Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer deaths worldwide. Risk factors include hepatitis and excessive alcohol use. Complete surgical resection or liver transplantation offers the best outcomes for eligible patients with early-stage HCC. For patients who cannot undergo surgery, radiofrequency ablation and chemoembolization provide good local control of small, localized tumors. Systemic therapies are minimally effective for HCC due to resistance, and palliation is the main goal for widespread disease. Long-term survival requires a multidisciplinary approach and close monitoring for recurrence.

1. Hepatocellular Carcinoma
Amr Khayat, MBBS

2. • Hepatocellular carcinoma (HCC) is a primary
malignancy of the liver.
• It is now the third leading cause of cancer deaths
worldwide, with over 500,000 people affected.
• Hepatitis and excessive alcohol are the leading causes
of HCC.
• (Hepatitis B or hepatitis C, 20%) or with cirrhosis (about
80%).
• HCC may present with right upper quadrant pain,
weight loss, jaundice, bloating from ascites, and signs
of decompensated liver disease.

3. • Microscopically, there are four cytological
types:
– fibrolamellar,
– pseudoglandular (adenoid),
– pleomorphic (giant cell) and
– clear cell.
• Local expansion, intrahepatic spread, and
distant metastases.
• Serum AFP rise in 40-64%.
• On CT, HCC can have three distinct patterns of growth:
– A single large tumor
– Multiple tumors
– Poorly defined tumor with an infiltrative growth pattern

5. Diagnostic Procedures
• In patients with lesions less than 1 cm, >>>>
conservative management with close follow-up
and no biopsy is recommended.
• In patients with 1- to 2-cm lesions, a biopsy
should be performed,.
• Patients with lesions greater than 2 cm, cirrhosis,
characteristic imaging studies, and elevated AFP
values can be managed without biopsy.
• Patients with large tumors who are not
candidates for resection or transplantation,
>>>>>> biopsy is frequently not indicated.
• Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and
treatment of hepatocellular carcinoma. Liver Transpl. Feb 2004;10(2 Suppl
1):S115-20.

6. • Important features that guide
treatment include: -
– Size
– Spread (stage)
– Involvement of liver vessels
– Presence of a tumor capsule
– Presence of extrahepatic metastases
– Vascularity of the tumor

7. AJCC/UICC Classification System

8. Child-Pugh score
• The Child-Pugh score is used to assess the
prognosis of chronic liver disease, mainly cirrhosis.
To determine treatment required and the necessity
of liver transplantation.
• The score employs five clinical measures of liver
disease. Each measure is scored 1-3, with 3 indicating
most severe derangement.

9. Chronic liver disease is classified into
Child-Pugh class A to C, employing the
added score from above.

10. Treatment/Management
• Surgical resection
• Liver transplantation
• Percutaneous ablation
– Alcohol injection
– Radiofrequency ablation
• Transarterial embolization and chemoembolization
• Chemotherapy.
“Radical”
“Potentially
Curative”
“ Palliative ”

11. • There is no agreement on a common
treatment strategy for patients with HCC
worldwide, and several proposals have
been published.The three major curative
therapies, resection, liver transplantation
and percutaneous treatments, compete
as first-line treatment option for small
single HCC in patients with well-preserved
liver function.
• Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. The Lancet
2003; 362: 1907–17.
• Poon RT, Fan ST, Tsang FH, Wong J. Locoregional therapies for
hepatocellular carcinoma: a critical review from the surgeon's perspective.

12. Surgery: Resection and Transplantation
• Surgery is the mainstay of HCC treatment and achieve the best
outcomes in well-selected candidates.
• Less than 5% patients resectable
• Factors affecting resectability:
– Size<5cm
– number of tumors
– involvement of major structures
– hepatic function
– no extra-hepatic spread
– no portal hypertension ·
• Requires experienced surgical and supporting team ·
• 5 year survival 60%-70% ·
• 3 year recurrence 45 - 60%
Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus
transplantation. Hepatology 1999; 30: 1434–40.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients
with cirrhosis. N Engl J Med 1996; 334: 693–9.

13. Transplantation
• Milan Criteria :
 Single HCC ≤5 cm or
 Up to three nodules ≤3 cm
 No extra hepatic spread
• About 10 % qualify for listing
• The major drawback of transplantation is
 The scarcity of donors.
 The long waiting time.
While Waiting :
Adjuvant therapies whilst on the waiting list are used
in most centers to prevent tumor progression.

14. Resection Vs Transplantaion
• 138 pt with cirrhosis and HCC
• 85 LT and 53 Resection
• Child’s A and B
Liver
Transplantation
Resection
1, 3, 5-year Survival 84, 74, 62 % 83, 57, 50 %
1, 3, 5-year Disease
free
83, 72, 60 % 70, 44, 31 %
Liovet hepatology 1999

15. Percutaneous Treatments
• For patients who cannot undergo resection.
• Complete responses in more than 80% of tumors smaller than 3
cm in diameter, but in 50% of tumors of 3-5 cm in size.
• 5-year survival rates of 40%-60%. reported in patients with small
single tumors, commonly <2 cm in diameter.
• Although these treatments provide good results, they are unable to
achieve response rates and outcomes comparable with surgical
treatments.
• Transarterial Embolization and Chemoembolization is
recommended as first line non-curative therapy for non-surgical
patients with large/multifocal HCC who do not have vascular
invasion or extrahepatic spread.
• Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts
survival in patients with hepatocellular carcinoma. Hepatology 2004; 40: 1352–60.
• Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in
patients with cirrhosis: long-term results of percutaneous image-guided
radiofrequency ablation. Radiology 2005; 234: 961–7.
• Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma
by percutaneous tumor ablation methods: ethanol injection therapy and
radiofrequency ablation. Gastroenterology 2004; 127: S159–66.

16. Percutaneous Ethanol Injection
• 207 patients with cirrhosis + HCC <
5 cm ·
• 100% Ethanol
• Follow up was 25 months
• No complications
• 4.3 sessions per patient
• 88% complete necrosis
• 1 ,2,3-year survival rates:
90,80,63%
Cancer 1992;69:925

17. Radiofrequency Ablation

18. BEFORE RF AFTER RF

19. PEI RFA
Complete
Necrosis
88 % 96 %
Progression
(3ys)
40,4% 15,3 %
Survival
(3ys)
57,6 % 71,1 %
RFA (52) PEI (60)
Complete
Necrosis
47 (90%) 48 (80 %)
Mean No.
of Sessions
1,2 4,8
RFA : More expensive, more complication, more seeding.
PEI: More Sessions, less effective in tumors 2cm
Lin et al. 2004
Radiology 1999; 210:655

20. Palliative Therapies
• Primary treatment for unresectable HCC.
• Embolization agents – usually gelatin or microspheres – may be
administered together with selective intra-arterial chemotherapy
mixed with lipiodol (chemoembolization).
• Doxorubicin, mitomycin and cisplatin are the commonly used
antitumoral drugs.
• Arterial embolization achieves partial responses in 15-55% of
patients, and significantly delays tumour progression and vascular
invasion.
# Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma.
Gastroenterology 2004; 127: S179–88.
# Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation
versus symptomatic treatment in patients with unresectable hepatocellular
carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734–9.
# Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol
chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;
35: 1164–71.

21. Transarterial Chemoembolization
Meta-analysis of 7 randomized controlled
trials
• 2 yr survival: 41% (19-63%)
• Treatment response: 35% (16-61%)
• Average no. of sessions: 1-4.5
• Risks:
– Infection
– Tumor lysis syndrome
– Hepatic failure
• Llovel J He aloI2003"37:429

22. Systemic Treatments
• A meta-analysis of seven RCTs comparing tamoxifen vs.
conservative management, comprising 898 patients, showed
neither antitumoral effect nor survival benefit of tamoxifen.
Thus, this treatment is discouraged in advanced HCC.
• Systemic chemotherapy has been tested in nine RCT. The
most active agents in vitro and in vivo are doxorubicin and
cisplatin. Systemic doxorubicin has been tested in more than
1000 patients within clinical trials and provides partial
responses in around 10% of cases, without any evidence of
survival advantages .
• Llovet JM, Bruix J. Systematic review of randomized trials for
unresectable hepatocellular carcinoma: chemoembolization improves
survival. Hepatology 2003; 37: 429–42.
• # Fong Y, Kemeny N, Lawrence T. Cancer of the liver and biliary tree. In:
De Vita VT, Hellman S, Rosenberg S, eds. Cancer: Principles and
Practices of Oncology. Philadelphia, USA: Lippincott Williams and
Wilkins, 2001: 1162–204.
• # Palmer D, Hussain S, Johnson P. Systemic therapies for hepatocellular
carcinoma. Expert Opin Investig Drugs 2004; 13: 1555–68.

23. Chemotherapy
• Palliative not Curative.
• Regional (Intra-arterial) better that
systemic.
• Resistant to many agents.

24. Follow-up
• Despite optimal treatment, hepatocellular
carcinoma continues to have a high recurrence
rate. majority of which occur within 2 years.
• Early recurrence after resection is associated
with a dismal prognosis, reducing 5-year survival
rates from 70% to 30%.
• Common extrahepatic sites of metastatic
disease include lung, bone, CNS, and adrenal
glands.
• Factors that increase the likelihood of recurrence
include the presence of :
– multiple foci of hepatocellular carcinoma,
– liver capsule invasion,
– tumor size (>5 cm).
– Vascular invasion, both microscopic and macroscopic.

25. • In general, a CT scan at 1 month
postresection.
• Serum alpha-fetoprotein measurements
and repeat imaging studies (eg, ultrasound,
CT, MRI) every 3-6 months.
• After 2-3 years, safe to increase the follow-
up interval.

26. Bruix J, Sherman M, 2005: Hepatology 42:1208-1236.

27. Summary
• Early-stage hepatocellular carcinoma is typically clinically silent,
and HCC is often advanced at first manifestation.
• Without treatment, the 5-year survival rate is less than 5%.
• Complete surgical resection followed by hepatic transplantation
offers the best long-term survival, but few patients are eligible for
this therapy.
• Radiofrequency ablation is the preferred method for managing
unresectable small HCCs that are few in number. More
widespread disease is treated with percutaneous therapies such
as chemoembolization.
• Systemic administration of biologic and chemotherapeutic agents
is minimally successful in slowing the growth of HCC and typically
is used to control symptoms in patients with overwhelming
disease.
• A multidisciplinary approach that includes surgery, systemic
therapy, and radiation therapy and that is based on the
cooperation of radiation oncologists, interventional and diagnostic
radiologists, hepatologists, and pathologists offer the best chance