This document provides an overview of hepatocellular carcinoma (HCC). It discusses the anatomy, epidemiology, screening, diagnosis, staging and management of HCC. HCC is commonly caused by viral hepatitis and cirrhosis. Diagnosis involves imaging such as ultrasound, CT or MRI showing characteristic arterial enhancement and venous washout. Staging systems include AJCC, Okuda, CLIP and BCLC which incorporate tumor burden, liver function and performance status. Management options include surgical resection, liver transplantation, ablation and arterially directed therapies like TACE.

1. Hepatocellular Carcinoma
Dr. Amina Abdul Rahman
Junior Resident
Dept. of Radiotherapy

2. Hepatocellular Carcinoma
• Anatomy
• Epidemiology
• Screening
• Diagnosis
• Staging
• Management

3. ANATOMY

5. EPIDEMIOLOGY

6. EPIDEMIOLOGY
• Sixth most common cancer
• Third most common cause of cancer death
• M:F = 2.4 : 1
• Common in areas endemic to viral hepatitis

7. Etiology
• Cirrhosis
Viral hepatitis B, C
Alcohol
Autoimmune chronic active hepatitis
NAFLD
Primary Biliary Cirrhosis
Hemochromatosis
Alpha 1 Anti trypsin Def

8. Etiology
• Without Cirrhosis
Hereditary Tyrosinemia
Glycogen storage disease
Galactosemia
Alagille syndrome

9. 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%

10. Hepatitis C
• Chronic hepatitis in 75-85% of pts with Hep C
• 17 fold increase in risk of HCC
• Annual risk of 3-5%

11. 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

12. Prevention of HCC in viral hepatitis
• Use vaccines
• Early treatment with nucleoside analogues

13. Clinical features
Hepatitis 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

14. SCREENING

15. 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

16. 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

18. PATHOLOGY

19. Pathology
• Epithelial tumors
• Mesenchymal tumors

20. Tumors of the liver
Epithelial tumors
Hepatocellular Carcinoma
childhood
fibrolamellar
Combined
Spindle cell
Clear cell
Giant cell
Carcinosarcoma
Sclerosing HCC
Cholangiocarcinoma
Hepatoblastoma
Biliary cystadenocarcinoma

21. Tumors of the liver
Mesenchymal Tumors
Angiomyosarcoma
Leiomyosarcoma
Embryonal Sarcoma
Lymphoma
Schwannoma

22. DIAGNOSIS

23. Diagnosis
• Imaging
• Serum Markers
• Biopsy

24. Imaging
• Ultrasound
• CT
• MRI

25. USG
• Useful screening tool
• Expansive HCC : discrete nodules with a
hypoechoeic rim
• Infiltrative HCC: heterogeneous echogenicity,
may be missed

26. Computed Tomography
• Multi Slice , Multi Phase contrast enhanced CT
• Phases:
unenhanced
arterial
venous
delayed
• Intense arterial uptake with washout in
venous and delayed phase

27. 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”

28. MRI
• Best for detecting intrahepatic lesions
• If one is inconclusive, the other may be used

31. 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

32. Differential Diagnosis
• Early HCC ‘hypovascular’
• Metastatic liver lesions
Peripheral, multiple, cause umblication of liver
surface
• Dysplastic nodules

33. Serum Markers
• Serum AFP
• PIVKA II

34. 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

35. 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’

36. Serum AFP
• Prognostic indicator
• Higher levels correlates with
larger size
higher grade
more of vascular invasion
early tumor recurrence

37. Serum AFP
Higher AFP Lower AFP
Younger Age Elderly
HBsAg positive Hep C positive
P53 mutation Beta catenin mutation

38. Serum AFP
• Normal level < 6.0 ng/ml
• Low levels 20- 400 ng/ml
• High levels > 400 ng/ml

39. PIVKA 2
• des-γ-carboxy Prothrombin protein Induced
by Vitamin K abnormality
• Not useful for screening or diagnosis
• May have a prognostic role

40. 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

41. Histological features
• Stromal invasion : invasion of fibrous septa
and portal tract
• tumor vessels is quantified by the inflow
vessels
1. Hepatic artery
2. Portal vein
3. Unpaired artery

42. Hepatocarcinogenesis
• High Grade Dysplastic Nodule
No stromal invasion
• Very Early HCC
Ill-defined, hypovascular
Stromal invasion, No vascular invasion
• Small/progressed HCC
Well-defined, hypervascular
Stromal and vascular invasion, unpaired artery

43. Stromal invasion : Invasion of fibrous septa

44. Vascular invasion

46. Immunohistochemistry
• Markers for HCC
Glypican 3, HSP 70, glutamine synthetase
• Vascular epith CD 34 +ve
• Biliary epith stains CK 7, CK 19 negative

47. Work Up
• Viral Markers
Hep B : HBsAg +ve HBeAg, HBeAb, HBV DNA
Hep C : HCV Ab, HCV RNA
• LFT
• Look for comorbidities
• Chest imaging : MC site of mets
• Bone Scan : if bone pain

48. Tumor Burden
• CE CT/ MRI
Site size, number of lesions
Nodal disease
Vascular invasion
Portal hypertension
Extent of CLD
Estimate future liver remnant (FLR)

49. Child-Pugh Score

50. Portal Hypertension
• Esophageal varices
• Splenomegaly
• Abdominal collaterals
• Thrombocytopenia
• CT/MRI
• Measure the Hepatic Venous Pressure
Gradient

51. STAGING

52. Staging
• AJCC
• Okuda
• CLIP
• BCLC

53. AJCC STAGING

54. TNM Staging
• Can only be used after surgical resection
• Does not take PS and liver function into
account
• Does not have adequate prognostic accuracy

56. Okuda Staging
• Used for identifying advanced disease
• Not useful for stratifying early or intermediate
disease

57. CLIP Staging

59. BCLC Staging
• Child-Pugh score
• Performance status
• Size and number of lesion
• Portal hypertension
• Comorbidities

60. 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

61. MANAGEMENT

62. Management of HCC
• Few RCTs
• The use of “disease free survival” is
discouraged
• Use “survival”

63. Management
• Curative
Surgical Resection
Liver Transplant
Radiofrequency Ablation
• Palliative
TACE/TAE
Sorafenib

64. Surgical Resection

65. Surgical Resection
˃70% survival at 5 yrs after resection
Selection 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

66. Surgical Resection
• Margin of 1 cm recommended
• Non anatomic wedge resection for surface
tumors
• Anatomic resection (couinaud segments) for
deeper tumors

67. Prevent post op Liver Failure
• Indocyanine clearance test
Retention rate
˂10% all resections can be done
10-20% 2 segments may be removed
20-29% single segment may be removed
˃30 % resection cannot be done

68. 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

69. Preop Portal V. Embolization
• Pre op PV embolization of the lobe hosting the
tumor
1. Atrophy of the affected lobe
2. Induces hypertrophy of the non affected lobe
Caution!!
• Malignant cells may respond to the
proliferative stimulus
• Increase in portal pressure

70. Recurrence after resection
• ˃ 70% risk of recurrence at 5 yrs
Factors :
1. Microvascular invasion
2. Additional tumor sites

71. 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

72. Liver Transplant

73. Liver Transplant
• For lesions meeting the UNOS criteria
1. Size ˂ 5 cm, ≤ 3 nodules with size ˂ 3 cm
2. No gross vascular invasion
3. No extra hepatic disease
• With moderate to severe cirrhosis, Child-Pugh
score B or C
• No cancer symptoms, no comorbid disease

74. 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

75. 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

76. 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

77. MELD Score
Score depends on
1. Serum bilirubin
2. Serum Creatinine
3. INR
4. Etiology

78. MELD
MELD Score = 3.78 xln[S. Bilirubin]+11.2x ln[INR]+
9.57x ln[S. Creatinine]+ 6.43 x aetiology

79. 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

80. 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

81. Bridge Therapy
• To decrease tumor progression while on
waiting list
• Options include
1. RFA
2. TACE
3. TARE
4. Sorafenib

82. Downstaging Therapy
• Reduce tumor burden in patients with
advanced HCC without mets
• Options include
1. PEI
2. TACE
3. TARE

83. Locoregional Ablation

84. Percutaneous Ablation
• Chemical :
Ethanol
Acetic Acid
Boiling Saline
• Temperature Modulation :
Radiofrequency
Microwave
Laser
Cryotherapy

85. 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

86. RFA
• 7 cm zone of necrosis adequate for a 5 cm
tumor
Caution!!
Tumors close to vascular structures
Tumors close to biliary duct
Peripheral tumors
Subcapsular tumors
Tumors with poor differentiation

88. Side Effects
• Pleural effusion
• Peritoneal bleeding
• Tumor seeding
• Bile duct damage

89. Response to Treatment
• Assessed by doing CE CT/MRI
• Absence of contrast uptake within tumor
reflects tumor necrosis
• S. AFP

90. 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

91. 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

92. Arterially Directed Therapy

93. 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

94. Arterially Directed Therapy
• TAE
• TACE
• DEB-TACE
• TARE

95. Embolization Agents
• Gel sponge cubes
• Polyvinyl alcohol particles
• Polyacrylamide microspheres
• Steel coils
• Autologous blood clot

96. 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

97. 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

100. 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

101. 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)

102. Complications of TAE/TACE
• Post embolization Syndrome
• Non-target embolization
• Liver Failure
• Cholecystitis
• Complications of chemo agent

103. 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

104. TAE/TACE with VEGFR
• Embolization causes hypoxia which
upregulates VEGFR which is associated with
increased risk of recurrence
• TAE/TACE with Sorafenib

105. TARE
• Intra arterial administration of Yttrium 90
embolic microspheres
• β emitting isotope
• Delivers internal radiation to the tumor

106. TARE Technique
• Work up session
1. Angiographic map of the patient’s vascular
anatomy is obtained
2. Technetium 99 labelled albumin is injected
and a SPECT CT taken to detect the extra
hepatic deposition

107. TARE Technique
• Treatment Session
1. Calculate dose to be delivered depending on
the liver mass
2. A dose of 100 to 120 Gy is the target dose
3. 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

109. SORAFENIB

110. Sorafenib
Mech of action:
Blocks tyrosine kinase receptors in the tumor
cells as well as the tumor vasculature
Inhibits :
Multi kinase inhibitor
Inhibits c-Raf, b-Raf, VEGFR, PDGFR-beta
Indication in HCC:
Locally advanced HCC and metastatic HCC but
with preserved liver function

111. 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

112. Side Effects
• Hand-foot skin reaction
• Diarrhoea
• Haemorrhage (cerebral or GI)
• Cardiac ischemia / hypertension
• Fatigue
• Weight loss

113. 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

114. Sorafenib
• Locally advanced or metastatic HCC
• With preserved liver function (Child-Pugh
score of A
• PS of 0-2

115. EXTERNAL BEAM RADIOTHERAPY

116. 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

118. 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

119. 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

120. 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

122. The End