Lecture in Surgery

1. HEPATOCELLULAR CARCINOMA
[HCC]
Dr. D.K.Sharma
M.S., MCh. (GI Surgery)
Prof. & Head, Deptt. Of Surgery
RNT Medical College, Udaipur, Raj.

2. EPIDEMIOLOGY

3. Worldwide Incidence of Hepatocellular Carcinoma
Epidemiology
High (> 30:100,000)
Intermediate (3-30:100,000)
Low or data unavailable (<
3:100,000)
Worldwide Incidence of Hepatocellular Carcinoma
Tumor incidence varies significantly, depending on geographical
location.

4. Epidemiology
 5th most common malignancy worldwide
 3rd most common cause of cancer related death
 5 yr survival < 10%
 Most common primary liver malignancy
 Reversal in cirrhosis
 Metastases >> Primary  Primary > Metastases
 80%-90% of HCC cases occur in cirrhotic livers

5. Epidemiology
 Male-to-female ratio
 5:1 in Asia
 2:1 in the United States
 Overall- 4:1
 Increases with age.
 53 years in Asia
 67 years in the United States.
 HCC incidence has tripled over last three decades
• Rising incidence of cirrhosis
• HCV (main reason)
• HBV
• Other (?NAFLD/insulin
resistance)
• Improved survival of patients
with cirrhosis

6. ETIOLOGY

7. • Hepatitis B
• increased risk 100 -200 fold
• 90% of HCC are positive for
HBs Ag
• Hepatitis C
• Cirrhosis- Any Cause
• 70% of HCC arise on top of
cirrhosis
• HBV, HCV, Alcoholic, NAFLD,
PBC
• Toxins -Alcohol -Tobacco -
Aflatoxins
• States of insulin resistance
• Overweight in males
• Diabetes mellitus
• Inherited metabolic diseases
• Hemochromatosis
• Alpha-1 antitrypsin deficiency
• Glycogen storage disease
• Porphyria cutanea tarda
• Tyrosinemia
• Autoimmune hepatitis
• Other Risk Factors
• Hepatic Adenomas
• Alcohol : Bad with concurrent
virus
• Aflatoxin- 3x
Etiology

8. PATHOGENESIS

9. Malignant Transformation
Multistep
HCC[2]
Potential Targets
Oxidative stress and
inflammation
Viral oncogenes Carcinogens
Growth factors Telomere
shortening
Cancer stem
cells
Loss of cell cycle
checkpoints
Antiapoptosis Angiogenesis
Normal liver
Liver cirrhosis
Hepatitis C
Hepatitis B
Ethanol
NASH
Epigenetic alterations
Genetic alterations
Dysplastic nodules[1]
1. Tornillo L, et al. Lab Invest. 2002;82:547-553.
2. Verslype C, et al. AASLD 2007. Abstract 24.

10.  Fibrolamellar Hepatocellular
Carcinoma
- Distinctive clinical and pathologic
subtype of hepatocellular carcinoma
(HCC)
-Young adults (20-40 y/o) without
underlying parenchymal liver disease
- AFP usually not elevated
- Non-encapsulated but well
circumscribed and contains fibrous
lamellae
- Arterial Enhancement
- Central Scar- 40% (Hypo, Delayed
enhancement
- Slowly growing tumor
- Better Prognosis

11. Signs & symptoms
 Nonspecific symptoms
 Abdominal pain
 Fever, chills
 Anorexia, Weight loss
 jaundice
 Physical findings
 Abdominal mass in one third
 Splenomegaly
 Ascites
 Abdominal tenderness

12. SCREENING / SURVEILLANCE FOR
HEPATOCELLULAR CARCINOMA
SOC

13. AASLD Practice Guidelines
(a) which patients are at high risk for the development of HCC &
should be offered surveillance
 AASLD recommends surveillance using AFP + US every 6-12 months for at-risk patient groups:
 Hepatitis B carriers
 Asian males >40 years
 Asian females >50 years
 All cirrhotic hepatitis B carriers
 Family history of HCC
 Africans >20 years
 Non-cirrhotic hepatitis B carriers with high HBV DNA levels or more severe current/past
levels of inflammatory activity
 Cirrhosis due to hepatitis C, alcohol, or other causes
 HCV: No screening before cirrhosis; and should screen once cirrhosis develops, but no specific
methods.
 Rationale for 6-month screening/surveillance interval
 Doubling time: median = 6 mo (range, 1-19 mo)
 Growth from 1 to 3 cm: 4 mo for most aggressive, 18 mo for moderately
aggressive, 5 yr for indolent HCC
 Median detectable subclinical period for HCC = 3.2 yr

14. DIAGNOSIS OF HCC

15. Diagnosis
(b) What investigations are required to make a definite
diagnosis
I. AFP produced by 70%of HCC
a) > 400ng/ml
b) AFP over time
II. Imaging
a) Focal liver lesion cirrhotic patient  highly likely to be HCC
b) Spiral CT of the liver
c) MRI with contrast enhancement
III. Biopsy is rarely required for diagnosis
a) Seeding in 1–3%.
b) Biopsy of potentially operable lesions should be avoided where
possible

16. STAGING

17. Staging Systems for Hepatocellular Carcinoma
Staging Systems for HCC
• Okuda Staging System
• Cancer of the Liver Italian Program (CLIP)
• American Joint Commission on Cancer (AJCC)/Union
Internacional Contra la Cancrum (UICC) Tumor Node Metastasis
(TNM)
• Japanese Staging System and Japan Integrated Staging score
(JIS)
• Chinese University Prognostic Index (CUPI)
• Barcelona Clinic Liver Cancer (BCLC)
• Group d’Etude de Traitement du Carcinoma Hepatocellulaire
(GRETCH)

18. MANAGEMENT

19. Management
 Liver transplantation
 Resection
 Tumor ablation
 Radiofrequency thermal ablation
 Cryotherapy
 Alcohol injection
 Chemoembolization
 Targeted molecular therapy
 Chemotherapy
 Regional/systemic
Potentially
curative

20. SURGICAL TREATMENT

21. Surgery
 Only proven potentially curative therapy
 Hepatic resection or liver transplantation
 Resection:
 HCC and a non-cirrhotic liver (including fibrolamellar variant)
 Highly selected patients with cirrhosis
 Well preserved hepatic function (Child-Pugh A) who are unsuitable for liver transplantation
 Carries a high risk of postoperative decompensation.
 Recurrence rates of 50–60% after 5 years after resection are usual (intrahepatic)
 Patients with single small HCC (≤5 cm) or up to three lesions ≤3 cm
 Involvement of large vessels (portal vein, Inferior vena cava) doesn’t automatically mitigate
against a resection; especially in fibrolamellar histology
 No RCTs comparing the outcome of resection and transplantation for HCC.
 Perioperative mortality in experienced centres remains between 6% and 20% depending on
the extent of the resection and the severity of preoperative liver impairment.
 The majority of early mortality is due to liver failure.

22. Liver Transplantation
 The only treatment with a major chance of cure for HCC
 Should be considered in any patient with cirrhosis
 Patients with replicating HBV/ HCV-Worse outlook
 Recurrence
 previously not considered candidates for transplantation.
 Effective antiviral therapy is now available and patients
with small HCC, should be assessed for transplantation

23. Liver Transplant for HCC in
cirrhosis
Milan Criteria (Stage I+II)
Single, not > 5cm Up to 3, none > 3cm
+
Absence of Macroscopic Vascular Invasion
Absence of Extrahepatic Spread
Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.

24. NON-SURGICAL TREATMENT

25. Should only be used where surgical therapy is not possible.
1. Percutaneous ethanol injection (PEI)
2. Radiofrequency ablation (RFA)
3. Cryotherapy
4. Chemoembolization
5. Selective Internal Radiation Therapy [SIRT]
6. Systemic chemotherapy
7. Hormonal therapy
8. Interferon-alfa
9. Retinoids and adaptive immunotherapy (adjuvant)
10.Targeted Therapy
11.Other Agents

26. Treatment (non-Surgical)
Selection of agents for targeted therapy
Name Target
Gefitinib
Erlotinib
Lapatanib
Cetuximab
Bevacizumab
Sorafenib (Nexavar)
Sunitinib
Vatalanib
Cediranib
Rapamycin
Everolimus
Bortezomib (Velcade)
EGFR
EGFR
EGFR
EGFR
VEGF
Raf1, B-Raf, VEGFR , PDGFR
PDGFR, VEGFR, c-KIT, FLT-3
VEGFR, PDGFR, c-KIT
VEGFR
mTOR (mammalian target of rapamycin)
mTOR
Proteasome

27. Summary
 Hepatocellular Carcinoma
 HCC is one the most rapidly increasing cancers
 Risk driven by cirrhosis
 Viral load in HBV
 Prevention is possible by vaccine
 Treatment of underlying disease decreases risk
 Treatment is mainly palliative
 The 5-year survival is 8-12%
 Less than 20% are candidates for surgery/transplant at
diagnosis
 HCC is curable in some patients
 Screening to detect early HCC is the main priority of
primary care physicians
 Referral to a tertiary center indicated
 Team approach is current standard to manage HCC