UPDATE

1. ARKAPROVO ROY
MS, GENERAL SURGERY
ASSISTANT PROFESSOR
MALDA MEDICAL COLLEGE
WEST BENGAL
INDIA

2.  Most common primary malignancy of the liver.
 Geographical distribution is clearly related to the
incidence of Hepatitis B infection.
 The highest incidence in - Southeast Asia and
Tropical Africa.
 The lowest incidence in - Australia, North
America and Europe.
 Epidemiologic evidence strongly suggests that
HCC is largely related to environmental factors.

3.  A significant rise in the incidence of HCC in the
United States and other Western countries over
the last 35 years.
 The explanation for this rising incidence is not
understood.
 The emergence of hepatitis C (HCV)infection
and immigration patterns have been suggested.

4.  HCC is two to eight
times more common in
males compared with
females in low- and
high-incidence areas.
 The higher incidence in
males is probably
related to higher rates of
associated risk factors.
 HBV infection,
 Cirrhosis,
 Smoking,
 Alcohol abuse, and
 Higher hepatic DNA
synthesis in cirrhosis.

5. Infections
 Hepatitis B virus
 Hepatitis C virus
Cirrhosis
 Alcohol induced
 Autoimmune hepatitis
 Primary biliary cirrhosis
Environmental
 Aflatoxins
 Pyrrolizidine alkaloids
 Thorotrast
 N-nitrosylated compounds
Metabolic diseases
 Hemochromatosis
 Alpha1-antitrypsin
deficiency
 Wilson's disease
 Porphyria cutanea tarda
 Type 1 and 3 glycogen
storage disease
 Galactosemia
 Citrullinemia
 Hereditary tyrosinemia
 Familial cholestatic
cirrhosis

6. INFECTION:
 75% - 80% of HCC cases are related to HBV (50%
to 55%) or HBC (25% to 30%) infections.
 Studies have estimated relative risks of 5 to 100
for the development of HCC in HBV-infected
individuals compared with non-infected
individuals.

7. Other evidence includes the following observations:
(1) Geographic areas high in HBV infection
have high rates of HCC;
(2) HBV infection precedes the development
of HCC.
(3) the sequence of HBV infection to cirrhosis
to HCC is well documented; and
(4) the HBV genome is found in the HCC genome.
The HBV has no known oncogenes, but insertional
mutagenesis into hepatocytes may be a contributing
factor to the development of HCC.

8. The risk of HCC is not simply related to HBV
exposure, but requires chronic infection (i.e.,
chronically positive HBV surface antigen).
There is a higher risk of persistent infection
(carrier state) when the infection is acquired at
birth or during early childhood.

9.  Hepatitis C has been discovered to be a major
cause of chronic liver disease in Japan, Europe,
and the United States, where there is a
relatively low rate of HBV infection.
 HBV and HCV infection are both independent
risk factors for the development of HCC but
probably act synergistically when an
individual is infected with both viruses.

10.  Factors associated with a more rapid
progression include male gender, chronic
alcohol use, and older age at the time of
infection.
 HCV is an RNA virus that does not integrate
into the host genome and therefore the
pathogenesis of HCV-related HCC may be
related to more chronic inflammation and
cirrhosis than to direct carcinogenesis.

11.  The true relationship of cirrhosis and HCC is
difficult to ascertain, and suggestions of
causation remain speculative.
 Cirrhosis is not required for the development
of HCC and hepato-carcinogenesis is not an
inevitable result of cirrhosis.
 The relationship of cirrhosis and HCC is
further complicated by the fact that they share
common associations.

12.  Furthermore, some associations (e.g., HBV
infection, hemochromatosis) are associated
with higher risk of HCC,
 whereas others (e.g., alcohol, primary biliary
cirrhosis) are associated with a lower risk of
HCC.
 Research has demonstrated that cirrhotic livers
with higher DNA replication rates are
associated with the development of HCC.

13.  Chronic alcohol abuse has been associated with an
increased risk of HCC and there may be a
synergistic effect with HBV and HCV infection.
 Alcohol causes cirrhosis, but has never been
shown to be directly be carcinogenic in
hepatocytes.Thus, alcohol likely acts as a
cocarcinogen.
 Cigarette smoking has been linked to the
development of HCC, but the evidence is not
consistent and the contributing risk independent of
viral hepatitis is likely small.

14.  Most commonly, patients presenting with HCC are
men 50 to 60 years of age who complain of right upper
quadrant abdominal pain and weight loss, and have a
palpable mass.
 In countries endemic for HBV, presentation at a
younger age is common and probably related to
childhood infection.

15.  Unfortunately, in unscreened populations,
HCC tends to present at a later stage because of
the lack of symptoms in early stages.
 Presentation at an advanced stage is often with
vague right upper quadrant abdominal pain
that sometimes radiates to the right shoulder.
 Nonspecific symptoms of advanced
malignancy such as anorexia, nausea, lethargy,
and weight loss are also common.

16.  Another common presentation of HCC is
hepatic decompensation in a patient with
known mild cirrhosis or even in patients with
unrecognized cirrhosis.
 HCC can rarely present as a rupture, with the
sudden onset of abdominal pain followed by
hypovolemic shock secondary to intraperitoneal
bleeding.

17. Other rare presentations include
 hepatic vein occlusion (Budd-Chiari syndrome),
 Obstructive jaundice,
 hemobilia, and
 fever of unknown origin.
Less than 1% of cases of HCC present with a
paraneoplastic syndrome, usually
 hypercalcemia, hypoglycemia, and erythrocytosis.
Small incidentally noted tumors have become a more
common presentation because of the knowledge of
 specific risk factors,
 Screening programs for diagnosed HBV or HCV
infection,
 Increasing use of high-quality abdominal imaging.

18. For patients suspected of suffering from HCC,
the aims of diagnostic investigations are
 (1) verification of diagnosis,
 (2) determine extent of disease,
 (3) determine functional liver reserve, and
 (4) assess biologic determinants that are
predictors of long-term prognosis.

19.  Diagnosis is often confirmed with a biopsy
 Diagnosis can sometimes be confirmed with blood
or imaging tests
 Physical examination
 Blood test for alpha-fetoprotein (AFP); 50%-70% of
people with primary liver cancer have elevated
levels
 Ultrasound of the abdomen
 Computed tomography (CT or CAT) scan
 Magnetic resonance imaging (MRI)
 Angiogram
 Laparoscopy

20.  Radiologic investigation is a critical part of the
diagnosis of HCC.
 Ultrasound plays a significant role in screening
and early detection of HCC, but definitive
diagnosis and treatment planning rely on CT
and/or MRI.
 Contrast-enhanced CT and MRI protocols
aimed at diagnosing HCC take advantage of
the hypervascularity of these tumors, and
arterial phase images are critical to assess the
extent of disease adequately.

21.  CT and MRI also evaluate the extent of disease
in terms of peritoneal metastases, nodal
metastases, and extent of vascular and biliary
involvement.
 Detection of bland or tumor thrombus in the
portal or hepatic venous system is also
important and can be diagnosed with any of
these modalities.

22.  AFP measurements can be helpful in the diagnosis
of HCC.
 An AFP level higher than 20 ng/mL is noted in
approximately 75% of documented cases of HCC.
 False-positive elevations of serum AFP levels can
be seen in inflammatory disorders of the liver,
such as chronic active viral hepatitis.
 The specificity and positive predictive values of
AFP improve with higher cutofflevels (e.g., 400
ng/mL), but at the cost of sensitivity.
 With improvements in imaging technology and
the ability to detect smaller tumors, AFP is largely
used as an adjunctive test in patients with liver
masses.
 AFP levels are particularly useful in monitoring
treated patients for recurrence after normalization
of levels.

23.  If atypical features appear on imaging, a biopsy
should be obtained for histologic diagnosis.
 For hepatic nodules larger than 2 cm, a triple-
phase CT or MRI scan is required if typical
features of HCC are identified in combination
with an AFP level higher than 200 ng/mL.
 If typical features appear on imaging, the
diagnosis of HCC is confirmed.
 If atypical features are seen, then biopsy is
required to confirm the histologic diagnosis.

24.  At present, the diagnosis of HCC can be made
according to the guidelines of the Barcelona-2000
European Association for the Study of the Liver
(EASL) Conference and to successive modifications
of guidelines from the American Association for
the Study of Liver Disease (AASLD).
 Pathologic diagnoses of HCC are made according
to the International Working Party criteria. For
hepatic nodules from 1 to 2 cm in size, a
triplephase CT and MRI scan must show typical
features of HCC— arterially enhancing mass with
washout of contrast in delayed phases—to confirm
the diagnosis.

25.  Histologically, HCC is graded as well, moderately, or poorly
differentiated. The grade of HCC, however, has neverbeen shown to
predict outcome accurately.
 Grossly, the growth patterns of HCC have been classified in a
number of ways.
 The most useful scheme divides HCC into three distinct growth
patterns that have distinct relationships to outcome. The hanging
type of HCC is connected to the liver by a small vascular stalk and is
easily resected without sacrifice of a significant amount of adjacent
non-neoplastic liver tissue. This type can grow to substantial size
without involving much normal liver tissue.
 The pushing type of HCC is well demarcated and often contains a
fibrous capsule. It is characterized by growth that displaces vascular
structures rather than invading them. This type is usually resectable.
 The last type is called the infiltrative type of HCC, which tends to
invade vascular structures, even at a small size. Resecting the
infiltrative type is often possible, but positive histologic margins are
common.

26.  Small tumors (<5 cm) usually do not fall into any
of these groups and are often discussed as a
separate entity.
 Finally, HCC can present in a multifocal manner.
 Most HCC probably starts as a single tumor, but
ultimately multiple satellite lesions can develop
secondary to portal vein invasion and metastases.
Multifocal tumors throughout the liver probably
represent the end stage of HCC, with multiple
metastases and multiple primary tumors.

27.  There are a large number of treatment options for
patients with HCC, reflecting the heterogeneity of
this disease and the lack of a proven superior
treatment, except complete resection.
 Selection of the appropriate patient for resection is
critical and must take into account the condition
of the liver and extent of disease.
 Patients with Child-Pugh class B or C cirrhosis or
portal hypertension do not tolerate resection.

28. Surgical
 Resection
 Orthotopic liver
transplantation
Ablative
 Ethanol (EtOH) injection
 Acetic acid injection
 Thermal ablation
(cryotherapy, radiofrequency
ablation, microwave)
Transarterial Embolization
 Chemoembolization
 Radiotherapy
Combination Transarterial
and Ablative:
External Beam Radiation
Systemic
 Chemotherapy
 Hormonal
 Immunotherapy

30. Measurements 1 point 2 points 3 points
Bilirubin (mg/dL) 1–1.9 2–2.9 >2.9
Prothrombin
time
prolongation
(secs)
1–3 4–6 >6
Albumin (g/dL) >3.5 2.8–3.4 <2.8
Ascites none mild moderate to
severe
Child's A: 5–6 points; B: 7–9 points; C: 10–15 points.

31. CLINICAL
PARAMETERS
CUT OFF VALUES POINTS
Child-Pugh class A 0
B 1
C 2
Tumor morphology Uninodular, <50% extension 0
Multinodular, <50% extension 1
Massive or extension >50% 2
AFP (ng/dL) <400 0
>400 1
Portal vein thrombosis No 0
Yes 1
Score ranges from 0 to 6; a score of 4 to 6 is generally considered advanced
disease, whereas a score of 0 to 3 has the potential for long-term survival.

32.  Most successful in patients with small tumors
(smaller than 5 cm) and with good liver
function
 Hepatectomy: portion of the liver is removed
when the cancer is limited to one part of the
liver
 Liver transplantation: used to treat cancer
confined to the liver if a suitable donor is
found. Must fulfill strict criteria

33.  A variety of prognostic factors predictive of survival
after resection have been identified, but none are
universally agreed on .
 The most commonly cited negative prognostic factors
are
tumor size, cirrhosis, infiltrative growth pattern,
vascular invasion, intrahepatic metastases, multifocal
tumors, lymph node metastases, margin less than 1 cm,
and lack of a capsule.
 The best outcomes are found in patients with single
small tumors, but size alone should not contraindicate
resection.
 Multifocal tumors and major vascular invasion are
generally associated with a poor outcome but some
groups advocate resection in highly select patients.

35. 1. Percutaneous
2. Laparoscopy
3. Open method
Percutaneous technique is best choice
for early stage liver tumor who are not
surgical candidates.

36.  Single tumor < 5cm
 Multiple tumors< 3 nodule and < 3cm
 No evidence of vascular invasion
 No extrahepatic spread
 Performance status test– 0
 Cirrhosis with Child Pugh class A or B

37. A-Chemical ablation :-
1- ethanol injection
2- acetic acid injection
B- Thermal ablation :-
1- RFA
2- Microwave
3- Laser ablation
4- Cryoablation

38.  Mechanism:- coagulative necrosis,
protein denaturation
chemical occlusion of small tumor vessels.
 Well established technique for cirrhotic liver with
tumor nodule results in 70% tumor necrosis but
ineffective in metastatic nodule.
 Performed under USG guidence.
 4-6 session is required

39.  Radiofrequency ablation uses electrical current,
passed through a small needle placed directly
into a liver tumor, to destroy cancer cells with
heat
 As the temperature within the tissue becomes
elevated beyond 60°C, necrosis happens. RFA
can be performed by percutaneous, surgical, or
laparoscopic approaches

40.  The electrical current is actually passed
across an array of hook electrodes that
are deployed from the tip of the needle
after the needle is placed into the
tumor. The hook electrodes look like
the ribs of an umbrella, with a diameter
of 3.5 cm when fully deployed.
 Early RFA electrode were unipolar and
they produce only 1.5-2 cm cylindrical
zone of necrosis, but current were
multiarray electrode ,created larger
more spherical zone of ablation .

41.  RFA has been most widely assesed alternate to PEI for local
ablation. Compele tumor necrosis was shown by pathology in
83% of tumor <3 cm and 88% of tumor in nonperivascular
location.
 In two comparative studies , the rate of complete tumor
response shown by post treatment CT were higher in patient
who underwent RFA compared with patient who underwent
PEI.
 In a comparative study of RFA versus surgical resection in
patients with Child-Pugh score of 5 and a single HCC of <4
cm , no difference in over all survival and cumulative
recurrence free survival rate were observed, despite a higher
rate of local recurrence in RFA group.

42.  Three separate multicenter survey reported acceptable
morbidity and mortality rate. The mortality range from
0.1-0.5%, major complication 2.2 – 3.1% and minor
complications 5-9%.
 Most common cause of death were sepsis, hepatic
failure, colonic perforation and portal vein thrombosis .
 The most common of intraperitonial bleeding, hepatic
abscess, bile duct injury, hepatic decompensation and
ground pad burn.

43.  Abscess, one of the most frequent complication of RFA ,
typically occurs 1 week after ablation and require
percutaneous or surgical drainage . Patients with bilio-
enteric anastomosis or biliary stenting seem to have a
higher rate of abscess formation.
 Tumor seeding vary from 0.5 to 12% , possibly reflecting
difference in follow-up.
 Injury to bile duct during RFA can result in stenosis and
proximal biliary dilatation. Most physician agree that
tumors within 15 to 20 mm of a major bile duct should
not be treated by RFA.

44.  RFA can treat primary or metastatic liver tumors
with success rate of 90% and little morbidity or
mortality.
 Best for early stage liver tumor who are not
candidate for surgery.
 A randomized prospective study is necessary to
determine survival and recurrence rate after RFA
versus resection.
 For now, resection remains the initial choice for
patients whose disease is confined to liver. RFA
may be alternate for patients unable to undergo
resection.

45.  RFA can treat primary or metastatic liver tumors with
success rate of 90% and little morbidity or mortality.
 Best for early stage liver tumor who are not candidate
for surgery.
 A randomized prospective study is necessary to
determine survival and recurrence rate after RFA
versus resection.
 For now, resection remains the initial choice for
patients whose disease is confined to liver. RFA may be
alternate for patients unable to undergo resection.

46. Image courtesy of www.hopkinscoloncancercenter.org.

47.  The use of high-energy x-rays to destroy cancer
cells
 The use of high energy x-rays or other particles to
destroy cancer cells
 Internal beam: use of implants inside the body.
Radioactive beads may be inserted into the artery
that supplies the tumor with blood
 External beam: outside the body – rarely used for
HCC
 Side effects can include fatigue, mild skin
reactions, upset stomach and loose bowel
movements

48.  Use of drugs to kill cancer cells
 One or a combination of drugs may be used
 Side effects may include nausea and vomiting,
loss of appetite, diarrhea, fatigue, and risk of
infection
 Side effects often go away after treatment is
finished

49.  Targets faulty genes or proteins that contribute
to cancer growth and development
 Sorafenib (Nexavar), an anti-angiogenic and
anti-proliferative drug (starves the tumor by
disrupting its blood supply), may be used to
treat tumors that cannot be removed with
surgery

50. Characteristic
HCC Fibrolamellar
HCC
Male: Female 4:1–8:1 1:1
Median age 55 25
Tumor Invasive Well
circumscribed
Resectability <25% 50–75%
Cirrhosis 90% 5%
AFP + 80% 5%
HepB+ 65% 5%

51.  Targeting Signaling Pathways in HCC: Novel
Molecular Targeted Therapies on the Horizon

52. HCC CONTEXT
INVESTIGATIONAL
STRATEGIES
 Staging
 Sorafenib
– Sunitinib
– Brivanib
– Linifanib
– Sorafenib ± erlotinib
– Doxorubicin ± sorafenib
– Ramucirumab
– Everolimus ± sorafenib
– Tivantinib

53. NEW TARGETED AGENTS SORAFENIB COMBINATION THERAPY
 Sorafenib + chemotherapy
 Sorafenib + another targeted agent
 Brivanib
 Erlotinib
 Linifanib
 Sunitinib
 Bevacizumab
 Ramucirumab
 Everolimus

54.  VEGFR-2 and its ligands (including VEGF-A, -C,
and -D) are important mediators of angiogenesis
and angiogenesis is integral to HCC carcinogenesis
and pathogenesis
 Ramucirumab is a recombinant human IgG1
monoclonal antibody that binds to the extracellular
domain of VEGFR-2 with high specificity and
affinity
 Ramucirumab was well tolerated in 2 phase I
studies involving patients with advanced,
refractory solid tumors; 2 HCC patients (receiving
doses of 10 mg/kg q2w) achieved disease
stabilization on-study for 9 and 14 months,
respectively