaselineBaseline
After 15 days
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Results- Contrast-uptake time intensity curves -
Clinical example of non-RESPONDER
No significant differences in perfusion parameters among different time points
T0
T2
T1
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Results- D-CEUS parameters and overall survival-
Kaplan Meier survival distribution according to the AUC percentage variation during Sorafenib treatment: association between early decrease in AUC
and overall survival
p=0.045
AUC ≤ 10%
AUC > 10%
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Thank you very much for your kind attention…