This document discusses hepatocellular carcinoma (HCC). It outlines that HCC is the second most common cause of cancer death worldwide. The major risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol use, and non-alcoholic fatty liver disease. Diagnosis involves blood tests, imaging like ultrasound or CT scan, and biopsy. Treatment options include surgery, chemotherapy, and liver transplantation, though prognosis is often poor due to late stage at presentation. Prevention focuses on vaccination against hepatitis B virus and screening for early detection.

1. HEPATOCELLULAR CARCINOMA
JESSE A. OTEGBAYO, Ph.D, FACG, FWACP.
DEPT OF MEDICINE, COLLEGE HOSPITAL,
IBADAN
&
BABCOCK UNIVERSITY TEACHING
HOSPITAL, ILISHAN-REMO

2. OUTLINE
• INTRODUCTION
• RISK FACTORS
• CLINICAL FEATURES
• DIAGNOSIS
• INVESTIGATIONS
• TREATMENT
• PREVENTION
• PROGNOSIS
• CHALLENGES
• STRATEGIES6/13/2015 SOGHIN ILORIN 2015 2

3. INTRODUCTION
• The prevalence of NCDs is rising rapidly.
• World-wide, cancer incidence is increasing
• 12.7 mn new cases of cancer diagnosed in 2008.
• 21.4 mn projected by 2030.
• IARC Globocan Database estimated in 2008 that in
Africa 715,600 (325,000 in men, 390,600 in women)
new cases of cancer
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4. 6/13/2015 SOGHIN ILORIN 2015 4
African Network for Gastrointestinal and Liver Diseases 2015

5. INTRODUCTION
• 541,800 deaths attributed to cancer (78%
mortality).
• In men the 5 most frequent cancers: prostate, liver,
KS, NHL and lung cancer.
• In women : breast, cervix, liver, colorectal and NHL
• In N. America the 5 most common cancers in men
are prostate, lung, colorectum, bladder and NHL.
• Women: breast, lung, colorectal, cervix and NHL
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7. INTRODUCTION
• Liver cancer is the 2nd most common cause of death
from cancer worldwide. (WHO/IARC 2014)
• Estimated to be responsible for nearly 746,000
deaths in 2012 (9.1% of the total).
• Prognosis is very poor (overall ratio of mortality to
incidence of 0.95)
• The geographical patterns in incidence and
mortality are similar.
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8. INTRODUCTION
• Two categories: primary and secondary
• In countries with low prevalence of HBV infection,
hepatic secondary is the major cause of HCC
• HBV is the main aetiologic agent in regions with
high prevalence of HBV eg South-east Asia and
sub-Saharan Africa
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12. RISK FACTORS/AETIOLOGY
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13. RISK FACTORS
• Liver cirrhosis
• HBV (pre-S deletion mutations), 60-80%.
Risk of HCC increases with:
o The viral load.
o Male sex.
o Older age.
o The presence of cirrhosis.
o Exposure to aflatoxins
o Location in sub-Saharan Africa, where patients develop HCC at a younger age.
• HCV
Risk of HCC with:
o Cirrhosis
o Concurrent alcohol abuse.
o Obesity/insulin resistance.
o Previous or concurrent infection with HBV.
• Others: AFB1, alcohol, tobacco, A1AT def., AIH, PBC, Haemochromatosis, Tyrosinosis
• Emerging risk factors: NAFLD, NASH, Obesity, DM
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14. 6/13/2015 SOGHIN ILORIN 2015 14
N A J Med Sci. 2009;2(3):111-117

15. MOLECULAR PATHOGENESIS & ONCOGENIC FACTORS
• Mutations of the
ᵝ-catenin gene.
• Mutations in TP53 tumor suppressor gene
- p53 reduces miR-18a levels.
- miR-18a slows oestrogen receptor-alpha
Over-expression of p53 leads to increase miR-18a.
(P53 could be useful therapeutic target in female
HCC – Li et al Int. J. Cancer 2015).
• Deletion of the Axin 1 and Axin 2 genes (-ve
regulators of beta-catenin)
• Overexpression of VEGF gene (angiogenicity)
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16. MOLECULAR PATHOGENESIS & ONCOGENIC FACTORS
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17. MOLECULAR PATHOGENESIS & ONCOGENIC FACTORS
• Overexpression of metallo-protease inducers
(vascularization, invasion, metastases devt and
tumor recurrence).
• Xsomal instability:
-amplification of xsome 1q, 8q,5p
-Xsomal deletions 4q, 8p, 13q, 16q,17p
• HBx and pre S2/S: modulate signaling pathways and
gene activation - HBV viral integration
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18. CLINICAL FEATURES
Mostly diagnosed on clinical grounds in
Africa.
Triad of:
»Abdominal Swelling
»Abdominal Pain (RUQ)
»Weight Loss.
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19. CLINICAL FEATURES
Clinical Feature Number (%)
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Otegbayo et al JNMA 2006.

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22. Signs of HCC in previously compensated cirrhosis:
• Rapid deterioration of liver function.
• New-onset (or refractory) ascites.
• Acute intra-abdominal bleeding.
• Increased jaundice.
• Weight loss and fever.
• New-onset encephalopathy.
• Variceal bleeding.
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24. INVESTIGATIONS
• FBC
• Serum glucose
• LFT
• PT/PTTK
• HBsAg and anti-HCV
• USS
• CXR and/or CT scan/MRI
• Ascitic fluid cytology.
• AFP
• Liver biopsy
• Other Oncomarkers-DCP, CTA, GP-3, Anti-p53, codon-249
mutation with plasma cell-free DNA, SCCA,
Osteopontin(comparable accuracy to AFP), MicroRNAs (miR)
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25. TUMOUR MARKERS IN HCC IN NIGERIA
Marker Patients/Centre/Year Author
Alpha Fetoprotein (AFP)
Serum Ferritin
14 HCC/UCH Ibadan /1994
14 HCC/UCH Ibadan /1995
Ola SO et al
Ola SO et al
Anti-p53 antibody 41 HCC/UCH Ibadan /2007 Akere A & Otegbayo JA
P53 codon 249 mutation using
plasma Cell-free DNA.
Urinary metabolites (creat,
carnitine, creatine, acetone
85 HCC/UCH Ibadan/2008
18 HCC/JUTH/2010
Igetei R et al
Sharrif et al
Squamous Cell Carcinoma
Antigen (SCCA)
60 HCC/UCH Ibadan /2012 Soyemi et al
Cancer Testis Antigens (CTA) 42 HCC/UCH Ibadan/In press
2015
Ogoh S et al
Glypican-3 (GP-3)
Des Gamma
50 HCC/UCH Ibadan
(Ongoing)
OAUTHC, Ife / In press 2015
Oke et al
Ette et al
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26. USS FINDINGS
• Probe tenderness (RUQ) -22 (41.5%)
• Hepatomegaly -49 (92.5%)
• Hepatic nodules (intrahepatic met)- 33(62.3%)
• Splenomegaly -10(18.9%)
• Splenic irregular outline, no definite mass -4 (7.5%)
• Para-aortic lymphadenopathy- 8(15.1%)
• Portal hepatic lymphadenopathy -2(3.8%).
• Pleural effusion 7 (13.2%).
Otegbayo et al 2006, JNMA.
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27. FINDINGS ON CXR
• Metastatic deposits-11 (20.8%)
• Peri-hilar lymphadenopathy
• Consolidation-2(3.8%)
• Elevated rt diaphragm-18(34%)
• Pleural effusion-4(7.5%)
• Rt-sided basal pneumonitis -1
• Multiple cavitatory lesions in the lung fields-1.
• No CXR abnormality-7 (32.1%).
Otegbayo et al 2006, JNMA
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28. TREATMENT
Goals:
-Cure: rather elusive
-Supportive:
improve the QOL (70% poor/v. poor). Otegbayo et al. Afr
J Med, 2005.
palliation:
• pain control
• spiritual support and information
• emotional support
• ascitic fluid control
Otegbayo et al Afr J Haematol Oncol, 2010.6/13/2015 SOGHIN ILORIN 2015 28

29. TREATMENT
-Surgical resection: 10-20% suitable. (5% cured).
-Transplantation
-Systemic chemotherapy- Std not useful. Sorafenib
(brivanib, linifanib, sunitinib, Met inhibitors, bevacizumab, EGFR
inhibitors, everolimus)
-PEI
-TACE
-Hepatic artery infusion chemotherapy
-Cryoablation
-RFA
-Hormonal therapy
-Immunotherapy
-Multimodal therapy
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30. Experimental
• Conventional ethiodized oil transarterial
chemoembolization (C-TACE)
• Small or large doxorubicin drug-eluting beads TACE
chemoembolization
• Bioelectric Ablation with Microsecond Pulsed
Electric Fields (μsPEFs). Chen et al 2015.
•
• Sorafenib+erlotinib in advanced HCC. No improved
survival (Zhu et al 2015).6/13/2015 SOGHIN ILORIN 2015 30

31. EXPERIMENTAL TREATMENT
• Co-administration of propranolol+etodolac
+sorafenib in advanced HCC (De La Torre et al
2015). Some Improvement.
• Selective Internal Radiation Therapy (SIRT, sir-
spheres)
• Metformin decreases IL-22 secretion to suppress
HCC growth in mouse models. Zhao et al. Int. J.
Cancer 2015.
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32. PROGNOSIS
• In untreated patients, 1-year survival is 17.5% and
7.3% at 2 yrs. Cabibbo et al 2010, Hepatol.
• In Nigeria:
-6 mo from diagnosis to death
-3 wks from admission to death. Olubuyide, 1992.
-14 wks. from onset of illness. Ndububa et al
1999
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33. PROGNOSIS
• Histological type: Fibrolamellar type- 5% in the
West/<1% in the East. (trabecular,
pseudoglandular, compact/schirrous-not
prognostic)
• Tumour size and morphology- >8cm- poor. (< 3
mo).
• Uninodular tumour VS multinodular
• Vascular invasion- peritumoral, portal vein
thrombosis (10% at px, 25% in the course).
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34. PROGNOSIS
• Tumour marker- Negative AFP survive longer. AFP
reflect the rate of tumour growth. (Johnson et al.
1980).
• Signs/Symptoms- Pain/Hepatomegaly/Liver failure
etc- poor prognosis.
• Stage/Grade of disease: (Johnson PJ. Prognostic
factors in Cancer. UICC,2001)-TNM-6, Okuda, BCLC
• Edmondson-Steiner grade (without MVI).
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35. PROGNOSTIC FACTORS IN HCC -UICC
Prognostic
factors
Tumour related Host related Environmental
related
Essential • Tumour size
• Vascular
invasion
• Portal vein
thrombosis/in
vasion
• Resectability
Liver function
(LFT, Child’s,
Clinical signs and
symptoms of
liver disease)
Birth in a high
HCC incidence
area
Additional Multifocal
disease
Performance
status
Ready access to
liver
transplantation
New and
promising
P53 gene
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36. MAJOR REASONS FOR POOR PROGNOSIS
• Background CLD
• Tumour and CLD have independent
natural histories
• Large reserve of the liver
• Aggressive nature of tumour in some
geographical areas
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37. PREVENTION
The soul of prevention of HCC: primary prevention of HBV:
-Universal INFANT hepatitis B vaccination of newborns
WGO- the only effective strategy
• Gambia/Senegal/Taiwan experience
-Infants of HBV-positive mothers
-PEP
-Healthcare workers
-Multiple sexual partners
-Dwellers in closed institutions
-Multiply transfused SCD, haemophiliacs
-Haemodialysis patients
-IVDU
-Transplant recipients
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38. PREVENTION
• Health education: metabolic syndrome, Innovative
campaigns eg TfD, DfD etc
• ANC screening
• Follow-up of carriers
• Treatment of chronic hepatitis
• Screening of blood/products -NBTS
• Control of HIV infection
• Specialized centres of excellence for infectious and
liver disease
• Coffee decrease risk of HCC. Bamia et al. Int. J.
Cancer 20156/13/2015 SOGHIN ILORIN 2015 38

39. PREVENTION
• Screening (AORTIC 2013)
-First level screening: for risk factors -primary,
secondary, and tertiary healthcare levels and various
“entry points”
-Second level screening: for HCC (non-invasive,
readily available and affordable):
AFP: main screening parameter for HCC
Combination of AFP and liver USS
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40. PREVENTION
• Combination of markers:
-increases predictability of HCC compared to AFP
alone.
-anti-p53 antibody, SCCA, CTA, p53 codon 249
mutations using plasma cell-free DNA.
• Glypican 3 has also been found to be specific to
HCC
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41. CHALLENGES IN AFRICA
• Low immunisation coverage for HBV
• Lack of trained hepatologists, GI pathologists and
specialists GI nurses
• Poor health infrastructure for liver diseases
• Lack of population-based cancer registries with
accurate data and notification of cause of death
• Late presentation
• High illiteracy rate
• Cultural beliefs and practices
• Charlatanry/Quackery6/13/2015 SOGHIN ILORIN 2015 41

42. Liver Cancer strategies (AORTIC)
Strategies must be anchored on the tripod of:
• Prevention
• Early detection or diagnosis
• Treatment and palliative care.
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43. STRATEGIES
A. Capacity development strategies:
1. Train doctors and laboratory scientists about
current devts in the mgt of hepatitis.
2. Equip secondary and tertiary health facilities for
screening of hepatitis viruses
3. Continuous health education of health workers
and the general population.
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44. Liver Cancer strategies
B. Research strategies
4. National govts and funding agencies to encourage
research on vaccine for HBV and HCV.
5. Devt of new non-invasive tests for biomarkers of HCC
using serological antibodies, metabolomics and proteomics
6. Generation of data base for HBV, HCV and Cancer
registries
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45. LIVER CANCER STRATEGIES
C. Training strategies
7. Train and retrain health workers about available preventive
and therapeutic interventions for viral hepatitis.
D. Community engagement strategies
8. Voluntary screening for viral hepatitis.
9. Health education and encouragement of active
participation in the World Hepatitis Day
10. Improved grain storage to prevent aflatoxin
contamination, through proper care of crops and food
storage.
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46. LIVER CANCER STRATEGIES
E. Policy engagement strategies
11. Compulsory universal newborn immunisation for
HBV.
12. Surveillance and Screening programmes eg
Downstaging cancer in rural areas in Tanzania. Ngoma
et al. Int. J. Cancer 2015.
13. Vaccination of at risk groups such as health
workers,
prostitutes, butchers etc.
14. Establishment of effective Task force on Hepatitis
15. Prevention of alcohol abuse6/13/2015 SOGHIN ILORIN 2015 46

47. WGO ASK A LIBRARIAN
Justus Krabshuis’ message from WGO:
• Offers a unique service to members of Member Societies of
Gastroenterology (with no easy access to high quality clinical and research
information).
• The 'Ask a Librarian' desk is manned by professional medical librarians who
can provide support with searching all relevant research and clinical
literature databases for you.
• Help you find a simple citation or provide support for complex evidence-
based gastroenterology literature searches.
• Should you be planning a lecture or writing a paper and need an overview
of the latest or all available literature on your topic, simply complete the
form to be found on the website.
• Whilst exceptions can be made - please note that this service is made
available to those countries with poor access as defined by HINARI criteria.6/13/2015 SOGHIN ILORIN 2015 47

48. 6/13/2015 SOGHIN ILORIN 2015 48
“The ultimate challenge in managing HCC in the
Black African Will, of course, be to prevent rather
than attempt to cure this devastating tumour.
This goal Will require the elimination of the major
causes of HCC as it occurs in the sub-continent , in
particular chronic HBV infection, but also dietary
exposure to the fungal toxin , aflatoxin B1, chronic
HCV infection, and dietary iron overload in the
African”.
-Professor Michael C. Kew. Challenges of managing hepatocellular
carcinoma in sub-Sahara Africa. Nig. J. Gastroenterol & Hepatol. 2009.
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