Hepatocellular carcinomas
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Transcript of Hepatocellular carcinomas
Hepatocellular Carcinoma
Dr. Amina Abdul RahmanJunior Resident
Dept. of Radiotherapy
Hepatocellular Carcinoma
• Anatomy• Epidemiology• Screening• Diagnosis • Staging• Management
ANATOMY
EPIDEMIOLOGY
EPIDEMIOLOGY
• Sixth most common cancer• Third most common cause of cancer death• M:F = 2.4 : 1• Common in areas endemic to viral hepatitis
Etiology
• Cirrhosis Viral hepatitis B, CAlcohol Autoimmune chronic active hepatitisNAFLDPrimary Biliary CirrhosisHemochromatosisAlpha 1 Anti trypsin Def
Etiology
• Without CirrhosisHereditary TyrosinemiaGlycogen storage diseaseGalactosemia Alagille syndrome
Hepatitis B
• Less than 1 yr 80-90% become chronic• 1 – 6 yrs 30 -50 % become chronic• Adults ˂ 5 % become chronic• Annual risk of HCC in c/c Hep B is 0.5%
Hepatitis C
• Chronic hepatitis in 75-85% of pts with Hep C• 17 fold increase in risk of HCC• Annual risk of 3-5%
Risk Factors for HCC in Viral Hepatitis
• Male sex• ˃ 50 yrs• Family history• Cirrhosis• Obesity• Larger HBV DNA load• Co infection with HIV, HCV, HDV • DM and liver Fe stores for Hep C
Prevention of HCC in viral hepatitis
• Use vaccines• Early treatment with nucleoside analogues
Clinical featuresHepatitis B Hepatitis C
Larger Lesions Smaller lesions
Bilobar disease More liver dysfunction
Doesn’t meet Milan criteria Meets Milan’s criteria
Younger age Older age
Better response to Sorafenib
Better response to TACE
Better response to surgery
SCREENING
Screening
• AASLD Guidelines• Recommend enrolling patients at high risk for
HCC for screening programs• Based on a study conducted in China which
screened 18,800 people with Hep B with AFP and USG every 6 months
Candidates for screening
• Cirrhosis induced by viral hep B,C• Cirrhosis due to alcohol, GH, NASH, Stage IV
PBC, • Hep B without cirrhosis• Less risk: Wilson’s disease, Sclerosing
Cholangitis, Type IV Glycogen Storage Disease, chronic right heart failure, TR
PATHOLOGY
Pathology
• Epithelial tumors
• Mesenchymal tumors
Tumors of the liver
Epithelial tumors
Hepatocellular Carcinoma childhood fibrolamellar Combined Spindle cell Clear cell Giant cell Carcinosarcoma Sclerosing HCC
Cholangiocarcinoma Hepatoblastoma Biliary cystadenocarcinoma
Tumors of the liver
Mesenchymal Tumors
Angiomyosarcoma
Leiomyosarcoma
Embryonal Sarcoma
Lymphoma
Schwannoma
DIAGNOSIS
Diagnosis
• Imaging
• Serum Markers
• Biopsy
Imaging
• Ultrasound
• CT
• MRI
USG
• Useful screening tool
• Expansive HCC : discrete nodules with a hypoechoeic rim
• Infiltrative HCC: heterogeneous echogenicity, may be missed
Computed Tomography
• Multi Slice , Multi Phase contrast enhanced CT• Phases: unenhanced arterial venous delayed
• Intense arterial uptake with washout in venous and delayed phase
Two classical enhancements
• Liver supplied by the portal vein (75%) and the hepatic artery (25%)
• The HCC is supplied solely by the hepatic artery
• Arterial Phase: contrast in the hepatic artery“intense arterial uptake”• Venous Phase: contrast in the portal vein,
“wash out”
MRI
• Best for detecting intrahepatic lesions
• If one is inconclusive, the other may be used
AASLD Diagnosis Guidelines
• Is only for cirrhotic liver or those with liver disease
• Radiological diagnosis not sufficient for a liver nodule picked up on routine scanning in an otherwise healthy liver
Differential Diagnosis
• Early HCC ‘hypovascular’
• Metastatic liver lesions Peripheral, multiple, cause umblication of liver surface
• Dysplastic nodules
Serum Markers
• Serum AFP
• PIVKA II
Serum AFP
• Not specific : can be normal in some HCC
• Not sensitive: maybe elevated in colorectal metastases, IHCC
• Not recommended for screening
• Not used for diagnosis
Serum AFP
‘Plays an important role in the regulation of tumor growth and cell differentiation and can stimulate proliferation of human hepatoma cells, probably through AFP receptors’
Serum AFP
• Prognostic indicator
• Higher levels correlates with larger size higher grade more of vascular invasion early tumor recurrence
Serum AFP
Higher AFP Lower AFP
Younger Age Elderly
HBsAg positive Hep C positive
P53 mutation Beta catenin mutation
Serum AFP
• Normal level < 6.0 ng/ml
• Low levels 20- 400 ng/ml
• High levels > 400 ng/ml
PIVKA 2
• des-γ-carboxy Prothrombin protein Induced by Vitamin K abnormality
• Not useful for screening or diagnosis
• May have a prognostic role
Biopsy
• Fine needle aspiration : deep seated tumors, near blood vessels rapid staining
• Core biopsy: Tissue architecture IHC tests can be done
• Caution : bleeding, tumor seeding
Histological features
• Stromal invasion : invasion of fibrous septa and portal tract
• tumor vessels is quantified by the inflow vessels
1. Hepatic artery2. Portal vein3. Unpaired artery
Hepatocarcinogenesis
• High Grade Dysplastic NoduleNo stromal invasion
• Very Early HCC Ill-defined, hypovascularStromal invasion, No vascular invasion
• Small/progressed HCCWell-defined, hypervascularStromal and vascular invasion, unpaired artery
Stromal invasion : Invasion of fibrous septa
Vascular invasion
Immunohistochemistry
• Markers for HCC Glypican 3, HSP 70, glutamine synthetase
• Vascular epith CD 34 +ve
• Biliary epith stains CK 7, CK 19 negative
Work Up
• Viral MarkersHep B : HBsAg +ve HBeAg, HBeAb, HBV DNAHep C : HCV Ab, HCV RNA• LFT• Look for comorbidities• Chest imaging : MC site of mets• Bone Scan : if bone pain
Tumor Burden
• CE CT/ MRISite size, number of lesionsNodal diseaseVascular invasionPortal hypertensionExtent of CLDEstimate future liver remnant (FLR)
Child-Pugh Score
Portal Hypertension
• Esophageal varices• Splenomegaly• Abdominal collaterals• Thrombocytopenia• CT/MRI • Measure the Hepatic Venous Pressure
Gradient
STAGING
Staging
• AJCC
• Okuda
• CLIP
• BCLC
AJCC STAGING
TNM Staging
• Can only be used after surgical resection
• Does not take PS and liver function into account
• Does not have adequate prognostic accuracy
Okuda Staging
• Used for identifying advanced disease
• Not useful for stratifying early or intermediate disease
CLIP Staging
BCLC Staging
• Child-Pugh score• Performance status• Size and number of lesion• Portal hypertension• Comorbidities
BCLC Staging
• Stage 0 & A : 5 yr survival 50-75%• Stage B : 3 yr survival 50%• Stage C : 1 yr survival 50%• Stage D : Mean survival < 3 months
MANAGEMENT
Management of HCC
• Few RCTs
• The use of “disease free survival” is discouraged
• Use “survival”
Management
• CurativeSurgical ResectionLiver TransplantRadiofrequency Ablation• PalliativeTACE/TAESorafenib
Surgical Resection
Surgical Resection
˃70% survival at 5 yrs after resectionSelection criteria• Normal bilirubin• Normal hepatic venous pressure• Single lesion, size ≤ 5 cm• 3 or less tumors of size ≤3 cm• No evidence of gross vascular invasion
Surgical Resection
• Margin of 1 cm recommended• Non anatomic wedge resection for surface
tumors• Anatomic resection (couinaud segments) for
deeper tumors
Prevent post op Liver Failure
• Indocyanine clearance testRetention rate ˂10% all resections can be done10-20% 2 segments may be removed20-29% single segment may be removed ˃30 % resection cannot be done
Prevent post op Liver Failure
• Assess putative Functional Liver Remnant (FLR)
• Functional liver remnant Total Liver Volume• This ratio should be 20% without cirrhosis and
30-40% with cirrhosis
Preop Portal V. Embolization
• Pre op PV embolization of the lobe hosting the tumor
1. Atrophy of the affected lobe2. Induces hypertrophy of the non affected lobeCaution!!• Malignant cells may respond to the
proliferative stimulus• Increase in portal pressure
Recurrence after resection
• ˃ 70% risk of recurrence at 5 yrs
Factors :1. Microvascular invasion2. Additional tumor sites
Treatment of recurrence
• Solitary recurrence my benefit from repeat resection
• Liver transplantation may be attempted
• No role for pre-op chemoembolization to increase resectability
• No role for adjuvant treatment after resection to prevent recurrence
Liver Transplant
Liver Transplant
• For lesions meeting the UNOS criteria1. Size ˂ 5 cm, ≤ 3 nodules with size ˂ 3 cm2. No gross vascular invasion3. No extra hepatic disease• With moderate to severe cirrhosis, Child-Pugh
score B or C• No cancer symptoms, no comorbid disease
Advantage of Transplant
• Removing both the detectable and the undetectable disease
• Treating cirrhosis• Avoiding problems due to inadequate FLR• 4 yr OS of 85% in patients who have
undergone transplant, strictly acc to Milan criteria
Expanded Milan criteria(UCSF)
• For providing marginally larger HCC a chance for transplant
• Tumors 6.5 cm or smaller• Max of 3 tumors, none ˃ 4.5 cm or cumulative
size ˂ 8 cm
MELD Score
• The Model for End-Stage Liver Disease (MELD)• from 6 (less ill) to 40 (gravely ill)• It gives each person a ‘score’ (number) based
on how urgently he or she needs a liver transplant within the next three months
Now used by UNOS for prioritizing allocation of liver transplant
MELD Score
Score depends on1. Serum bilirubin2. Serum Creatinine3. INR4. Etiology
MELD
MELD Score = 3.78 xln[S. Bilirubin]+11.2x ln[INR]+ 9.57x ln[S. Creatinine]+ 6.43 x aetiology
MELD Exception
Additional score for patients with cancer Solitary HCC ˂ 2 cm score is 0 HCC 2 to 5 cm, or 3 nodules each ˂ 3 cm score is 22
Post Transplant Management
• No adj treatment to prevent recurrence
• Treat the Hep B infection to prevent re infection of graft, not effective in Hep C
Bridge Therapy
• To decrease tumor progression while on waiting list
• Options include1. RFA2. TACE3. TARE4. Sorafenib
Downstaging Therapy
• Reduce tumor burden in patients with advanced HCC without mets
• Options include1. PEI2. TACE3. TARE
Locoregional Ablation
Percutaneous Ablation
• Chemical :Ethanol Acetic AcidBoiling Saline• Temperature Modulation :Radiofrequency MicrowaveLaserCryotherapy
Mechanism of action of RFA
• Induce temp change by utilising high freq AC of 400-500Hz
• Generate ionic agitation , causing localised friction heat of tissue surrounding electrode
• Coagulative necrosis• Energy level rapidly dissipates with increasing
distance from the electrode
RFA
• 7 cm zone of necrosis adequate for a 5 cm tumor
Caution!!Tumors close to vascular structuresTumors close to biliary ductPeripheral tumorsSubcapsular tumorsTumors with poor differentiation
Side Effects
• Pleural effusion• Peritoneal bleeding• Tumor seeding• Bile duct damage
Response to Treatment
• Assessed by doing CE CT/MRI• Absence of contrast uptake within tumor
reflects tumor necrosis• S. AFP
Percutaneous Ethanol Injection
• Direct destruction of cancer cells• May destroy normal tissue also• Useful for tumors upto 3 cm• Requires multiple injections• Easier to perform, cheaper
RFA Vs. PEI
• RFA is similar in efficacy to PEI for tumors less than 2 cm
• RFA is superior to PEI for tumors more than 2 cm
• RFA has lesser risk of recurrence, but more expensive
• 5 yr survival rate 70% Vs. 68% for RFA and PEI
Arterially Directed Therapy
Principle of Arterially Directed Therapy
• Tumor is solely supplied by the hepatic artery as a result of neovascularisation
• Selectively blocking the artery feeding the tumor will result in tumor ischemia followed by necrosis with no damage to the surrounding normal liver
Arterially Directed Therapy
• TAE• TACE• DEB-TACE• TARE
Embolization Agents
• Gel sponge cubes• Polyvinyl alcohol particles• Polyacrylamide microspheres• Steel coils• Autologous blood clot
TACE
• When embolization is preceded by injection of concentrated dose of chemotherapeutic agent
• Chemo agent is usually Doxorubicin or Cisplatin
• Chemo agent is suspended in Lipiodol
TAE/TACE Procedure
• Femoral artery is punctured in the right groin pass a catheter the abd aorta to the ceoliac trunk to the hepatic artery
• Then a selective angiogram is done to identify the vessel feeding the tumor
• Chemotherapy injected followed by embolization agent
TACE VS TAE
• Both procedures have shown superiority over best supportive care
• But no reliable study to compare TACE with TAE
• At present, no evidence suggests that TACE is better than TAE
Contraindications to TACE
• Portal Vein Thrombosis• Advanced Liver Disease (Child-Pugh B to C)• Clinical symptoms of end stage cancer• Biliary obstruction (S. Bilirubin ˃ 3 mg/dl)
Complications of TAE/TACE
• Post embolization Syndrome• Non-target embolization• Liver Failure• Cholecystitis• Complications of chemo agent
DEB-TACE
• Chemo agent is eluted onto embolic beads for higher concentrated delivery of the chemo agent to the neoplastic cells
• Occlude feeding vessels while chemo agent is released gradually
TAE/TACE with VEGFR
• Embolization causes hypoxia which upregulates VEGFR which is associated with increased risk of recurrence
• TAE/TACE with Sorafenib
TARE
• Intra arterial administration of Yttrium 90 embolic microspheres
• β emitting isotope• Delivers internal radiation to the tumor
TARE Technique
• Work up session1. Angiographic map of the patient’s vascular
anatomy is obtained2. Technetium 99 labelled albumin is injected
and a SPECT CT taken to detect the extra hepatic deposition
TARE Technique
• Treatment Session1. Calculate dose to be delivered depending on
the liver mass2. A dose of 100 to 120 Gy is the target dose3. Hepatic artery will be catheterized and the
Yttrium 90 will be injected at the exact same position as where the Technetium labeled albumin was injected
SORAFENIB
Sorafenib
Mech of action:Blocks tyrosine kinase receptors in the tumor cells as well as the tumor vasculatureInhibits :Multi kinase inhibitorInhibits c-Raf, b-Raf, VEGFR, PDGFR-betaIndication in HCC:Locally advanced HCC and metastatic HCC but with preserved liver function
Sorafenib
• Dose : 400 mg PO twice daily one hour before or two hour after food
• Dosage need not be modified in mild to moderate renal and hepatic failure but to be avoided in severe renal/hepatic failure
Side Effects
• Hand-foot skin reaction• Diarrhoea • Haemorrhage (cerebral or GI)• Cardiac ischemia / hypertension• Fatigue• Weight loss
SHARP Trial
• 602 patients with advanced HCC (not eligible for TACE or failed with TACE) were randomized to Sorafenib and best supportive care
• Median survival was 10.7 months for Sorafenib Vs 7.9 months for placebo
• Stopped at interim analysis
Sorafenib
• Locally advanced or metastatic HCC• With preserved liver function (Child-Pugh
score of A • PS of 0-2
EXTERNAL BEAM RADIOTHERAPY
SBRT Stereotactic Body RT
• Advanced tech of EBRT to deliver large ablative doses of radiation
• Effective local therapy for patients unsuitable for locoregional therapy
• SBRT : shorter radiation schedule with very high conformal doses delivered at each fraction for focal HCC
• Image guided RT and enhanced management of breathing motion has allowed delivery of very high focal doses of RT
SBRT
• Most effective if size ˂ 6 cm with local control rates of 70-95% at 2 yrs
• Can sustain growth of HCC tumors of size ˃ 6 cm
• Toxicity increases with Child-Pugh score of B or C
• 15 to 45 Gy delivered over 1 to 5 fractions• 63 Gy in 15 fractions
Radiation induced Toxicity
• RILD : clinical syndrome of anicteric hepatomegaly, ascites, elevated liver enzymes 3mnths after RT
• Gastrointestinal ulceration, fistula or bleed• Chest pain, rib fracture• Biliary stenosis
Prevent RILD
• Keep the mean dose for uninvolved liver to less than 32 Gy in 2 Gy per fraction
• Or ensure that no greater than 30% of liver recieves 21 Gy in 3 fractions
The End