Malignant Tumors of the Liver
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Transcript of Malignant Tumors of the Liver
Malignant Tumors of the Liver
Hepatocellular Carcinoma (HCC)
Dr. Izhar Levy
Liver Unit/Hadassah Ein-Kerem
Primary Malignant Tumors of the Liver
Hepatocellulr Origin• Hepatocellular carcinoma (HCC) • Common cause of death in cirrhotic patients
Bile duct origin• Cholangiocarcinoma
Mesenchymal origin• Hemangiosarcoma
HCC - Pathogenesis
• HCC develop in cirrhotic liver• (>90% of cases) rarely within normal liver
• Pathogenesis: Multifactorial • Fibrosis/Ischemia/Chronic inflammation
Mature HepatocyteTelomerase shortening DNA damage
New clones neu – vascularization
HCC
IschemiaOxidative stressProliferative cytokines
Similar scenario?
HCC - Epidemiology
• HCC is the most common malignancy in East Asia and Sub-Saharan Africa and the 5th common malignancy worldwide- 600,000/y
• The incidence of HCC in different countries correlate with the geographic distribution of chronic liver disease mainly - viral hepatitis
• China - Shanghai 60/105/y , Israel 3/105/y
HCC- Epidemiology
• HCC incidence in cirrhotic patients 2% /year.• Colombo M et al, NEJM 1991 325, 675-680
• BRCA positive • 1%/y
• Lung cancer – heavy smoker >age 50
• 1%/y
• 200 new HCC cases/year in Israel, most of them with pre-existing liver cirrhosis
HCC- Prognostic factors
Most HCC patients has also liver cirrhosis • Two diseases in one person:
Liver Cirrhosis and Liver Tumor Prognostic tumor factors:
Tumor number Tumor sizeAFPVascular invasion(portal vein thrombosis)
Prognostic liver factorsChild-Pugh score:Albumin , Bili, INR Ascites , Encephalopathy
MELD: Bili, INR, Creat
HCC- Natural history - prognosis
• Advance and symptomatic tumor -poor prognosisMedian survival : several weeks to 3 months
• Wolf D & Shouval D 1984
• Asymptomatic HCC Child – Pugh A • Without treatment- : • 3 year survival – 102 patients - no treatment - 50% Llovet et al Hepatology 1999:1:62-67
• 2 year survival – 25 patients- no treatment - 50 % Cotton et al. Gastroenterology 1989:96:1566-71
HCC screening & surveillance
Case for screening & surveillance 1- Very high incidence in the target
population – Liver Cirrhosis 2- Poor prognosis in Advance stage 3- Curative treatments in early disease 4- Low cost for screening & survaillance
HCC - Screening
Goal of screening:
Early diagnosis of small tumor– Curative treatment
Early diagnosis:• Transplantation• Resection or RFA 5 year survival 50-60 %
Late diagnosis • Clinical symptoms 2 year survival 0%
10 year survival 50-70% } Early diagnosis
HCC - Screening
Screening for HCC is recommended in cirrhotic patients
US of the liver is the screening tool. It is performed every 6 months in cirrhotic patients
HCC- Screening
Alpha-Feto-Protein (AFP) rise in: Pregnancy , Embryonic tumors (testis) , Cirhhosis (10-20%) and HCC
• Early HCC (20-30%)• Advance HCC (70-80%)
AFP is used combined with US.
.
HCC- Diagnosis
• Tumor biopsy is unnecessary in 70-80% of cases
• HCC within the normal liver – without liver disease tumor biopsy is necessary (<10% of the cases)
• HCC within the cirrhotic liver (>90% of the cases) :• Hypervascular tumor• Elevated AFP• Different appearance from benign tumors and MET’s
HCC- Diagnosis
• HCC within: cirrhosis /advance fibrosis• clinical –radiological diagnosis
• Liver mass
AFP>400ng/ml Biopsy unnecessary
• Live mass , Typical Hyper vascular , cirrhotic liver AFP - normal Biopsy unnecessary
• Liver mass – Atypical hypo-vascular
AFP- normal Biopsy necessary
HCC- Diagnosis
HCC in cirrhosis /advance fibrosis clinical –radiological diagnosis
Different appearance from benign tumors and MET’s
Accuracy of clinical/radiological diagnosis is 95-97%Equal or better then pathological diagnosisMinimize the risk of tumor biopsy – bleeding & tumor seeding
HCC- clinical manifestation
• Asymptomatic in early HCC• RUQ pain: most common and non specific symptom
• Systemic manifestations:• weakness, weight loss, fever, ascites
• Systemic symptoms are poor prognostic signs
HCC- Treatment
Systemic chemotherapy – no benefit • Most patient are cirrhotic • Hepatic decompensation , Infections, etc’
More than 40 RCT in the last 30 years failed to show any benefit of systemic chemotherapy
HCC- Treatment
Liver Resection - not option 90% of patients: • nonresectable
• inoperable
Systemic Chemotherapy • Not effective , limited due to cirrhosis
There were no treatment for HCC until mid 1980’s Median survival was 3 months
HCC- Treatment
Since early 1990’s US Screening programs Mid 1990’s Dynamic imaging: CT (later on
MRI) Early diagnosis Small and single tumors Curative and palliative Tx for HCC
HCC- Treatment
Tumor resection - treatment of choice
Liver Cirrhosis and liver Tumor
• Most patients (90%) has either :• non-resectable tumor• or advance cirrhosis - inoperable patients
HCC-Treatment
Loco-regional treatments: “Killing methods”:
• Alcohol ablation - 90% cure - single lesion <2cm
• Radiofrequency ablation - 90% cure- lesion <4cm
• TACE: Transe Arterial Chemo Embolaization
HCC – RFA- Radio frequency ablation Child A cirrhosis
60 yr femaleAFP elevated
Pre RFA 1 month post RFA
HCC - treatments
Loco-regional treatments TACE : Trans Arterial Chemo Embolization
• Improve survival (Llovet et al, lancet 2002, 359 :1734-9)
• Choice for non resctable and not eligible for Alcohol /RFA
• Arterial catheterization - Targeted chemotherapy• Embolization of tumoral artery (temporary)
HCC- Treatment
RFA - Treatment of choice for • Single HCC < 5 Cm’
• Cure rate of single tumor ≤2cm’ 216 Pt’ - 97%• Livraghi T et al Hepatology. 2008 Jan;47(1):82-9.
TACE - Treatment of choice for • Mmultifocal and large HCC
TACE and RFA – Combined treatment
- common practice
HCC- Recurrence
• The cirrhotic liver, once develops an HCC focus, is the fertile ground for the next HCC focus.
• 15-20% risk of new HCC/Year
• HCC recurrence rate after resection or RFA :• 70-80% in 5 years • >90% in 7 years
HCC- Recurrence
Liver resection recurrence in cirrhotic patients
• 15 - 20% / year 5 year- disease free survival for small HCC
• <10-15%
Liver Transplantation (OLT or LRLT) 5 year – disease free survival for small HCC
• 60-70%
HCC – Liver Transplantation
• Orthotopic Liver transplantation (OLT) is currently the only treatment that offer cure for both liver cirrhosis and HCC
• OLT is not performed• Large and multifocal tumor- recurrence rate > 50%• Age >67 due to organ shortage and old age
• 10% - are eligible for OLT
HCC- Liver Transplantation
• International criteria for liver transplantation• “Milan criteria” *
• Single tumor <5cm or 3 nodules <3 cm’
• 5 year disease free survival (DFS) 70%. • Recurrence rate 5-10% at 5 years
* N Engl J Med. 1996 Mar 14;334(11):693-9.
HCC- Liver Transplantation
limitations:• lack of organs• Cost • Only small tumors are candidate for OLT ,
advanced tumors has very high recurrence rate and are not eligible for OLT.
HCC - Treatment
Liver transplantation ~ 5-10% Liver resection ~ 5-10% Loco-regional treatments ~ 30-40%
• No treatment - 50% of patients• Multifocal or diffuse tumor , • Vascular invasion, metastasis• Advance cirrhosis
• Sorafenib - Nexavar
Treatment of advance HCCMolecular target therapy
Sorafenib : TK and multikinase inhibitor and anti-angiogenic, and Raf kinase inhibitory activity
Improve survival in advance HCC• Prolonged median survival from 7 to 10 months
Approved for child-A advance HCC patients who are not eligible for any other therapy.
N Engl J Med. 2008 Jul 24;359(4):378-90.
Cautious with side effects: weakness , diarrhea, rash
HCC - Summary
HCC incidence in cirrhotic patients 2-3% /y
Screening and early diagnosis is mandatory for early diagnosis and curative treatments
Diagnosis – Biopsy unnecessary in 70-80% of cases
Prognostic Factors : Liver and tumor factors
Liver resection - Early Child A cirrhosis• High recurrence rate• Large tumor not eligible for OLT
HCC - Summary
Loco-regional therapy is very effective in small tumors
RFA, Alcohol, TACE • High recurrence rate
Liver Transplantation• Best treatment /<67Y / Milan criteria
Molecular Target Therapy - Evolving
HCC+HBV Dx- 1/2001
RFA + Chemoembolization (TACE)
RFAC
RFA
TACE
RFA
Normal liver 2013
Liver Transplantation 9/2003
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