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?

Hepatic Nodules

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.

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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

Tri-phasic CT

Angiography

HCC - Hypervascular lesion with in cirrotic liver

Hypervascular lesion - HCC

Non contract CT

Contract CT

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

Tumor resection

6 Month post resection

מה דעתכם על ? ניתוח

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

60 year old man – HBV + HCC

One year post Alcohol ablation

HCC – RFA- Radio frequency ablation Child A cirrhosis

60 yr femaleAFP elevated

Pre RFA 1 month post RFA

RFA -74Y, M ( HCV-HCC)

Wide Necrosis

TT

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)

Male age 78 HCV

AFP 3 90 490

6 weeks post TACE

AFP 490 6

תמונה

Male age 84 HCC

Chemoembolization AFP>2500

Post Tx AFP-70

Pre Tx

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

RFA + Chemoembolization 61y ♀ HBV+HCC

1

2

3

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.

5 Year Survival 65%

57 HCC patients transplanted in Hadassah between 1/2001 -9/2013

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

RFA + Chemoembolization 61y ♀ HBV+HCC Dx 1/2001

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2

3

HCC+HBV Dx- 1/2001

RFA + Chemoembolization (TACE)

RFAC

RFA

TACE

RFA

Normal liver 2013

Liver Transplantation 9/2003

4

HCC – 2009 – Students update