Introduction
INTRODUCTION
There is a range of alternative ventilator strategies that
are mostly used when conventional ventilation has failed to
improve gaseous exchange in patients. These interventions also
involve high risks and have limited clinical evidence (Bill
Tunnicliffe, 2010).
Conventional mechanical ventilation is a critical element
of the management of patients with respiratory failure. It must
be remembered that it is a supportive rather than therapeutic
intervention, and that its application has limitations. It is also
potentially injurious to the ventilated lung, particularly in the
presence of intrinsic lung diseases or acute lung injury. A range
of interventions have been devised to try to extend the potential
range for conventional ventilation, as well as alternative
strategies to support patients with respiratory failure beyond the
current limits of conventional ventilation (Bill Tunnicliffe,
2010).
Many critically ill patients are unable to effectively clear
secretions that accumulate in the central and peripheral airways.
This can be due to factors such as increased secretion
production, impaired cough reflex, weakness, and pain. The
presence of an endotracheal tube prevents closure of the glottis
to generate the high expiratory pressures necessary for an
1
Introduction
effective cough, thereby promoting the retention of secretions.
In addition, in critically ill patients, cilia in the pulmonary tree
are impaired in function and reduced in number. This leads to
an increased risk of aspiration, atelectasis, and pneumonia,
which are all detrimental in the critically ill patient. Adjunctive
respiratory therapy is able to prevent and treat respiratory
complications that are encountered in the critically ill patient.
Measures available range from those that are simple to institute,
such as proper body positioning and suctioning, to more
complex
interventions
such
as
chest
physiotherapy,
bronchoscopy, and use of aerosolized/inhaled medications that
act directly on the pulmonary system. (Konrad et al., 1994)
2
Aim of the Work
Aim of the work
The aim of this essay is to throw some lights on adjunctive
respiratory therapy in the ICU and to explore the new
approaches in the field of adjunctive respiratory therapy for
critically ill patients.
3
Anatomy and Physiology of respiration
ANATOMY OF THE LIVER
T
he liver is the largest glandular structure in the body. It
weighs 1200-1500 gm (Sherlock and Dooley, 2002).
Hepatic surfaces:
The superior, anterior, and posterior surfaces of the
liver are continuous at a rounded border, and so called
globally disphragmatic surface. A sharp inferior border
separates the right and anterior surfaces from the inferior
visceral surface. So, the liver has two surfaces, the
diaphragmatic and the visceral surfaces. The diaphragmatic
surface is convex, molded to the diaphragm. The visceral
surface is flat, slopes down to the right and forward too.
Shallow visceral impressions are molded on this surface.
From the diaphragmatic and visceral surfaces peritoneal
folds pass respectively across to diaphragm and down to
the stomach (McMinn, 1994).
Arterial supply of the liver
The liver has a double blood supply from the hepatic
artery (30%) and the portal vein (70%). The right and left
hepatic arteries carry oxygenated blood to the liver and the
portal vein carries venous blood containing the products of
digestion absorbed form the gastrointestinal tract. The
arterial blood is conducted to the central vein of each liver
lobule (Gore and Remer, 2000).
4
Anatomy and Physiology of respiration
The common hepatic artery arises from the celiac
trunk. After giving off the gastroduodenal artery. It passes
between the layers of the lesser omentum as the hepatic
artery proper. This artery ascends in the free edge of the
lesser omentum anterior to the portal vein and to the left of
the bile duct. Near the porta-hepatis the hepatic artery
proper divides into right and left hepatic arteries (Poston
and Blumgart, 2003).
The portal vein supplying most of the blood is
formed posterior to the neck of the pancreas by the union of
the superior mesenteric and splenic veins. It runs in the
right edge of the lesser omentum, posterior to the bile duct
and hepatic artery. The portal vein terminates by dividing
into right and left branches each of which supplies about
half of the liver (Williams et al., 1999).
Venous drainage of the liver
The hepatic veins draining blood from the liver are
formed by the union of the central veins in its lobules. The
hepatic veins open into the inferior vena cava just inferior
to the diaphragm (Menu and Lencioni, 1999).
Bile ducts:
The intrahepatic bile ducts have a segmental and
lobular pattern that closely follows the course of the hepatic
artery, so that the right and left lobes of the liver are
5
Anatomy and Physiology of respiration
respectively drained by the right and left hepatic ducts
whereas the caudate lobe is drained by several ducts joining
both the right and left hepatic ducts. The right and left
hepatic ducts join at the liver hilum to constitute the
common hepatic duct. The common hepatic duct in turn
joins the cystic duct to form the common bile duct (Poston
and Blumgart, 2003).
The common bile duct, the mean diameter of which
is about 6 mm, courses downwards anterior to the portal
vein in the free edge of the lesser omentum to drain finally
into the duodenum (Blumgart and Fong, 2000).
Lymphatics of the liver:
There are numerous lymphatics within the liver
parenchyma and liver capsule. The deep lymphatics carry
approximately 80% of the hepatic lymph and converge into
two main trunks. The major trunk passes into lymph nodes
in the porta hepatic, then to the retropyloric nodes and so to
the celiac nodes. The smaller trunk accompanies hepatic
veins and terminates in lymph nodes near the IVC (Gore
and Remer, 2000).
The superficial lymphatics originate in the
subperitoneal tissue of the liver surface. Most visceral
surface is drained by lymph nodes in the port hepatic. The
diaphragmatic surface drains into the lymph nodes around
IVC or towards the celiac nodes via the inferior phrenic
6
Anatomy and Physiology of respiration
nodes. through the bare area and coronary ligaments, some
lymphatics penetrate the diaphragm to enter the
retrosternal, and phrenic nodes, then to the internal
mammary nodes, to the right thoracic duct (Williams et al.,
1999).
Functional anatomy: sectors and segments:
The liver is separated into right and left hepatic lobes,
by a vertical line (Cantlie's line) drawn from the gall
bladder fossa to the IVC. The middle hepatic vein can be
found within the liver parenchyma along this line. The left
lobe is further divided into a medial sector (quadrate lobe)
and a lateral sector. The right lobe is further divided into
anterior and posterior sector. The caudate lobe is generally
considered separately because it usually receives portal
pedicle branches from both the right and left portal veins
and has an isolated hepatic venous drainage through
multiple short veins that enter directly into IVC (Byrd,
2001).
This separation, however, does not correlate with
blood supply or biliary drainage. A functional anatomy is
now recognized based upon studies of vascular and biliary
drainage made by injecting vinyl into the vessels and bile
ducts. This classification correlates with that seen by
imaging techniques. Three plains separate the four sectors
7
Anatomy and Physiology of respiration
and contain the three major hepatic vein branches (Menu
and Lencioni, 1999).
The left, middle, and right hepatic veins course in
three vertical planes called vertical scissurae, which divide
the liver into four sectors. Each of these four sectors is
subdivided into segments base don a transverse line drawn
through the main right and left portal veins within these
sectors, known as the transverse scissurae (Byrd, 2001).
Closer analysis of these four hepatic sectors produces
a further subdivision into segments (Fig. 1). The right
anterior sector contains segments V and VIII, right
posterior sector contains VI and VII; left medial sector
contains IV; left lateral sector contains segments II and III.
There is no vascular anastomosis between the macroscopic
vessels of the segments but communications exist at
sinusoidal level. Segment I is the equivalent of the caudate
lobe, it is separated from the other segments. This
functional anatomical classification allows interpretation of
radiological data and is of importance to the surgeon
planning a liver resection (Leeuwen et al., 1994).
8
Anatomy and Physiology of respiration
Figure (1): Functional anatomy of the liver (Sherlock and Dooley, 2002)
9
Histology of the Liver
HISTOLOGY OF THE LIVER
K
ieman (1833) introduced the concept of hepatic
lobule as the basic architecture. He described lobules
consisting of a central tributary of the hepatic vein and at
the periphery a portal tract containing the bile duct, portal
vein radicle and hepatic artery branch. Columns of liver
cells and blood containing sinusoids extend between these
two systems (Sherlock and Dooly, 2002).
The central hepatic canals contain radicles of the
hepatic vein and their adventitia. They are surrounded by a
limiting plate of liver cells. The portal triads contain the
portal vein radicle, the hepatic arteriole and bile duct with a
few round cells and a little connective tissue. They are
surrounded by a limiting plate of liver cells (Crawford et
al., 1998).
The liver cells (hepatocytes) comprise about 60% of
the liver. They are polygonal and approximately 30 µ in
diameter. The nucleus is single or, less often, multiple and
divides by mitosis. The lifespan of liver cells is about 150
days. The hepatocyte has three surfaces: one facing the
sinusoid and space of Disse, the second facing the
canaliculus and the third facing neighbouring hepatocytes.
There is no basement membrane. The sinusoids are lined by
endothelial cells. Associated with the sinusoids are the
phagocytic cells of the reticulo-endothelial system (Kupffer
10
Histology of the Liver
cells), and the hepatic stellate cells, which have also been
called fat storing cells, Ito cells and lipocytes. The space of
Disse is a tissue space between hepatocytes and sinusoidal
endothelial cells (Alison et al., 2000).
The excretory system of the liver begins with the bile
canaliculi. These have no walls but are simply grooves on
the contact surfaces of liver cells. Their surfaces are
covered by microvilli. The intralobular canalicular network
drains into thin walled terminal bile ducts or ductules
(cholangioles, canals of Hering) lined with cuboidal
epithelium. These terminate in larger (interlobular) bile
ducts in the portal canals (Crawford et al., 1998).
11
Epidemiology and Risk Factors
Methods to Improve Pulmonary Mucociliary Clearance
PERCUSSION
Percussion of the chest can aid in secretion clearance. It is
performed by clapping cupped hands over the thorax in
a rhythmic fashion or using mechanical devices that
mimic the same action. The energy of the force generated
by the cupped hands is transmitted through the thorax
to dislodge secretions. When used in conjunction with
postural drainage, this is an effective method to mobilize
secretions from the pulmonary tract. It is a technique often
used in the daily management of cystic fibrosis patients 3
and those with severe bronchiectasis.
HIGH-FREQUENCY CHEST COMPRESSION
High-frequency chest compression (HFCC) relies on
rapid pressure changes to the respiratory system during
expiration to enhance movement of mucus from the
peripheral airways to the central airways for clearance. This
method employs an automated vest device worn by the
patient. The vest is attached to an air-pulse generator,
and small volumes of gas are introduced into it at a rapid
rate ranging from 5 to 25 Hz, producing pressures up to 50
cm H2O. This technique, mainly used in cystic fibrosis
patients, is equivalent to conventional chest physiotherapy
techniques of percussion and postural drainage.
4-6
One study examined the use of HFCC in nine long-term
mechanically ventilated patients.7In this small
observational study, HFCC was compared to percussion
and postural drainage. No difference was seen in
the amount of sputum production, oxygen saturation,
or patient
comfort between the two methods, but HFCC was
determined to be
12
Epidemiology and Risk Factors
safe and felt to save staff time. It is difficult to apply this
technique to
most critically ill patients because of the size of the vest;
covering the
thorax may prevent adequate monitoring.
MANUAL HYPERINFLATION
Manual hyperinflation with an inflation bag and using
high tidal
volumes involves disconnecting the patient from the
ventilator. Typically the lungs are inflated slowly to 1.5 to
2 times the tidal volume or
to peak airway pressures of 40 cm H2
O (as measured by a manometer)
and then at end inspiration with an inspiratory pause
to allow for
filling of alveoli with slow time constants. This is followed
by a quick
release to allow for rapid expiration. The goal of manual
hyperinflation
is to recruit atelectatic lung regions to improve
oxygenation and
improve clearance of secretions. Similar to recruitment
maneuvers
described with mechanical ventilators, manual
hyperinflation leads to
only transient improvements in oxygenation, without any
long-term
clinically significant improvement in outcomes.
8-12
It also has the disadvantage of requiring a ventilator
disconnect, and this method can
be mimicked by a mechanical ventilator.
13
13
Epidemiology and Risk Factors
Contraindications to manual hyperinflation include
hemodynamic
compromise and elevated intracranial pressure. There is
also a risk of
barotrauma due to preferential inflation of open lung
regions that are
highly compliant compared to collapsed regions.
POSITIONING AND MOBILIZATION
Mobilization of patients in the intensive care unit (ICU)
either through
active or passive limb exercises may improve overall
patient well being
and, in the long term, may lead to better patient outcomes.
In a recent
randomized controlled trial of ventilated patients, the
addition of early
physiotherapy and occupational therapy to daily
interruption of sedation resulted in slightly more ventilatorfree days and improved functional capacity.
14
Positioning also plays an important role in improving
physiology
and outcome in critically ill patients. Position of the patient
with the
head of the bed elevated at least 30 degrees significantly
reduces the
risk of aspiration and ventilator-associated pneumonia.
15
Upright
positioning of patients in whom there is no contraindication
improves
14
Epidemiology and Risk Factors
lung volumes and therefore gas exchange and work of
breathing, especially in those where the supine or
semirecumbent position leads to
increased work of breathing. In some individuals with
unilateral lung
disease, positioning with the affected side up can lead
to improved
ventilation/perfusion ( V Q) matching by increasing
perfusion to the
dependent “good” side.
16,17
If atelectasis secondary to retained secretions is the
cause, having the affected side up leads to improved
postural drainage.
Postural drainage involves positioning the body to allow
gravity to
assist in the movement of secretions and is indicated in
patients with
sputum production of more than 25 to 30 mL/day who have
difficulty
clearing their secretions.
18
In cystic fibrosis, postural drainage with
percussion is an effective method to clear pulmonary
secretions and is
associated with improved lung function.
19,20
TRACHEAL SUCTION
Used in conjunction with other techniques to mobilize
secretions from
the peripheral to the central airways, suctioning is an
effective way of
15
Epidemiology and Risk Factors
removing secretions to improve bronchial hygiene. It can
be performed
using open methods where the patient is disconnected from
the ventilator and a disposable suction catheter is placed.
The closed system
involves a suction catheter placed in a protective sheath and
directly
connected to the ventilator circuit. No disconnect is
required, and the
risk of environmental cross-contamination is reduced.
Routine changes
of in-line suction catheters are not required and are costeffective.
21,22
Overall, the risk of nosocomial pneumonia between the two
systems
is not different.
23-25
EPIDEMIOLOGY OF HEPATOCELLULAR
CARCINOMA (HCC)
H
epatocellular carcinoma (HCC, also called hepatoma
or hepatocarcinogenesis) is a primary malignancy
(cancer) of the liver. Most cases of HCC are secondary to
either a viral hepatitis infection (hepatitis B or C) or
cirrhosis (alcoholism being the most common cause of
hepatic cirrhosis in Europe) (Kumar et al., 2003). In
countries where hepatitis is not endemic, most malignant
cancers in the liver are not primary HCC but metastasis
16
Epidemiology and Risk Factors
(spread) of cancer from elsewhere in the body, e.g., the
colon. Treatment options of HCC and prognosis are
dependent on many factors but especially on tumor size and
staging.
Outside of the West, the usual outcome is poor,
because only 10-20% of heptocellular carcinomas can be
removed completely using surgery. If the cancer cannot be
completely removed, the disease is usually deadly within 3 to
6 months (American Society of Clinical Oncology, 2005).
Epidemiology
The ultimate cause of HCC is largely known, that is,
chronic liver disease, in particular chronic hepatitis B and C
and alcoholic liver disease. Although other forms of
chronic liver disease are risk factors for HCC.
 Mortality/Morbidity: HCC is the fifth most common
solid tumor in the world and accounts for ~ 500.000
deaths each year (Parkin et al., 2001). Morbidity and
mortality directly correlate with surgical respectability
of the primary tumor. Although chemotherapy and
radiation control may improve in the clinical course, in
selected patients. The overriding objective of these
modalities is to render the tumor completely respectable.
 Race: In older adults, race may play a role in the
development of HCC, but it is difficult to exclude
17
Epidemiology and Risk Factors
environmental factors from these determinations.
Because the condition is so rare in adolescents and
children (0.5 cases/million), ethnic data are not readily
available for thee age groups. Most studies of HCC have
involved patients of Asian descent (Kew, 2002).
 Age and sex: the greatest increase in HCC incidence
occurred in white men aged 45 to 49 years (El-Serag et
al., 2003).
Worldwide distribution of HCC
The incidence of HCC is not uniform across the
world but varies according to the prevalence of the
underlying liver disease. The highest incidence of HCC is
seen in China (~100 per 10000 population) (Ferlay et al.,
2000). Where the major component of the attributable risk
is related to chronic hepatitis B (range 40 to 90%) (Bosch
et al., 2004). Similarly, in Africa, where the HCC incidence
is also very high, the major component of the attributable
risk is chronic hepatitis B. In contrast, in Europe hepatitis C
accounts for ~63% of the attributable risk. In the United
States hepatitis C is the major contributor, but the
attributable risk related to alcohol is also high at ~45%
(Bosch et al., 2004).
North America and Western Europe are generally
considered to be low incidence regions (incidence 2.6 to .8
per 100000 population) (Ferlay et al., 2000). But in these
18
Epidemiology and Risk Factors
regions the incidence of HCC is rising. Studies from cancer
registries have shown a rising trend in HCC incidence and
death in the United States, France, Japan, Scotland,
Australia, and Italy (Levi et al., 2004). In the United States
this increase, from 1.4 to 2.4 per 100000 per year, has been
seen in all races and is mainly due to an increase in the
incidence of HCC related to hepatitis C, with much smaller
increase in the incidence of HCC associated with alcohol
and hepatitis B (El-Serag et al., 2003).
Time trends in the incidence of HCC
An important epidemiological fact is the rising
incidence of HCC in developed countries during the last
two decades (Yoshizawa, 2002).
In Japan, the HCC-related mortality rate has sharply
increased since 1975 from 10/100.000 to almost 40/100000
in 2000. An analysis of the Shinshu University (Japan)
showed a change in etiology of the HCC. Whereas in the
1971-1980 decade, hepatitis B was the predominant cause
of HCC, in the 1991-1995 period hepatitis C was largely
predominant. However, the total numbers of yearly deaths
because of HCC in HBsAg carriers stays constant,
approximately 10% in the survey conducted in 1995. The
Rapid increase of mortality due to HCC in Japan is mainly
attributable (80%) to persistent infection with HCV
(Hoshizawa, 2002). The incidence of HCV in Japan is
decreasing. As the interval between the time of the initial
19
Epidemiology and Risk Factors
infection with the hepatitis C virus and the development of
HCC is 30 years, the growing incidence of HCC in Japan
is expected to reach a plateau around the year 2010, and
then to decrease.
Also in Italy the mortality rate of HCC is rising from
4.8/100000 in 1969 to 10.9/100000 in 1994, reflecting the
large cohort of subjects infected with HCV through
iatrogenic route during the 50s and 60s when glass syringes
were commonly used for medical treatment. Likewise in
Australia, France and the United States of America (US)
the HCC mortality is increasing, most probably because
people infected with HCV have grown old and reach the
cancer bearing age (Law et al., 2000). In the US, an
increase of about 80% in the incidence of HCC over the
past 20-30 years is described, it is estimated that
approximately 15000 new cases occur each year. Also in
France the incidence of HCC is steadily and markedly
increased, the estimated number being about 4000 per year
(Armstrong et al., 2000).
Analysis of long term serial HCV samples from the
US and Japan suggest that HCV was introduced into the US
population around 100 years ago and widely disseminated
in the 1960s. In contrast, HCV was introduced in Japan >
100 years ago and widely disseminated in the 1930s and
40s. The HCV genotype 1b population in Japan started to
decrease around 1995 whereas HCV genotype 1a in the US
20
Epidemiology and Risk Factors
is still growing exponentially. It is predicted that an
increased HCC prevalence will occur in the US over the
next two to three decades (Tanaka et al., 2002).
The reasons advocated for explaining the increased
incidence of HCC are the increased rate of HCV infection
and an improvement of the clinical management of
cirrhotic patients. Enhancing the survival of patients with
advanced cirrhosis leads to an increased incidence of HCC.
In fact, a decade ago, most of the deaths in cirrhotic
patients were due to digestive hemorrhage or bacterial
infections, two
conditions that are now efficiently
prevented and cured (Garcia-Tsao, 2001). Therefore, HCC
has become the leading cause of death in patients with
cirrhosis.
21
Risk Factors
RISK FACTORS OF HCC
S
everal factors have been identified as being related to
the etiology of HCC. In many case, these factors, such
as chronic viral hepatitis, alcoholism and hemochromatosis
also cause chronic liver disease and cirrhosis. In some
instances, several etiologic factors may be identified in the
same patient, suggesting a synergistic role (Di Bisceglie,
1999).
1. VIRAL HEPATITIS
Hepatitis B virus (HBV) infection:
Infection with HBV is probably the most common
underlying factor associated with HCC worldwide and
seems to be most prevalent in high incidence countries.
Evidence of infection with HBV may include serologic
markers of active current infection, such as HBsAg or HBV
DNA in serum, or the presence of antibodies to HBV
antigens, such as anti-HBc and anti-HBs. In some
instances, HBV DNA can be isolated from liver or tumor
tissue in patients with HCC who have no serologic
evidence of HBV infection. In high incidence countries, 60
to 70% of patients have HBsAg in serum and more than
90% have anti-HBc, indicating current or prior infection
with HBV (Kew, 1995). In contrast, in the United States
less than 20% of patients with HCC have anti-HBc in
22
Risk Factors
serum and only a small fraction are HBsAg-positive, except
among immigrants from high incidence areas, such as
China.
The presence of anti-HBs has also been identified as
a risk factor for HCC in some populations (Yu et al., 1997).
HBsAg may be identified by immunostaining within or
adjacent to HCC tissue in some patients. Long term natural
history studies have shown a high relative risk of
developing HCC among individuals seropositive for
HBsAg (Beasley et al., 2001). The association of HBV and
HCC is confined to chronic HBV infection, particularly
when acquired at birth or during childhood. The period
from acquisition of the virus to tumor development can be
as short as 4 years and as long as 80 years (Johnson, 2000).
The mechanism by which HBV infection results in
HCC may be due to HBV results in chronic liver injury
(including inflammation, regeneration and fibrosis), which
may predispose to HCC by itself. However, not all cases of
HBV-related HCC have cirrhosis, which suggests that HBV
may have some intrinsic hepatocarcinogenic properties.
HBV is a DNA virus that may become integrated within the
genome of liver cells. Integrated HBV DNA is often
damaged in some way and, thus, may contain deletions,
rearrangements, duplications or inversions of the normal
DNA sequence. Finally, the virus may have some direct
carcinogenic properties itself, because the X protein of
23
Risk Factors
HBV functions as a transcriptional activator and may
therefore activate some growth related genes (Geissler et
al., 1997).
It is hoped that vaccination against HBV will
dramatically decrease the incidence of the tumor.
Preliminary evidence from Taiwan where mass vaccination
was introduced in 1984 for children of mothers who were
HBsAg carriers, and universally in 1986, shows that this is
a realistic aim. A steady decrease in the number of children
who have HBV, aged 6-14 years, is already evident. The
incidence rate has fallen from 0.7/100.000 (1981-1986) to
0.57 (1986-1990) and 0.36 (1990-1994) (Johnson, 2000).
Hepatitis C virus (HCV) infection:
Many HCC patients with chronic liver disease do not
have HBV infection or alcohol abuse. Non-A, non-B virus
infection was first suggested in 1982 to predispose to
hepatocarcinogenesis (Iwama et al., 1982). Infection with
HCC has now been identified as a leading cause of HCC in
many countries around the world. Evidence of an important
role for HCV infection in HCC includes high
seroprevalence of anti-HCV among patients with HCC.
There is documented progression from chronic HCV
infection to cirrhosis to HCC among patients with chronic
HCV infection (Kiyosawa et al., 2000). In some countries
in Southern Europe and Japan, as many as 50% to 75% of
24
Risk Factors
patients with HCC have detectable anti-HCV in serum
(Bruix et al., 2001).
Most of these patients also have HCV RNA present
in serum as well as liver tissue, and in many cases within
tumor tissue. Among patients with post transfusion
hepatitis C or other conditions in which the onset of HCV
infection can be determined accurately, HCC has developed
in an intermediate step of cirrhosis. Typically, HCC
develops 2 to 3 decades after onset of HCV infection (Tong
et al., 1995).
The majority of patients with HCV related HCC have
underlying cirrhosis, which suggests that it is the presence
of liver inflammation, injury and regeneration that results
in HCC. Unlike HBV DNA, HCV RNA does not become
integrated within the host genome, although HCV RNA
may be detected within liver or tumor tissue of some
patients with HCC. Nonetheless, there is some evidence
that the core protein of HCV may be directly carcinogenic,
at least in vitro (Ray et al., 1996).
Whether particular genotypes of HCV are more likely
to result in HCC is controversial, HCV genotype Ib has
been suggested as being associated with more severe liver
diseases and HCC, although this has not been confirmed in
all studies. It is clear however that HCV genotypes do
affect the outcome of therapy with interferon, which
suggests that there may be biological basis for the theory
25
Risk Factors
that viral factors play a part in determining risk of HCC
(DiBisceglie, 1999). Although it is clear that HCV infection
with cirrhosis is sufficient to lead to HCC.
Hepatitis D virus (HDV) infection:
Infection with HDV occurs exclusively among
patients with HBV infection. Because HBV infection is
associated with HCC, there has been speculation about the
role of HDV in hepatocarcinogenesis. Evidence of HDV
infection includes the presence of anti-HDV in serum. The
prevalence of HDV infection varies considerably around
the world and even among patients with HBV infection
(Kew, 1996).
Thus in Southern Africa, HDV infection is rare, even
though as much as 10 to 15% of the population may have
HBsAg in serum. This variability has made it difficult to
assess the role of HDV in causing HCC accurately. Some
studies suggest that HCC may develop more rapidly among
patients with both HBV and HDV infection than among
those infected with HBV alone by increasing the risk of
development of cirrhosis (Di Bisceglie, 1999).
Coinfection of HBV and HDV
Verme et al. (1991) suggested that HBsAg positive
patients with HDV superinfection develop cirrhosis and
HCC at an earlier stage (mean age 48 year) than HBsAg
26
Risk Factors
carriers without HDV infection (mean age 62 years)
(Verme et al., 1991).
Coinfection with HBV and HCV
Hepatitis B virus (HBV) and hepatitis C virus (HCV)
infections are the most common causes of chronic liver
disease in the world. Both viruses induce chronic hepatitis,
which may progress to cirrhosis and eventually to
hepatocellular carcinoma (Ke-Qin, 2002). It is estimated
that there are 350 million HBV carriers and 170 million
HCV carriers worldwide. HCV is an RNA virus of the
Flaviviridae family and HBV is a DNA virus of the
hepadnaviridae family (Squadrito et al., 2002).
HBV and HCV share modes of transmission, and
their combined infection seems to be frequent, particularly
in areas where the two viruses are endemic and among
people at high risk for infection such as IV drug abusers,
blood receivers like hemophiliacs and thalassemics, and by
parenteral transmission (Cacciol et al., 1999).
The diagnosis of HBV infection is usually based on
the detection of hepatitis B surface antigen (HBsAg) in
serum, and disappearance of this antigen indicates the
clearance of HBV. HCV infection is diagnosed by
detection of anti HCV and viral RNa in the serum (Brechot
et al., 2001).
27
Risk Factors
Pathogenesis of hepatitis B and C-induced hepatocellular
carcinoma
Carcinogenesis is believed to be a multistage process,
occurring through a sequence of steps termed initiation,
promotion and progression. This process evolves over
several or many years. Tumor initiation begins in cells
through mutations induced by exposure to carcinogens.
DNA changes, maintained during successive cell divisions,
activation of oncogenes and inactivation of suppressor
genes lead to dysregulation of the cell division and to
immortalization. Tumor-initiated cells have a decreased
responsiveness to both intercellular and intracellular signals
that maintain normal cellular architecture and regulate
homeostatic growth. Tumor promotion results in a further
selective clonal expansion of initiated cells. During tumor
progression, pre-malignant cells continue to develop
progressive phenotypic changes and genomic instability
(dysplasia), culminating as overt carcinoma (Idilman et al.,
1998).
HBV and HCV can be implicated in the development
of HCC in an indirect way, through induction of
inflammation, necrosis and chronic hepatocellular
regeneration, or directly by means of viral proteins or, in
the case of HBV, by creating insertional mutations by
integration in the genome of the hepatocyte.
28
Risk Factors
Indirect carcinogenicity of HBV and HCV
In most patients with chronic hepatitis B and/or C the
occurrence of HCC is preceded by a process of
longstanding inflammation. It is probable that malignant
transformation is related to continuous or recurring cycles
of hepatocyte necrosis and regeneration. The resulting
accelerated cell turnover rate may act as a tumor promotor
by increasing the probability of spontaneous mutations or
damage to DNA by exogenous factors. The accelerated rate
of cell division leaves less time for altered DNA to be
repaired before the cell divides again, resulting in
transmission of altered DNA to the daughter cells. In this
way a series of mutations may accumulate in individual
cells over time. This process can lead to focal uncontrolled
liver cell growth and eventual malignant cell
transformation (Idilman et al., 1998). Another mechanism
of induction of malignant transformation is the generation
of mutagenic reactive oxygen species as a result of the
inflammatory process, such as nitric oxide (NO),
superoxide anion (O2-), hydroxyl radical (OH•) and
hydrogen peroxide (H2O2).
Direct carcinogenicity of HBV and HCV
Hepatitis B
A significant proportion of HBV-related HCCs arise
in an otherwise normal liver, implicating that the virus can
also be directly oncogenic.
29
Risk Factors
It has been demonstrated that HBV integrates into the
DNA of the host cells. This integration may dysregulate the
control mechanisms on the cell cycle by chromosomal
abnormalities, production of viral proteins or alteration of
human genes and proto-oncogenes. It is, however,
controversial whether viral integration plays an important
role in the process leading to development of HCC. The
hepadnaviral integration process appears to involve
recombination mechanisms that do not preserve the viral
genome sequence. Thus it is impossible for the viral
integrant to function as a template for subsequent virus
replication. Several studies suggest that DNA integration
sites are at random times during the course of a chronic
viral infection. HBV integration can be present in
chronically infected liver tissue without evidence of HCC.
Non-neoplastic hepatocytes may have a similar pattern of
rearrangement of viral sequences following integration into
human DNA (Kew, 1998).
Chromosomal DNA instability
Several studies have shown that HBV DNA
integration enhances chromosomal instability. In many
hepatic tumors large inverted duplication insertions,
translocations and micro- and macrochromosomal deletions
have been associated with HBV insertion. These changes
can result in loss of important cellular genes, sometimes
30
Risk Factors
involving tumor-suppressor genes and other genes involved
in the regulation of regeneration and growth processes
(Robinson, 1994).
Trans-activation of cellular genes
HBV DNA may induce malignant transformation in
another way:
Mammalian hepadnaviruses contain a gene (the HBX
gene), of which the protein (HBX protein) can transactivate several cellular promotors and up-regulate their
expression of different cellular and viral genes. Integrated
HBX, even when truncated, frequently encodes
functionally active trans-activator proteins. This protein has
been shown to transform mouse fetal hepatocytes into a full
malignant phenotype. There are studies in transgenic mice
with the HBX gene that developed multifocal areas of
altered hepatocytes, adenomas and HCCs (Collier and
Sherman, 1998).
A gene that may be affected by the HBX gene is the
p53 tumor suppression gene. This gene has been shown to
play an important role in hepatocarcino-genesis. It is
considered to negatively regulate the cell cycle. The HBX
protein has been shown to complex p53 protein and to
inhibit its function. In a transgenic mouse model it was
shown that HCC development correlates with p53 binding
to HBX (Ueda et al., 1995).
31
Risk Factors
Growth factors
Growth factors and their receptors function as
positive or negative modulators of cell proliferation and
differentiation. Insulin-like growth factor-II and
transforming growth factor- expression correlate with
HBX protein expression in animal models (Yoo et al.,
1996) suggesting trans-activation of these growth factors
facilitating tumor formation.
Role of PreS mutations
PreS deletion mutants accelerate the storage of large
envelope proteins in hepatocyte cytoplasm, which could
induce cytotoxic effects toward the development of endstage liver disease (Bock et al., 1999). The accumulation of
large envelope protein can activate cellular promoters by
inducing endoplasmic reticulum stress. Furthermore, preS1 sequences can stimulate the transcription of
transforming growth factor  (TGF). Coexpression of
TGF and HBsAg could accelerate hepatocellular
carcinogenesis by stimulation of hepatocyte proliferation.
Hepatitis C
In contrast to HBV, HCV is an RNA virus that lacks
a reverse-transcriptase enzyme and cannot integrate into the
host genome. Thus, insertional mutagenesis can be
excluded as a pathogenic mechanism for the development
of HCC associated with chronic HCV infection. The
32
Risk Factors
molecular patho-genetic mechanisms by which HCV
contributes to cell transformation remain unclear.
One possibility is that the development of HCC is
simply related to chronic necro-inflammatory liver disease.
Overall, 97% of patients with HCV markers and HCC have
cirrhosis (Yano et al., 1996) and most of the remainder
develop HCC in the presence of chronic hepatitis.
An alternative mechanism of HCV-induced
hepatocarcinogenesis may be that HCV has a direct
oncogenic action. Viral replication might cause
inappropriate expression of two growth factors that may be
implicated in hepatic carcinogenesis: transforming growth
factor-α and insulin-like growth factor II.
The non-structural HCV protein NS3 has both
protease and helicase activity. HCV may therefore induce
genomic instability and favor mutations through its helicase
activity . The protein also has an activity similar to protein
kinase A, and could disturb cellular homeostasis (Borowski
et al., 1997).
The HCV envelope protein E2 and the non-structural
protein NS5A inhibit RNA-dependent protein kinase, key
mediator of the antiviral, antiproliferative and antioncogenic effect of interferon (Taylor et al., 1999).
33
Risk Factors
The HCV core protein has characteristics that imply
that this protein could function as a gene-regulator. The
presence of the protein in transgenic mice can induce HCC.
After mutation, the HCV core protein can also inhibit
tumor suppressor genes such as p53, as has been
demonstrated in hepatic oncogenesis (Ray et al., 1998). It
has been shown that the HCV core protein induces nuclear
factor B (NF-B), thereby suppressing TNF--induced
apoptosis (Tai et al., 2000). This anti-apoptosis may be a
mechanism by which HCV leads to viral persistence and
possibly to hepatocarcinogenesis.
Coinfection of HBV and HCV with HIV
A series of HCC in HIV-HCV coinfected patients
was published, indicating an unusually rapid development
of HCC in these patients (Garcia-Samaniego et al., 2001).
This is not surprising, as chronic hepatitis C is more
aggressive in HIV positive subjects, leading to cirrhosis
and end-stage liver disease in a shorter period of time.
2. CIRRHOSIS
There is a very close connection between cirrhosis
and HCC. As many as 10% of patients dying with cirrhosis
are found to have unsuspected HCC at autopsy. This is
borne out in transplant studies in which 3 to 6% of
examined livers contained small, unsuspected HCCs. It is
34
Risk Factors
not clear if all disease associated with cirrhosis present an
equal risk for HCC. The best documented risk appears to be
in cirrhosis with chronic viral hepatitis, alcoholism,
hemochromatosis and alpha-1-antitrypsin deficiency.
Conditions in which the risk is thought to be lower include
Wilson's disease, primary biliary cirrhosis and autoimmune
hepatitis (Cheng et al., 1992).
The prevailing hypothesis for how cirrhosis results in
HCC is that dysplasitc nodules (maroregenerative nodules)
develop within the cirrhotic liver. These are hepatocytic
nodules greater than 1 cm in diameter and bounded by
fibrosis, which are suspected of being the major
premalignant lesion for HCC. Areas of cellular atypia
develop with these large nodules, leading to dysplasia and
then foci of well differentiated HCC. The genesis of
dysplastic nodules is, however, somewhat controversial.
They may simply by cirrhotic nodules that have grown
beyond the size of those adjacent to them, or, as recent
evidence suggest, they may represent clonal expansions of
transformed hepatocytes which have risen outside cirrhotic
nodules (Ferrell et al., 2001).
3. SCHISTOSOMIASIS
In Egypt, Schistosoma mansoni and hepatitis viruses
constitute the most common cause of chronic liver disease.
Recent studies suggested a decrease in the prevalence of
schistosomal infection and a corresponding increase in
35
Risk Factors
hepatitis C viral infection. The overall prevalence of
schistosoma mansoni in the Nile Delta during 1981 was
40% for males and 27% for females (Abdel Wahab et al.,
1994).
The schistosomiaiss cancer association was proposed
in the etiology of liver, colon, lymphoma and bladder
cancers. An association between schistosoma japonicum
and hepatocellular carcinoma was reported in a study on
Japanese necropsies and relationship between schistosoma
mansoni infection and heptaocellular carcinoma was
reported from Saudi Arabia (Nouh et al., 1990).
As regards the role of schistosomiasis mansoni and
japonica as an etiological factor in the development of
hepatocellular carcinoma, there have been conflicting
accounts on the relationship between the two diseases.
Luchi et al. (1993) postulated that schistosomiasis mansoni
played on role in the etiology of hepatocellular carcinoma.
Similarly, Cheever (1988) in Brarzil, stated that
hepatocellular carcinoma was more common in uninfected
cases than in those suffering from schistosoma manosni.
However, high prevalence of heptocellular carcinoma in
patients with schistosomiasis japonica and mansoni has
been reported from endemic areas in Japan (Kamo and
Ebato, 1992), and it has been suggested that schistosomal
infection may have an etiological role in the development
of hepatocellular carcinoma.
36
Risk Factors
In Saudi Arabia, Nouh et al. (1990) similarly found
that most of hepatocellular carcinoma cases associated with
schistosomiasis mansoni had previous hepatitis B virus
infection. HBsAg was positive in 24% of patients who had
positive serological tests for schistosoma mansoni.
In Egypt, Kamel et al. (1983) reported one coarse
periportal bilharzial fibrosis out of 37 autopsies of
hepatocellular carcinoma (2.7%). Edington (1979) showed
no association between hepatocellular carcinoma and
schistosomiasis infection. However, Abdel Ghaffar and
Khalil (1984) found that the incidence of positive rectal
snip for schistosoma ovum in hepatocellular carcinoma
cases was 72% compared to 57% in chronic liver disease.
Zayadi (1986) found a single schistosoma mansoni ova
among the tumor cells in one case (2. %) of hepatocellular
carcinoma.
Schistosoma mansoni is not classified as hepatic
carcinogen in humans (International Agency for Research
on Cancer 1994). However, an interaction between
schistosomiasis and hepatitis due to HBV and HCV in
chronic liver disease has been reported.
The high prevalence of a single or combined
infection with schistosomiasis, HCV and/or HBV in the
Egyptian population should be considered for the possible
impact on the occurrence of liver carcinoma. More in depth
understanding of the possible hepatocarcinogenic role, or
37
Risk Factors
interactive effect of schistosomiasis with HBV, HCV and
other recognized risk factors is the objective (Madwar et
al., 1989).
An Egyptian study showed that schistosoma infection
increased the risk of HCC, only in the presence of HCV,
whereas isolated S. mansoni infection does not (Hassan et
al., 2001).
4. ALCOHOL
Ethanol is not carcinogenic in animals; rather it
seems to be a promoter or co carcinogen (Okuda and
Kondo, 1995).
In temperate climates, alcohol has been associated
with heptocellular carcinoma, particularly in older patients.
There is a four fold risk of primary hepatocellular
carcinoma with alcoholism in Northern America (Hardell
et al., 1984).
Alcohol may be a co-carcinogen with hepatitis B
virus. Hepatitis B markers are highly prevalent in alcoholic
cirrhotic patients complicated by hepatocellular carcinoma.
Alcohol mediated enzyme induction may increase the
conversion of cocarcinogens to carcinogens, so
contributing to hepatocarcinogenesis. Alcohol may also
promote carcinogenesis through depression of immune
responses.
38
Risk Factors
The development of hepatocellular carcinoma in
alcoholic cirrhotics is sometimes accompanied by the
finding of integrated hepatitis B viral DNA in malignantly
transformed
hepatocytes.
However,
hepatocellular
carcinoma can develop in alcoholics with no evidence of
past or present hepatitis B infection (Brechot et al., 1980).
Habitual heavy drinking was reported to be a
significant risk factor for HCC in patients with HCV
related liver cirrhosis by multiple logistic regression
analysis. A recent study showed synergism between alcohol
drinking and HBV or HCV infection, with approximately a
twofold increase in the odds ratio for each hepatitis virus
infection for drinkers (Donato et al., 2002).
5. METABOLIC DISEASES
Several inherited metabolic diseases have been
associated with the development of HCC (Ishak, 1991). In
most instances, it seems to be that the liver disease
associated with the metabolic abnormality results in HCC.
They can be grouped into diseases that occur against a
background of cirrhosis and those what do not. Those that
occur with cirrhosis include hemochromatosis, alpha-1antitrypsin (AAT) deficiency, prophyria cutanea tarda,
Wilson's disease, and tyrosinemia. Those that occur without
cirrhosis include glycogen storage disease, acute
intermittent and variegate porphyria, hypercitrullinemia,
and hereditary fructose intolerance, the latter being very
rare overall (Di Bisceglie, 1999).
39
Risk Factors
It has been recognized that HCC occurs very
commonly in patients with cirrhosis due to hemochromatosis
(Niederau et al., 1985). But it has become clear over the last
few years that HCC may occur in patients with
hemochromatosis who do not have cirrhosis, although they
virtually always have significant fibrosis and architectural
distortion (Di Bisceglie, 1999). While studying the
pathogenesis of HCC in hemochromatosis investigators have
developed a considerable interest in the role of hepatic iron
free foci (Deugnier et al., 1993). These are clear cut
sublobular nodules of more than 20 hepatocytes, which are
free of iron against a background of liver cells loaded with
iron. They are found in almost all patients with
hemochromatosis who develop HCC, and one can often see
dysplastic changes within them. Furthermore, they have
increased staining for proliferative cell nuclear antigen, a
marker of cellular proliferation. The presence of iron free
foci carries a significant risk for the subsequent
development
of
HCC
among
patients
with
hemochromatosis. Thus, it seems that iron free foci may
represent premalignant lesions or, at least, markers of a
premalignant state (Di Bisceglie, 1999).
Alpha-1-antitrpsin (AAT) deficiency is associated
with the development of HCC, particularly its homozygous
ZZ state. It occurs virtually always with cirrhosis and may
be diagnosed histologically by the presence of periodic acid
Schiff stain (PAS) positive globules in liver tissue
surrounding the tumors. The role of cofactors, such as
40
Risk Factors
alcohol and viral hepatitis, has not been examined in detail
and remains unknown (Di Bisceglie, 1999).
The hereditary forms of porphyria (acute, intermittent
and variegate porphyria) are uncommonly reported to be
associated with the development of HCC; when this has
occurred, it has been in the absence of cirrhosis (Bjersing
et al., 1996). On the other hand, prophyria cutanea tarda,
which is usually an acquired disease, is much more
commonly associated with HCC, particularly in regions
where this disease is more common (i.e., Spain) (Salata et
al., 1985).
The glycogen storage diseases comprise a somewhat
unique group of diseases associated with HCC (Bianchi,
1993 and Haagsma et al., 1997). They are unique because
they represent the one clear instance in which hepato-cellular
adenomas may progress to malignancy. There are many
distinct types of glycogen storage disease, but only a few are
typically associated with liver tumors. The best described is
type I or Von Gierke's disease, which is associated with
deficiency of glucose-6-phosphatase (G6p, type Ia) or G6P
translocase (type Ib). In this type, adenomas occur in up to
50% of cases and commonly progress to become malignant
or to contain areas of malignancy. Type III (Cori Forbes
disease) is the next most commonly associated glycogen
storage disease, although the risk of developing liver tumors
with this type is definitely less than with type I. liver tumors
have been described with other types, but they are so
41
Risk Factors
uncommon that the exact risk is not clear. Although the
mechanism of carcinogenesis is not known, it is possible that
the excess glycogen stored within hepatocytes is sufficient to
stimulate uncontrolled growth of liver cells (Di Bisceglie,
1999).
Hereditary tyrosinemia is a well known but rare
metabolic disease associated with severe liver disease
(Weinberg et al., 1976). Histologically, it is associated with
steatosis, cholestasis, nodular regeneration, fibrosis and a
remarkable amount of iron accumulation. Clinically
patients with tyrosinemia develop a cirrhosis like picture
that typically results in death from liver failure before 10
years of age. It is interesting that patients with tyrosinemia
have persistently high serum levels of -fetoprotein (AFP)
from infncy, even in the absence of HCC. Approximately
40% of patients develop HCC. Tyrosinemia in theory is one
of the few metabolic liver diseases that may be amenable to
gene therapy (Di Bisceglie, 1999).
6. SYNTHETIC LIVER CARCINOGENS:
 Azo Dyes and Aromatic Amines: Experimental liver
cancer was first done in Japan in 1932 by prolonged
feeding of o-aminoazotoluene-an azo dye structurally
related to scarlet red which was known to induce
hyperplasia of the epidermis of the ear in rabbits.
Several carcinogenic aromatic amines were found after
the discovery of carcinogenicity of an insecticide, N-2fluroenylacetamide (Kunio et al., 1985).
42
Risk Factors
 Nitrosamines and Nitrosamides: These compounds
were thought to be purely laboratory carcinogens, but
studies suggest that exposure of man to N-nitroso
compounds occurs in alimentary tract, either through
ingestion of performed nitroso compounds or through
their formation in the digestive tract in the presence of
nitric and nitrostable substances in food (Sen et al.,
1969). The magnitude of the risk of developing cancer
from the nitrosamines introduced or produced in the
alimentary tract in man is difficult to assess (Kunio et
al., 1985).
 Clorinated hydrocarbons: These synthetic compounds
have become more broadly distributed in the
environment with industrialization. They are capable of
inducing cancer in the liver under certain experimental
conditions (Kunio et al., 1985).
7. AGRICULTURAL PESTICIDES
AND INSECTICIDES
Chlordane:
Chemical class: Organochlorine
Chlordane is a persistent organochlorine insecticide.
It kills insects when ingested and on contact.
Formulation: Formulations include dusts, emulsifiable
concentrates, granules, oil solutions, and wettable powders
43
Risk Factors
Trade and other names: In addition to chlordane,
common names have included: Belt, Chlori Kil, Chlortox,
Cordone, Gold Crest C-100, Kilex Lindane, Kypchlor, Niran,
Octachlor, Synclor, Termex, Topiclor20, Toxiclor and
Velsicol 1068.
Carcinogenic effects: The U.S environmental
protection agency (EPA) has classified chlordane as a
probable human carcinogen. Chlordane has caused liver
cancer in mice given doses of 30 to 64 mg/kg/day for 80
weeks.
Regulatory status: Because of the concern about the
risk of cancer, use of chlordane was canceled in April, 1988.
Between 1983 and 1988 the only permitted use for chlordane
was for control of subterranean termites. Chlordane is no
longer distributed in the U.S. the only commercial use still
permitted is for fire control in power transformers. It was
classified toxicity class II moderately toxic. Products
containing chlordane bear the Signal Word: WARNING
(Institute for Environmental Toxicology, Michigan State
University, Extoxnet, June 1996).
Nitrophenolic and nitrocresolic pesticides:
 Action in human system: toxic to liver.
 Internal exposure: Headache, weakness, thirst,
excessive sweating, feeling of overall illness, yellow
stain of skin, hair and urine is characteristic.
44
Risk Factors
 External exposure: moderately irritating sensation to
skin, eyes, nose and throat.
 Chronic exposure: weight loss.
 Type of pesticides: Herbicides.
Chlorophenoxy pesticides
 Action on human system: injure liver.
 Internal exposure: prompt vomiting, burning sensation
in stomach, diarrhea, muscle twitching.
 External exposure: moderately irritating to eyes, skin
and lungs.
 Chronic exposure: Do not remain in body; passed out
within hours or days.
 Type of pesticide: Herbicides.
Paraquat and Diquat:
 Action on human system: injure liver.
 Internal exposure: burning pain, nausea, vomiting and
diarrhea.
 External exposure: Irritate and injures skin and nails.
 Type of pesticides: Herbicides.
Arsenical pesticides:
 Action on human system: toxic to liver.
 Internal exposure: Headache, burning stomach pain,
vomiting, diarrhea, dizziness and garlic odor of breath
and feces.
45
Risk Factors
 External exposure: minimal.
 Chronic exposure: Accumulates in body. Chronic
headaches, dizziness, stomach aches, salivation, low
grade fever and garlic breath.
 Type of pesticides: Rodenticides, insecticides, marine
antifouling compounds, herbicides, fungicides
Zinc phosphide:
 Action on human system: Severe injury to liver.
 Internal exposure: Intense nausea, stomach pain,
excitement, chills and cough.
 External exposure: Minimal.
 Type of pesticide: Rodenticides.
Halocarbons:
 Action on human system: injure liver.
 Internal exposure: Shock, drowsiness, shaking and
weakness.
 External exposure: Liver damage, weight loss and
jaundice.
 Type of pesticides: Fumigants.
Copper salts and organic complexes:
 Action on human system: injure liver.
 Internal exposure: prompt vomiting, burning pain in
chest, diarrhea, headache and sweating.
46
Risk Factors
 External exposure: Irritate skin and eyes; damages
mucous membranes.
 Type of pesticides: fungicides.
(A Pesticide Information Project of Cooperative Extension Offices of
Cornell University, Oregon State University, the University of Idaho, and
the University of California at Davis, EXTOXNET, June 1996).
Table (1): Synthetic organic compound:
pesticides, insecticides
Contaminant
Herbicides,
Health Effects
Reduction
2,4-D
Liver and kidney damage
98.00%
2,4,5-TP (Silvex)
Liver, kidney, nervous system damage; cancer
99.80%
Carbofuran (Furdan)
Liver, kidney, reproductive and nervous system
damage; cancer
99.00%
Endrin
Heart, liver, kidney, nervous system damage; cancer
99.00%
Methoxychlor
Liver, kidney, nervous system damage; cancer,
anaemia
94.60%
Pentachlorophenol
Liver and kidney damage; cancer
99.96%
(Kunio et al., 1985)
47
Risk Factors
Table (2): Volatile organic compounds: household cleaning
compounds, industrial wastes, insecticides
Contaminant
Health Effects
Reduction
1,1-Dichlorethane
Liver, kidney, nervous system damage
99.80%
1,1-Dichloroethylene
Liver, kidney damage; cancer
99.80%
1,1,1-Tetrachlorethane
Pending study
99.76%
1,1,2,2-Tetrachloroethane
Pending study
99.76%
1,2,4-Trichlorobenzene
Liver, kidney damage
99.80%
1,2-Dichlorobenzene
Liver, kidney, lung damage; cancer
99.70%
1,2-Dichloropropane
Liver, kidney, circulatory, nervous system
damage
99.80%
1,2-Dichloropropane
Liver, kidney, circulatory, nervous system
damage
99.80%
Chlorobenzene
Liver, kidney, nervous system damage
99.80%
Cis1,2-dichlorenthylene
Liver, kidney, circulatory, nervous system
damage
99.80%
Ethylebenzene
Liver, kidney, nervous system
99.43%
Styrene
Liver, kidney, nervous system
99.43%
Toluene (Methylbenzene)
Liver, kidney nervous system damage
99.80%
Total-Xylene
Liver, kidney,
nervous system
lungs mucous membrane,
99.80%
Trans-1,2Dichloroethylene
Liver, kidneys, circulatory, nervous system
damage
99.80%
Trichloroethylene (TCE)
Cancer
99.76%
Vinyl chloride
Liver, immune system, nerve damage
99.80%
(U.S National Agricultural Pesticide Impact Assessment Program,
Extoxnet, June 1996)
48
Risk Factors
8. HORMONES
Oral contraceptives:
Many hepatocellular adenomas and a few
hepatocellular carcinomas have been reported in young
women taking oral contraceptives for several years. A
statistically significant association has been demonstrated
between the use of oral contraceptive steroids and the
occurrence of hepato-cellular carcinoma in countries where
the incidence of the tumor is low and no overriding risk
factor for HCC is known (Austin, 1991). The tumor arises in
a non cirrhotic liver; the risk is associated with the use of
combination products and is closely related to duration of
use, the increased risk persists for about 10 years after the
agents are stopped (Tavani et al., 2003).
Steroids:
Several cases of hepatic tumors in androgen treated
boys or men were reported in the last few years. There are
several well documented case of HCC occurring among
males taking androgenic steroids for atheletic purposes (Di
Bisceglie, 1999).
9. MYCOTOXIN CARCINOGENS
Among the most common toxigenic fungi affecting
the human food chain are Aspergillus species, infecting
major agricultural commodities such as corn, peanuts,
49
Risk Factors
cotton, sorghum, and other oil seed sources. Aspergillus
parasiticus produces the polyketide mycotoxin aflatoxin
(AF), one of the most mutagenic and carcinogenic natural
compounds described to date. Ingestion of food
contaminated with AF has been associated with
hepatotoxicity, teratogenicity immunotoxicity, and even
death (Calvo et al., 2004).
Aflatoxin is a common contaminant of foods,
particularly in the staple diets of many developing
countries. This toxin is produced by fungal action during
production, harvest, storage, and food processing, and it is
considered by the US Food and Drug Administration
(FDA) to be an unavoidable contaminant of foods
(Williams et al., 2004).
Mycoses and Mycotoxicoses:
Fungi are major plant and insect pathogens, but they
are not as important as agents of disease in vertebrates, i.e.,
the number of medically important fungi are relatively low.
Frank growth of fungi on animal hosts produces the
diseases collectively called mycoses, while dietary,
respiratory, dermal, and other exposures to toxic fungal
metabolites produce the diseases collectively called
mycotoxicoses (Barrett, 2000).
Mycotoxins are secondary metabolites produced by
microfungi that are capable of causing disease and death in
50
Risk Factors
humans and other animals. Because of their pharmacological
activity, some mycotoxins or mycotoxin derivatives have
been used as antibiotics, growth promotants, and other kinds
of drugs (Bennett and Klich, 2003).
The term mycotoxin is used to describe
pharmacologically active mold metabolites characterized
by vertebrate toxicity. Mycotoxins usually enter the body
via ingestion of contaminated foods, but inhalation of
toxigenic spores and direct dermal contact are also
important routes. Molds may be present without producing
any toxin. Thus, the demonstration of mold contamination
is not the same thing as the demonstration of mycotoxin
contamination (Bayman et al., 2002).
Molds can be divided into two main groups: field
fungi and storage fungi. The former group contains species
that proliferate in and under field conditions and do not
multiply once grain is in storage. Field fungi are in fact
suppressed by storage fungi if conditions of moisture and
oxygen allow. However the presence of mold does not
guarantee the presence of mycotoxin, which is elaborated
only under certain conditions. Further, more than one mold
can produce the same mycotoxin. Also, more than one
mycotoxin may be present in intoxication (Klaassen,
2001).
Mycotoxin-producing mold species are extremely
common, and they can grow on a wide range of substrates
51
Risk Factors
under a wide range of enviornmetnal conditions. For
agricultural commodities, the severity of crop
contamination tends to vary from year to year based on
weather and other environmental factors. Mycotoxins
occur, with varying severity, in agricultural products all
around the world. The estimate usually given is that one
quarter of the world's crops are contaminated to some
extent with mycotoxins (Fink-Gremmels, 1999).
Mycotoxin problems are exacerbated whenever
shipping, handling, and storage practices are conducive to
mold growth. The end result is that mycotoxins are
commonly found in foods. Kuiper-Goodman, a leading
figure in the risk assessment field, ranks mycotoxins as the
most important chronic dietary risk factor, higher than
synthetic contaminants, plant toxins, food additives, or
pesticide residues (Kuiper-Goodman, 1998).
Aflatoxins Producing Fungi
Aflatoxins, a group of polyketide-derived furanocoumarins, are the most toxic and carcinogenic compounds
among the known mycotoxins. Among the at least 16
structurally related aflatoxins characterized, however, there
are only four major aflatoxins, B1, B2, G1, and G2 (AFB1,
AFG1, AFB2, and AFG2), that contaminate agricultural
commodities and pose a potential risk to livestock and
human health. Aspergillus flavus produces AFB1 and
AFB2. Aspergillus parasiticus produces AFB1, AFG1,
52
Risk Factors
AFB2, and AFG2. Some other species that produce
aflatoxins
are
Aspergillus
nomius,
Aspergillus
pseudotamarii,
Aspergillus
bombycis,
Aspergillus
ochraceoroseus, and Emericella venezuelensis. Aflatoxins
were discovered in Aspergillus flavus (hence the name
"aflatoxin") (Ito et al., 2001 and Peterson et al., 2001).
Because of their occurrence on food and feed crops,
aflatoxin contamination raises serious concerns related to
environmental safety, food quality, and human and animal
health (Roze et al., 2004).
Chemical and Physical Properties of Aflatoxins
Aflatoxins
are
difuranocoumarin
derivatives
produced by a polyketide pathway by many strains of
Aspergillus flavus and Aspergillus parasiticus', in
particular, Aspergillus flavus is a common contaminant in
agriculture. From the mycological perspective, there are
great qualitative and quantitative differences in the
toxigenic abilities displayed by different strains within
each aflatoxigenic species (Klich et al., 2000).
Aflatoxin biosynthesis is a complex process
involving up to 20 enzyme-catalyzed reactions; the genes
encoding the aflatoxin enzymes are clustered in the fungal
genome (Trail et al., 1995 and Rozeetal, 2004).
53
Risk Factors
There are four major aflatoxins: aflatoxin Bl, B2, G1,
G2, and two additional metabolic products, Ml and M2,
which are hydroxylated metabolites arising from the
biotransformation of aflatoxin Bl and B2, respectively
(Hicks et al., 2002). When cattle are fed feed contaminated
by aflatoxin, aflatoxin M is excreted in their milk.
Aflatoxins have a similar structure and form a unique
group of highly oxygenated, naturally occurring
heterocyclic compounds. The four major aflatoxin
molecular formulas (Figure 1) are:
 B1:C17H12O6
 B2:C17H14O6
 G1:C17H12O7
 G2:C17H14O7
Aflatoxins B2 and G2 were established as the
dihydroxy derivatives of Bl and G1 respectively. Whereas,
Aflatoxin Ml is 4-Hydroxy aflatoxin B1, aflatoxin M2 is 4dihydroxy aflatoxin B2. The subscripts 1 and 2 refer to the
separation pattern of these compounds on TLC plates.
These four main aflatoxins are found in foods and feeds.
When ingested they are metabolized in the liver and
excreted in the urine and stool unchanged or in less toxic
forms (Smela et al., 2001).
54
Risk Factors
Figure (2): Chemical structures of aflatoxins (Williams et al., 2004)
Toxigenic strains generally produce only two or three
aflatoxins under any given set of conditions, and one of the
products is always AFB1. Aflatoxins of the G series are
generally produced in lesser amounts and only certain
strains of A. parasiticus produce large quantities.
The four major aflatoxins are called B1, B2, G1, and
G2 based on their fluorescence under UV light (blue or
green) and relative chromatographic mobility during thinlayer chromatography (Klich et al., 2000).
55
Risk Factors
Aflatoxin B1 (Figure 2) is the most potent natural
carcinogen known and is usually the major aflatoxin
produced by toxigenic strains. The term aflatoxin can be
construed to mean aflatoxin B1. However, over a dozen of
other aflatoxins have been described, especially as
mammalian biotransformation products of the major
metabolites (Sweeney et al., 2000).
O
O
O
O
O
Figure (3): Aflatoxin B1 (Bennett and Klich, 2003)
Solubility:
They are very slightly soluble in water (1030ng/ml), insoluble in non-polar solvents and freely
soluble in moderately organic solvents (e.g. chloroform
and methanol); especially in dimethyl sulfoxide.
Stability:
They are unstable to ultraviolet light in the presence of
oxygen, to extremes of PH (<3, >10) and to oxidizing
agent (Sweeney and Dobson, 1999).
56
Risk Factors
Farag et al. (1996) found that the rate of destruction
of matoxin in model and food systems increased with the
increase of microwave oven power (setting/low, moderate
and high) and exposure time to microwaves. However,
MacDonald and Castle (1996) demonstrated that
aflatoxins levels in spiced sauces are not reduced by
domestic cooking with either microwave or conventional
gas oven heating.
Factors Affecting Fungal Growth and Aflatoxin
Production
Physical Factors:
Moisture:
If other factors are equal, the saprophytic fungi that
grow in the field require a higher moisture level than those
found in storage. Dew forming on plant material in the
field allows spore germination and consequent mold
invasion of the substrate. Mycotoxins often develop when
dried and stored products are remoistured by leaks in the
bins, floods or condensation. Moisture content at 16-30% is
optimal for mold growth and aflatoxin production
(Johansson et al., 2000).
Temperature:
Aflatoxin could be produced at about 11oC to slightly
above 36oC. The fungus will grow at 7oC to 45oC however;
at temperature above 37oC no aflatoxin is formed. Many of
57
Risk Factors
the toxigenic fungi over-winter as mycelium or resting
spore stages on plant debris or in the soil. Sporulation in or
on this over wintered material results in an inoculum's that
is often dispersed by air currents, splashing rains or insects.
Mechanical Injury:
Germination of conidia of aspergillus flavus occurs at
higher rate in physically damaged areas in the plant.
Light:
Light generally inhibits aflatoxin production and to a
lesser extent the mold growth (Johansson et al., 2000 and
Dorner, 2002).
Chemical Factors:
Carbon-dioxide:
The levels of aflatoxin production are greatly reduced
at high CO2 values and low relative humidity.
Oxygen:
All mycotoxin producing fungi are strongly aerobic.
Below a minimum O2 level, molds fail to sporulate, their
spores fail to germinate and mycelium fails to develop.
However, the lack of O2 does not mean that mycelia or
spores are killed.
58
Risk Factors
The Substrate:
The quantity of aflatoxins produced under similar
environmental conditions differed according to the
substrate. Substrates differ in their ability to support toxin
formation. A comparative study including three potent
aflatoxin producing isolates of aspergillus flavus showed
that starchy food as corn, wheat and rice stimulated the
production of aflatoxins at a higher level than sorghum,
peanuts and soybean (Smela et al., 2001).
Mineral and Vitamin Nutrition:
Fungi, like other living organisms, require a number
of trace elements such as iron and zinc for growth, so that
these and other trace elements would be required for
mycotoxins production. Vitamins enriched media greatly
stimulate fungal growth and aflatoxin production even
under anaerobic conditions.
Prior Chemical Treatment;
Treatment of grain by various chemicals especially
those used to control insects in stored products may affect
the amount of mycotoxin produced. If the grain is
moistured sufficiently for growth of toxigenic molds,
mycotoxins often increased appreciably (Wogan, 1992).
59
Risk Factors
Biological Factors;
Plant Stress:
Water stress, high temperature stress and insect
damage of the host plant are major determining factors in
mold infestation and toxin production. Similarly, specific
crop growth stages, poor fertility, high crop densities and
weed competition have been associated with increased
mold growth and toxin production.
Insect Vectors:
Saprophytic fungi which include some mycotoxin
producers are mechanically carried in the alimentary canal
of the insect along with the food.
Fungus Infection:
Toxin formation is affected by associated growth of
other molds, one infection may prevent the growth of a
second fungus and the converse is also true; infection by
one fungus makes a plant more susceptible to invasion by a
second (Wang et al., 1996).
Plant Varietals Differences:
The development of plant varieties that resist
infective fungi has proved success in disease control.
60
Risk Factors
Fungal Strain Species:
Strain variability is most common in toxigenic fungi.
Different strains of a toxigenic fungus can vary in
virulence, growth rate competitiveness, ability to produce
toxins and the type and quantity of toxin produced.
Interaction of Microorganisms;
Generally, little toxin is produced when fungi have to
compete with normal flora (Wogan et al., 2004).
Aflatoxin B1 and Liver
The assumption that HBV affects the rates of primary
liver cancer primarily by increasing and sustaining cell
proliferation is supported by the study of Evans et al.
(1998). Studies in woodchucks also seem to support the
contention that the most significant mechanism of
interaction between aflatoxins and hepatitis is increased
cell proliferation, which fixes the adducts formed from the
metabolism of aflatoxin B1 (Izzotti et al., 1995). In the
absence of altered cell proliferation due to cytotoxic effects
of either aflatoxin M1 or aflatoxin B1 per se, the induction
of liver tumours by a genotoxic mechanism is generally
correlated with adduct levels or other measures of
genotoxic damage, irrespective of the background tumour
rate (Wang & Groopman, 1999).
61
Risk Factors
This situation would appear to be likely for aflatoxin
M1 and aflatoxin B1 at current levels of human intake.
Hepatitis may also significantly alter the metabolism
of both aflatoxin B1 and aflatoxin M1, although there is
little evidence to suggest that the metabolism of one would
be altered preferentially. Consequently, for the purposes of
this assessment and in the absence of specific data to the
contrary, the potency of aflatoxin M1 and aflatoxin B1 is
assumed to be the same in HBsAg+ and HBsAg–
individuals.
Studies with more sensitive markers of exposure to
hepatitis B and/or C viruses in patients with liver cancer
strongly suggested that the estimated fraction of cases of
human liver cancer attributable to these viral infections is
increasing. As a consequence, estimates of the potency of
aflatoxin B1 estimated at the forty-ninth meeting in 1997
are likely to be overestimates. At its present meeting, the
Committee made a conservative estimate of the potency of
aflatoxin M1 on the basis of the estimates for aflatoxin
(Kuang et al., 2005).
Chronic HBV infection may induce the cytochrome
P450s that metabolize inactive AFB1 to the mutagenic
AFB1-8, 9-epoxide. Hepatocyte necrosis and regeneration
and the generation of oxygen and nitrogen reactive species
resulting from chronic HBV infection increase the
likelihood of the AFB1-induced p53 249ser and other
62
Risk Factors
mutations and the subsequent clonal expansion of cells
containing these mutations. Nuclear excision & repair,
which is normally responsible for removing AFB1 -DNA
adducts, is inhibited by HBV x protein, favoring the
persistence of existing mutations.
10) Health Effects of Drinking Water Contaminants:
Chemical contaminants occur in drinking water
supplies ranging from barely detectable amounts to levels
that threaten human health. Toxic doses of chemicals cause
either acute or chronic health effects (Boyd et al., 2001).
Most levels of chemicals in drinking water,
however, are seldom high enough to cause acute health
problems. They are more likely to cause chronic health
problems, which occur long after exposure to small
amounts of a chemical (U.S Safe Drinking Water
Committee. U.S. National Academy of Sciences U.S.
National Research Council, 1996).
The U.S. Environmental Protection Agency (EPA)
standard for drinking water, the "Maximum Contaminant
Level (MCL)", is the highest amount of a contaminant
allowed in drinking water supplied by municipal water
systems. The MCL is set as close as possible to the
"Maximum Contaminant Level Goal (MCLG)", which is a
preliminary standard set, but not enforced, by the EPA.
MCLGs are health goals based entirely on health effects.
63
Risk Factors
MCLs also take into consideration the feasibility and cost
of analysis and treatment of the regulated contaminant.
Although often less stringent than the corresponding
MCLG, the MCL is set to protect health (U.S. Water Test
Corporation, 2002).
Regulated contaminants:
Table (3): Inorganics
Contaminant
Possible chronic health
effects
Sources
Rocks and soil; commercial
phosphates in fertilizers and Skin and lung cancer,
laundry
detergents; liver and kidney damage
Arsenic
pesticide residues; smelting, MCL: 0.05 mg/L
glass
making and coal MCLG: 0.05 mg/L
mining
Rocks and soil; mining
sites,
chrome
plating, Liver, kidney and lung
cement production, waste damage
Chromium
incineration;
laundry MCL: 0.05 mg/L
detergent and bleaches; MCLG: 0.12 mg/L
septic systems
Rocks and soil; coal
Anemia;
digestive
burning, iron and steel
disturbance, liver and
production; industrial and
Copper
kidney damage
sewage treatment, plant
MCL: 1.3 mg/L
wastes; corrosion of brass
MCLG: 1.3 mg/L
and copper pipes
Soil and coal burning; Growth inhibition; skin
mining;
smelting; discoloration; dental and
manufacture of glass
digestive problems and
Selenium
Paints,
and
drugs; liver damage
fungicides
and
food MCL: 0.01 mg/L
additives
MCLG: 0.045 mg/L
The units of measurement are milligrams per liter (mg/L), micrometers
(um) and picoCuries (pCi) (National Primary Drinking Water
Regulations, 1997).
64
Risk Factors
Table (4): Organics
Contaminant
Alachlor
Chlordane
2,4-D
Dibromochloropropane
DBCP
Sources
Agricultural herbicide
Insecticide; hazardous waste sites
Agricultural herbicide and aquatic
weeds control
Soil fumigant
PDichlorobenzene
Dye and pesticide manufacturing
1,2Dichlorobenzene
Vinyl manufacturing, dry cleaning
solvent, metal
degreasers
and
adhesives; gasoline additive
Cis and trans
1,2-Dichloroethylene
Cis and trans
1,2-Dichloroethylene
1,2-Dichloropropane
Endrin
Transformed from other chlorinated
hydrocarbons in drinking water
Transformed from other chlorinated
hydrocarbons in drinking water
Industrial solvent and cleaning agents;
dry cleaning fluid component, soil
fumigants
Insecitide and rodenticide
Epichlorhydrin
Rubber
product
manufacturing
contamination of materials used to
process food and treat or store
drinking water
Ethylbenzene
Hazardous waste sites and styrene
production
Ethylene
dibromide
Pesticide and soil fumigants; leaded
gasoline additives
Heptachlor/
heptachlor
epoxide
Insecticide and hazardous waste sites
65
Possible chronic health effects
Cancer; damage to eyes and liver
MCL: NA
MCLG: 0 mg/L
Cancer; nerve and liver effects
MCL: NA
MCLG: 0 mg/L
Liver and kidney damage; skin
irritations and muscle effects
MCL: 0.01 mg/L
MCLG: 0.07 mg/L
Cancer; kidney and liver damage,
infertility
MCL: NA
MCLG: 0 mg/L
Liver and kidney damage; blood
disorder
MCL: 0.075 mg/L
MCLG: 0.075 mg/L
Central nervous system depression;
liver; kidney heart damage
MCL: 0.007 mg/L
MCLG: 0.007 mg/L
Liver and kidney damage
MCL: 0.007 mg/L
MCLG: 0.007 mg/L
Liver and kidney damage
MCL: NA
MCLG: 0.07 mg/L
Liver and kidney damage
MCL: NA
MCLG: 0.006 mg/L
Liver and nervous system effects;
birth defects
MCL: 0.0002 mg/L
MCLG: NA
Cancer; lung, liver and kidney
effets
MCL: NA
MCLG: 0 mg/L
Nerve, brain, liver and kidney
effects
MCL: NA
MCLG: 0.68 mg/L
Cancer; liver, kidney, nervous
system,
gastrointestinal
and
reproductive effects
MCL: NA
MCLG: 0 mg/L
Cancer; liver damage and nervous
system effects
MCL: NA
MCLG: 0 mg/L
Risk Factors
Lindane
Pesticides
Methoxychlor
Insecticides
Pentachlorophenol (PCP)
Herbicides and insecticides; water
contact with PCP-treated wood;
industrial waste sites
Polyclorinated
biphenyls
(PCBS)
Hazardos waste sites; disposals and
manufacture
of
electrical
transformers,
electromagnets,
fluorescent lights and plastics
Styrene
Manufacture of plastics, synthetic
rubbers, resins, and insulators
Tetrachloroethylene
Industrial metal, textile, and dry
cleaning solvent
Toxaphene
Insecticides
2,4,5-TP (Silvex)
Herbicides
Trichloroethylene
(TCE)
Hazardous waste sites; dry cleaning
solvent; manufacturing of chemicals
and drugs
Total
trihalomethanes
Formed when residual chlorine in
treated drinking water combines with
naturally occurring organic matter
Vinyl chloride
Manufacturing of plastics and
synthetic rubbers, corrosion of plastic
pipes
Liver and kidney damage
MCL: 0.004 mg/L
MCLG: 0.0002 mg/L
Nervous system, kidney, and liver
effects
MCL: 0.1 mg/L
MCLG: 0.34 mg/L
Liver and kidney damage; nervous
system, immune system, and
reproductive
effects;
blood
disorders
MCL: NA
Cancer; liver damage
MCL: NA
MCLG: 0 mg/L
Liver damage
MCL: NA
MCLG: 0.14 mg/L
Cancer; liver and kidney damage
central nervous system depression
MCL: NA
MCLG: NA
Cancer; liver and kidney damage
MCL: NA
MCLG: NA
Liver and kidney damage
MCL: 0.010 mg/L
MCLG: 0.052 mg/L
Cancer; nervous system depression
and heart effects; liver and kidney
damage
MCL: 0.005 mg/L
MCLG: 0 mg/L
Cancer; heart, lung, kidney and live
damage
MCL: 0.100 mg/L
MCLG: NA
Cancer; central nervous system
depression; liver and digestive tract
effects, and birth defects
MCL: 0.002 mg/L
MCLG: 0 mg/L
(US Council of Environmental Quality, 2001)
11) Plant Alkaloids:
Lasiocarpine: a pyrrolzidine alkaloid given with
aflatoxins to rats, produces hepatocellular carcinoma in
66
Risk Factors
cirrhotic liver, where as aflatoxin alone induces formation
of hepatocellular carcinoma without cirrhosis (Reddy et al.,
1992).
Cycasin: Cycad plants are widely distributed in
tropical and subtropical regions. Seeds, stems, and roots
are rich sources of starch that some populations use for
food after various detoxifying processes. The toxic
compound in Cycad plants is cycasin a glycoside that
contains an aglycone moiety, methylazoxymethanol- which
is a potent carcinogen for rats if fed orally not parenterally,
this is explained by the fact that methylazoxymethanol is
the potential carcinogen and has to be liberated from
cycasin by intestinal bacteria or -glucosidase (Wogan et
al., 2001).
Safrole and Related Compounds: These occur in
many essential plant oils such as star anise oil, camphor oil,
and sassafras oil. The compounds were used as flavoring
agents in soft drinks and food products, but are no longer
permitted in food items after the discovery of their
carcinogenic properties (Wogan et al., 2001).
Non Alcoholic Fatty Liver Disease
It is emerging as the most common chronic liver
condition in the Western world. It is associated with insulin
resistance and frequently occurs with features of the
metabolic syndrome. Disease presentation ranges from
67
Risk Factors
asymptomatic elevated liver enzyme levels to cirrhosis
with complications of liver failure and hepatocellular
carcinoma (Angulo, 2002).
The diagnosis of nonalcoholic fatty liver disease
(NAFLD) requires evidence of fatty changes in the liver in
the absence of a history of excessive alcohol consumption.
The histologic spectrum of NAFLD spans from generally
benign, bland steatosis to steatosis with evidence of
hepatocellular inflammation and damage (nonalcoholic
steatohepatitis, or NASH), which may be complicated by
progressive fibrosis and cirrhosis (Browning et al., 2004).
NAFLD can be primary or secondary depending on the
cause.
NAFLD is more frequent among people with diabetes
(50%) and obesity (76%), and it is almost niversal among
diabetic people who are morbidly obese (Gupte et al.,
2004). Obesity, diabetes and the metabolic syndrome are
also risk factors for NASH and for advanced fibrosis on
liver biopsy (Mofrad et al., 2003). NASH is present in
18.5% of obese subjects (compared with 2.7% of lean
individuals) and in 50% of severely obese people with
diabetes (Wattless and Lentz, 1990).
Among people who are not obese and do not have
diabetes, risk factors for NAFLD are impaired fasting
glycemia, hypertriglyceridemia, hyperuricemia, central
68
Risk Factors
obesity, hypertension and low levels of high-density
lipoprotein (HDL) cholesterol (Kirn et al., 2004).
An escalating cycle of liver damage and vascular
insufficiency (Magalottiet al., 2004).
Patients who have NAFLD appear to have a higher
mortality than people in the general population (Jepsen et
al., 2003). Patients with pure steatosis have a benign
prognosis: follow-up of 198 patients for up to 21 years
revealed progression to cirrhosis in 3 patients and liverrelated death in only 1 (Teli et al., 1995). In contrast, up to
11% of NASH patients may die of liver-related causes
(Matteoni et al., 1999).
Diabetes is a risk factor for fibrosis progression and
for overall and liver-related death among NAFLD patients
(Adams et al., 2005).
Many patients with cryptogenic cirrhosis have
metabolic risk factors for NAFLD and are likely to represent
cases of previously unrecognized NAFLD (Poonawala et al.,
2000), particularly because hepatic steatosis may disappear
with the development of cirrhosis (Adams et al., 2005).
NAFLD may also present as cirrhosis complicated by
hepatocellular carcinoma: at least 13% of cases of
hepatocellular carcinoma were attributable to NASH in one
study (Marrero et al., 2002). Overall, fibrosis, progression
patients with NAFLD appears to be slow: in previous studies
69
Risk Factors
it took several decades for cirrhosis, hepatocellular
carcinoma and liver decompensation to develop in a small
proportional patients with NASH (Adams et al., 2005).
13. Other risk factors:
The intravenous contrast agent Thorotrast, used for
a short period after the Second World War, included
radioactive particles that were taken up by Kupffer cells
within the liver and remained there for decades, eventually
resulting in some form of malignancy, including HCC,
cholangiocarcinoma, or angiosarcoma (Ito et al, 1998).
Thorotrast: is a colloidal preparation of thorium
dioxide first introduced commercially in 1930. Thorium
emits high-energy alpha, beta and gamma rays. After IV or
intra-arterial
administration
(previously
used
in
angiography), the colloid is taken up by macrophages in the
liver. Late effects include hepatic fibrosis, angiosarcoma,
cholangiocarcinoma, and hepatocellular carcinoma (Baserga
et al., 1960).
Radiation: Moore et al. observed a hepatocellular
carcinoma that developed in a 33-year-old woman 2
decades after hepatic irradiation for hemangioma (Moore
et al., 1996).
Smoking: Hammond, in 1966, reported a higher
mortality from cancers of the liver and biliary tract among
70
Risk Factors
smokers than among non-smokers. According to Hirayama,
the standardized mortality rate for cancer of the liver
among habitual drinkers who smoke heavily is more than
twice that among non-drinkers who do not smoke
(Hirayama et al., 1981). Cigarette smoking is clearly
associated with an increased risk of HCC, although its
effect may be difficult to distinguish from that of alcohol
and other associated lifestyle diseases, such as viral
hepatitis (Di Biscelgie, 1999).
71
Pathology of HCC
PATHOLOGY OF HCC
O
n gross inspection, HCC is often yellowish in color
but may also be dark red, greenish, or even black. Its
cut surface typically bulges out. A capsule may be present
even with some small HCC lesions (Craig et al., 1989).
Based on the gross anatomic features, HCC is classified as
nodular, massive, or diffuse (Anthony and Bannasch,
1994).
Figure (4): Gross picture of advanced HCC (Kojiro, 2005).
The nodular type occurs as a nodule sharply
delineated from the surrounding liver .The nodular variety
accounts for about 75% of HCC and usually coexists with
cirrhosis. It consists of numerous nodules rounded or
irregular of various sizes, scattered throughout the liver
(Anthony and Bannasch, 1994).
72
Pathology of HCC
Whereas the massive type is most common in noncirrhotic livers in young patients. This type is the one most
prone to rupture. The tumour consists of a large
circumscribed mass occupying a substantial portion of the
liver with small satellite nodules. The right hepatic lobe is
affected more often (Anthony and Bannasch, 1994).
The diffuse infiltrating variety is rare. A large portion
of the liver is homogeneously infiltrated with indistinct
minute tumour nodules, which may be difficult to
distinguish from regenerating nodules of cirrhosis but are
present almost invariably (Schaff et al., 1993).
Liver Cancer Study Group of Japan (1989) round
that these several growth patterns of HCC do not have clear
clinical correlates and are often obscured at autopsy
because massive replacement of the liver may have
occurred. Important characteristics that have been noted to
influence prognosis in HCC include the presence or
absence of a capsule, vascular invasion, and size of the
lesion (small HCC is defined as being less than 2 cm in
diameter).
The portal vein and its branches are occluded by the
tumour in as many as 70% of Japanese and black African
patients. The invasion may affect the hepatic veins, less
often the tumour may propagate into the lumen of the
inferior vena cava (IVC) and even into the right atrium
(Kew, 1997).
73
Pathology of HCC
Resembles that of normal hepatocytes typically
arranged (at least focally) in many years ago, Edmondson
and Steiner 1954 classified liver cell carcinoma into four
grades from I to IV on the basis of histological
differentiation (Saul, 1999).
Grade I HCC: The best-preserved, highly
differentiated form, closely resembling the normal liver.
These hepatocytes are arranged in trabeculae as in normal
liver.
Grade II HCC: The cells show marked resemblance
to normal hepatocytes, the cytoplasm is still eosinophilic
but the nuclei are usually larger and the nucleoli are
prominent, glandular like patterns are seen often filled with
bile or proteinaceous material.
Grade III HCC: It lacks the trabecular or glandular
pattern; syncitial giant cells and bizarre shape hyperchromatic nuclei are numerous. The nuclear/ cytoplasmic
ratio is increased and the cytoplasm is less acidophilic.
Grade IV HCC: In this stage the nuclei are large
hyperchromatic and occupy almost the entire cell. The
cytoplasm tends to be basophilic. Trabeculae and acini are
seldom seen. The cells are loosely coherent. Most of them
are spindle shape.
74
Pathology of HCC
HCC is classified histologically into well differentiated,
moderately differentiated, and undifferentiated (anaplastic
forms) (Schaff and Nagy, 1997).
Well-differentiated form (Grade I-II of Edmondson and
Steiner classification):
They are subdivided into trabecular (or sinusoidal, or
plate-like) and acinar (glandular) although both patterns
may be seen in the same tumour (Schaffand Nagy, 1997).
Trabecular: The malignant cells in this variety grow
in irregular anastomosing plates separated by sinusoids that
are lined by flat endothelial cells resembling Kupffer cells.
The trabeculae resemble those of normal liver. However
they are thicker and composed of several layers of cells.
The malignant hepatocytes are polygonal, with an
abundant, slightly granular cytoplasm that is less
eosinophilic than that of normal hepatocytes. The nuclei
are large and hyperchromatic, with well defined nuclear
membranes and prominent nucleoli (Schaff and Nagy,
1997).
Acinar: A variety of gland-like structures formed of
layers of malignant hepatocytes surrounding the lumen of a
bile canaliculus, which may be distended by inspissated
bile. The individual cells resemble those of the trabecular
variety, except that they may be 3ore elongated and
cylindrical, a tubular or pseudo-papillary appearance may
75
Pathology of HCC
be produced by degeneration and loss of cells or rysiic
spaces (Schaff and Nagy, 1997).
Figure (5): Stromal invasion in Well-differentiated early-stage
HCCs (Kojiro, 2005).
Moderately differentiated form (Grade II-III of
Edmondson and Steiner classification):
Solid scirrhous and clear types are described. In the
solid form: The cells are small, the cytoplasm contains small
amounts of glycogen. Pleomorphic, multinucleated giant
cells are seen rarely. The tumour grows in solid masses
or cell nests devoid of architectural arrangement. In the
scirrhous forms: The malignant hepatocytes grow in narrow
76
Pathology of HCC
bundles separated by abundant fibrous stroma, sometimes,
most of the cells are clear cell owing to its high glycogen
content but in some cases, it may be due to fat (Schaff and
Nagy, 1997).
Undifferentiated form (Grade III- IV of Edmondson
and Steiner classification):
The cells are pleomorphic, varying in shape and
staining properties with large numbers of bizarre giant
cells, the cells are spindle shape resembling those seen in
sarcomas (Schaff and Nagy, 1997).
Finally, special type of HCC has a distinct
histological pattern and natural history: is fibrolamellar
carcinoma. Fibrolamellar carcinoma is composed of large
eosinophilic cells arranged in thin or thick trabeculae that
are surrounded by fibrous bands with lamellar stranding.
The tumour occurs primarily in the noncirrhotic livers of
young adults with equal frequency in male and female
patients. In the United States the incidence of this tumour
is approximately 1% of all HCCs. The serum AFP is
elevated in only 20% of the patients. In half of the patients,
abdominal ultrasound reveals minute calcifications within
the tumour that are uncommon in HCC. Because it is
sharply demarcated and arises in noncirrhotic livers, fibro
lamellar carcinoma is more often suitable for resection than
the usual forms of HCC (Craig, 1997).
77
Pathology of HCC
Histologic Variants
Clear Cell HCC
Tumor cells have clear non-staining cytoplasm, often
foamy, lipids and sometimes glycogen are present in
excess abundant cytoplasm. The condition is often
associated with hypoglycemia and hypercholesterolemia
and has a variable prognosis. These tumors resemble renal
or adrenal cortical carcinoma (Ross et al., 1995).
HCC with Giant Cell
This rare entity shows osteoclast-like giant cells in
sheets with a background of mononuclear cells. Other areas
show typical features of HCC (Sherlock and Dooley,
1997).
Fibrolamellar Carcinoma
Also known as polygonal cell type HCC with
fibrous stroma and oncocytic hepatocellular tumor, is a
distinctive morphologic variant of liver cell carcinoma seen
predominantly in young patients without cirrhosis and
associated with favourable prognosis (Berman et al.,
2001).
Grossly, the tumor is well demarcated, but the
boundary is irregular. Histologically, the tumor cells
proliferate in small trabeculae with thick, lamellar, and
frequently hyalinized collagen. Calcification commonly is
78
Pathology of HCC
observed in the lamellar stroma. Tumor cells are large,
have abundant eosinophilic cytoplasm and typically
contain cytoplasmic inclusions, such as eosinophilic
globules, pale bodies and Mallory bodies.
Sarcomatous features consisting of spindle shaped
or pleomorphic anaplastic tumor cells occasionally are
found in part of the HCC (Schiff and Eugene, 1993).
Sclerosing HCC with Hypercalcemia
Another rare type of primary liver carcinoma was
seen equally in both sexes and often associated with
hypercalcemia and hypophosphatemia (Omata et al.,
2001).
Sarcomatoid HCC
Spindle cell transformation may be one of the most
confusing features among the variation of HCC.
The sarcomatoid portion morphologically resembled
fibrosarcoma or leiomyosarcoma, but the spindle cells were
still stainable for keratin and were producing albumin,
fibrinogen, or alpha fetoprotein as demonstrated by
immunohistochemistry. The lesion probably represents a
sarcomatous alteration of carcinoma cells, not a real sarcoma
(Kubosawa et al., 1998).
79
Pathology of HCC
V) Spread
Metastases and Vascular Invasion
Cancer metastases occur both intrahepatically and
extra-hepatically within the liver, invasion into contagious
non-tumor parenchyma and transportal metastases to other
parts of the liver are seen. Extra-hepatic metastases are
hematogenous, lymphogenous, infiltrative or disseminating
in the abdominal cavity (Okuda and Nakashima, 1995).
Intraportal Invasion
It can occur at any time, at any site during growth, it
tends to be early and more frequent in a poorly
differentiated carcinoma. Tumor thrombi may be
transported hepatofugally into collateral veins and
esophageal varices (Nakashima et al., 2001).
In cirrhotic liver, portal hemodynamics are often
altered in such a way that portal blood flow becomes to and
fro or even retrograde and cancer cells may be transported
from one lobe to the other (Okuda and Nakashima, 1995).
Hepatic Vein Invasion
Also occurs but less frequently as compared with
intra-portal growth. Tumor growth in portal vein occurs in
64.7% of cases and in major hepatic vein in 23.3%. In a
further 9% the inferior vena cava and/or the right atrium
were involved. Other reported figures range from 0.8% to
80
Pathology of HCC
85% for intraportal tumor growth and from 3.7% to 14.7%
for intravenous growth (Nakashima et al., 1993).
The lung is the most frequent site for hematogenous
metastases (51.6%) followed in descending order by the
adrenals (8.4%), pancreas (3.1%), brain (2.75%), and
kidney (2.2%) (Anthony, 2001)
Intra-Bile Duct Growth
Tumor invasion into the hepatic duct or common
bile duct is not a rare phenomenon at autopsy. It is seen in
2% to 6% of advanced HCCs (Kojiro, 2003).
In all patients with HCC who present with tumor
invasion into a major bile duct, progressive obstructive
jaundice is a major clinical sign (Schiff and Eugene,
1993).
Intra-Arterial Growth
It is not uncommon to find a tumor growth in the
right atrium in malignant neoplasm such as HCC, renal cell
carcinoma, pulmonary carcinoma and pancreatic cancer. It
is possible that recent prolongation of patient's survival has
increased its frequency. Tumor may extend into the vena
cava or right atrium. A tumor bolus may cross the tricuspid
valve and enter the right ventricle. Direct tumor invasion of
the myocardium may rarely occur (Schiff and Eugene,
1993).
81
Pathology of HCC
Lymphatic Spread
Lymphogenous metastases were seen in the lymph
nodes in the area of the hilum of the liver 14.7%), head of
the pancreas (10.7%), aorta (5.3%), retroperitoneum (5.8%),
stomach (5.3%), mediastinum (4%), neck (3.1%) and
virchow's node (2.2%) (Okuda and Nakashima, 1985).
So, the HCC has tendency for intravascular spread
ani involvement of major hepatic veins and of the portal
vein together with the much less common direct spread
into the hepatic and common bile ducts. The tumour
seldom reaches Glisson's capsule and growth into the
omentum, through the diaphragm or the abdominal wall,
and intraperitoneal dissemination are rarely seen. At
autopsy, metastases are present in 40-60% of cases
(Edmondson and Steiner, 1954 and Craig et al., 1989).
These are more commonly lymphatic nodes in the portahepatis, around the pancreas and the ceoliac axis.
Hematogenous spread occurs less often and most of all to
the lungs; other sites include adrenal, stomach, heart,
pancreas and kidney. Bone metastases may rarely be a
presenting feature (Liaw et al., 1989).
Screening and surveillance of HCC:
By the time patients present with symptoms of HCC,
it is usually too late for effective treatment because of the
presence of vascular invasion, metastatic disease, or
82
Pathology of HCC
extensive hepatic involvement. Therefore, interest has
focused on developing strategies to detect asymptomatic
tumours in high-risk populations (Russo and Jacobson,
2002).
The target populations for HCC screening and
surveillance includes HBV carriers, patient with HCV
infection, and patient with cirrhosis, as well as patients
with cirrhosis due to other forms of chronic liver disease
(Sherman, 2001).
Screening tests must be simple, safe, of low cost, and
reproducible. The most commonly used screening strategies
usually include measurement of Alpha-fetoprotein (AFP)
levels and ultrasonographic. Other tumours markers and
radiological imaging techniques have been studied for
detection of HCC but have yet widely to supplant AFP
measurement and ultrasonographic (Russo and Jucobson,
2002).
Reduction in mortality from HCC is theoretically
accomplished by earlier detection and provision of
effective therapy, which in the unscreened population,
presenting with more advanced disease, would not be
effective. In the absence of randomized controlled trials of
screening, other surrogate endpoints have been evaluated to
determine the efficacy of screening. One proposed
endpoint is stage migration; that is, tumors are found at an
earlier stage. Although early detection of cancer is required
83
Pathology of HCC
for screening to be effective, it is not in itself the objective
of screening. Earlier detection or stage migration cannot be
used as a substitute endpoint to determine efficacy because
early detection does not guarantee more effective
treatment. This has been clearly shown by analysis of the
Surveillance, Epidemiology and End Results (SEER)
Program of the National Cancer Institute, which
demonstrated that these endpoints did not correlate with a
reduction in disease-specific mortality (Welch et al., 2000).
Screening Tests
Screening tests fall into two categories, serological
and radiological.
Alpha feto-protein
Among the serological tests, the performance
characteristics of AFP have been best studied (Thimme et
al., 2002). Receiver operating curve analysis of AFP used
as a diagnostic test suggests that a value of >400 provides
the optimal balance between sensitivity and specificity.
Therefore, AFP is an inadequate screening test. AFP
still has a role in the diagnosis of HCC because in cirrhotic
patients with a mass in the liver an AFP greater than
100ng/mL has a very high PPV (positive predictive value)
for HCC. Furthermore, a persistently elevated AFP has
been clearly shown to be a risk factor for HCC. Thus, the
84
Pathology of HCC
AFP can be used to help define patients at risk rather than
as a screening test (Sherman, 2001).
Des-gamma-carboxy prothrombin
Another serological test used to diagnose HCC, also
known as prothrombin induced by vitamin K absence II
(PIVKA II) (Marrero et al., 2003). Most reports on the use
of DGCP have evaluated the use of this test in a diagnostic
mode rather than for screening. Although there are reports
of its use in a screening mode, these do not yet provide
sufficient justification for routine use of this marker. There
are also reports that DGCP is a marker for portal vein
invasion by tumor (Koike et al., 2001).
DCP had the highest sensitivity and PPV (positive
predictive value) for HCC diagnosis, had a direct
correlation with tumor size, and was not elevated in any
patients without HCC. DCP should be used as the main
serum test for HCC detection (Francisco et al., 2008).
Radiology
The radiological test most widely used for screening
is ultrasonography. Small HCC on ultrasonography may
take on one of several different appearances. The smallest
lesions may be echogenic because of the presence of fat in
the cells. Other lesions may be hypoechoic appearance.
None of these appearances is specific. Ultrasonography has
85
Pathology of HCC
been reported to have a sensitivity between 65% and 80%
and a specificity greater than 90% when used as a
screening test (Bolondi et al., 2001). These performance
characteristics, although not ideal, are considerably
superior to any of the serological tests.
Computed tomography and magnetic resonance
imaging have a high sensitivity and specificity in detecting
HCC, but are too expensive to be used in surveillance
(Bruix et al., 2001).
Screening Interval
US screening at an interval of 6 months is beneficial
to high-risk patients over 40 years old and the early
detection of HCC prolongs survival (Fen-Yu Ren et al.,
2006).
Approach to screening:
Based on screening studies, ultrasound and serum
AFP testing at regular intervals may identify patients with
small tumours that are potentially resectable. For high-risk
groups, ultrasound and AFP testing every 6 months is a
reasonable approach. For patients with an elevated AFP or
lesion on ultrasound, more surveillance or additional testing
may be needed. Including a spiral CT or MRI of the liver
(Russo and Jacobson, 2002).
86
Diagnosis of HCC
DIAGNOSIS OF HCC
Clinical picture:
T
he clinical picture is very variable. The patient may
be completely asymptomatic with no physical signs
other than those of cirrhosis. The tumour may have been
diagnosed accidentally. Alternatively, the presentation
may be so florid and liver failure so great that the picture
resembles a liver abscess. These are all intervening stages
(Malagon and Graham, 2001).
Rapid decline in a patient with hemochromatosis or
with chronic liver disease and positive HBsAg or antiHCV or cirrhosis suggests a complicating carcinoma. The
patient complains of malaise and abdominal fullness and
loss of weight. The temperature is rarely higher than 38°c.
Pain is frequent but rarely severe and is felt as nonspecific
continuous dull ache in the epigastrium, right upper
quadrant or back. Severe pain is due to perihepatitis or
involvement of the diaphragm (Sherlock andDooly,
2002).
Gastrointestinal symptoms such as anorexia,
flatulence and constipation are common. Diarrhea may be
a presenting symptom. This is due to cholestasis or
production of active substance, such as prostaglandins, by
the tumour (Chiesa et al., 2000).
87
Diagnosis of HCC
Dyspnea is late and due to the large size of the
tumour compressing or directly involving the diaphragm,
or to pulmonary metastases (Sherlock and Dooley, 2002).
Jaundice is rarely deep and has little relation to the
extent of hepatic involvement. Rarely the tumour presents
as an intrabiliary, pedunculated polyp causing obstructive
jaundice. The tumour may rupture into the common bile
duct. Hemobilia may be the immediate cause of death
(Okuda et al., 1991).
The liver is enlarged, and a hard irregular lump may
be felt in the right upper quadrant, continuous with the
liver. If the left lobe is involved, the mass is epigastric.
Sometimes multiple masses are palpable. Tenderness may
be so severe that the patient cannot tolerate palpation. A
friction rub due to perihepatitis is occasionally heard over
the tumour. An arterial murmur is due to increased arterial
vascularity; in the absence of acute alcoholic hepatitis this
is diagnostic of HCC (Terada et al., 1989).
Ascites is found in about half of the patient. HCC
should be considered if there is no improvement of ascites.
The protein content is high, also malignant cells may be
present; LDH and CEA may be increased and the fluid
may be blood stained. Rupture causes haemo peritoneum,
this may present insidiously or as an acute abdomen with
severe pain and the prognosis is very poor (Chen et al.,
1994).
88
Diagnosis of HCC
Failure to control variceal bleeding in a cirrhotic
patient is often due to complicating HCC with portal vein
invasion (Sherlock and Dooley, 2002).
Systemic effects:
The tumour may contain a parathyroid-like material
and serum parathyroid hormone levels are raised so lead to
hypercalcaemia (pseudohyperparathyroidism) (Sherlock
and Dooley, 2002)
Hypoglycemia can be found in up to 30% of
patients. This may be due to demand for glucose by an
enormous tumour mass and so is often associated with an
undifferentiated, rapidly progressive tumour. Rarely the
hypoglycemia is seen with a slowly progressive cancer. In
this type glucose-6-phosphotase and phosphorylase are
reduced or absent in the tumour while the glycogen
content in tumour and adjacent tissues is increased. In this
group, control is difficult even with enormous
carbohydrate intake. In patients with severe recurrent
hypoglycemia, the tumour tissue contains 10-20 fold more
high molecular weight insulin like growth factor II (IGFII) than normal liver (Sharprio et al., 1990).
Hyperlipidemia is rare, but about a third have
increased serum cholesterol levels when maintained on
low cholesterol diet. Hyperthyroidism may be due to
89
Diagnosis of HCC
inappropriate thyroid stimulating hormone production
(Sherlock and Dooley, 2002).
Pseudo-porphyria with markedly elevated levels of
porphobilinogen in urine and serum may be related to
porphyrin production by the carcinoma (Sherlock and
Dooley, 2002).
II-Serological Markers:
1-Alpha-fetoprotein (AFP):
Alpha-fetoprotein (AFP) was the first tumourassociated antigen to be used as a tumour marker in the
clinical management of human malignancies. AFP is an
oncofetal antigen that was detected in human fetal sera
1956 (Bergsfand Czar, 1957). It is a single-chain
glycoprotein containing asparagine binding, double chain
complex sugar with a molecular mass of 67 to 74 Kd with
95% proteins and 5% carbohydrate (Brummund et al.,
1980). It is synthesized by the liver, yolk sac, and
gastrointestinal tract of the developing fetus. This
glycoprotein is released into the circulation and is
normally found in sera from human about one third of the
total fetal serum protein. At birth, the serum AFP declines
to about 50 ug/ml, and by 1 year of age, the AFP level is at
very low concentrations. AFP is found in trace amounts by
2 years of age and is similar to concentrations observed
90
Diagnosis of HCC
during adult life (usually less than 20 ng/ml) (Michael et
al., 2000).
Elevation in AFP is observed in a wide variety of
malignant and benign disorders. For instance, elevated
AFP levels are seen in patients with HCC, testicular and
ovarian germ cell tumours, pancreatic carcinoma, gastric
carcinoma, and colonic carcinoma. AFP is a tumour
marker for managing patients with HCC. Nevertheless,
elevations of serum AFP, similar to levels observed in
malignant disease, are seen in non malignant hepatic
disorders such as viral hepatitis and chronic active
hepatitis. Serum AFP values can also be elevated in
ataxia, telangiectasia and tyrosinemia (Liu et al., 1983).
In high incidence areas of HCC, approximately 95%
of patients have abnormally elevated serum AFP levels
(greater than 10 ng/ml) while 70 to 90% of those in low
incidence areas have elevated AFP levels (Kew, 1999).
A cut-off value of 400 ng/l has been used for HCC.
However, a steadily rising value over a 1-2 moth period is
very suggestive of HCC. Levels of AFP correlate with
changes in tumour bulk in individual patients, but isolated
value are not reliable general indicators of the extent of
the tumour. Recently, hepatoma specific isoforms of AFP
have been described and may help to distinguish AFP
derived from HCC from that derived from benign liver
disease (Johnson, 2000).
91
Diagnosis of HCC
The level usually correlates with tumour size, but
there are exceptions. However AFP doubling time is
closely related to tumour doubling time. Resection of the
primary tumour, or hepatic transplantation, results in a fall
in serum AFT thus serial values are useful in assessing
therapy (Sherlock and Dooly, 2002).
AFP is less useful in distinguishing between primary
and secondary tumours in the non-cirrhotic liver. Only
50% of such cases of HCC arising in normal livers have
elevated levels, and up to 10% of patients who have
hepatic metastases will have elevated levels (Johnson,
2000).
2- Alpha-fetoprotein -L3;
There are increasing lines of evidence indicating a
subtraction of AFP, the serum level of which increases
along with the development of HCC. The difference is
reflected on the binding activity to Lens Culinaris
agglutinin A. The percentage of AFP that binds with LCulinaris agglutinin A, referred to as AFP-L3, is highly
specific for the presence of HCC (Fujiyama et al., 2002).
The cut-off AFP-L3 value was set at 10%; values
exceeding 10% are strongly suspected of reflecting HCC
even when the total AFP value is increased only slightly.
Moreover; AFP-L3 more than 10% signals the
92
Diagnosis of HCC
development of HCC, even if imaging modalities fail to
demonstrate it in the liver (Kumada et al., 1999).
High AFP-L3 values are associated with some
pathological characteristics of HCC. For HCCs with a
diameter less than 2 cm, those with elevated AFP- L3 are
frequently poorly differentiated and multifocal. Also,
AFP-L3 values in small HCCs are significantly higher for
hypervascular tumours, with negative portal blood supply,
with shorter doubling time, and with intrahepatic
metastases of HCC (Shimauchi et al., 2000).
After treating HCC patients, if AFP-L3 percentage
still increased, a residual HCC is suspected. There is a
danger of recurrence in the patients in whom AFP-L3 does
not decrease to less than 10% or re-elevates after it has
reached the normal range (Fujiyama et al., 2002).
3- Prothrombin induced by vitamin K absence or
antagonism (P1VKA-ID:
PIVKA-H is an abnormal prothrombin that is devoid
of coagulation activity. It is also called des-gammacarboxy prothrombin or (DCP). PIVKA-II behaves
independently of AFP, and wherefore they complement
each other as regards increased sensitivity in the detection
of HCC. The cut-off value is at 40 mAU/ml. PIVKA-II
was defected in 48% of HCC patients, as compared to 5%
of patients with liver cirrhosis, and 2% or absent of patients
93
Diagnosis of HCC
with chronic hepatitis and hepatic metastases. Accordingly,
the sensitivity was estimated to be 48% and the specificity
98%. PIVKA- II detected in 18-50% of the patients who
possessed HCCs, with a diameter less than 2 cm and in 3,560% of those with diameter of 2.1-3.0 cm (Okuda et al.,
2000).
The highly sensitive detection of PIVKA-II by
improved methods has made it possible to closely follow
the patients with chronic hepatitis or liver cirrhosis for the
development of HCC. It is predicted that on such patients,
if they have PIVKA-II levels around the cutoff values
from 30 to 40 mAU/ml, there is a higher probability either
of HCC that has escaped detection by imaging modalities
or will develop in the foreseeable future (Schachshol et
al., 2000).
PIVKA- II can reflect the therapeutic efficacy on
HCC much more promptly than AFP. PIVKA-II values
parallel the stage of HCC, and increase in the patients with
intrahepatic metastases, tumour thrombus in the portal or
hepatic vein, and invasion of tumour capsules (Fujiyama et
al., 2002).
4- Alpha L-fucosidase:
Alpha L-fucosidase has been reported in European
patients with HCC to have a sensitivity of 75% and a
specificity of 40%, but the use of alpha L-fucosidase as a
94
Diagnosis of HCC
single tumour marker failed to distinguish between
cirrhosis and HCC. This marker proved to be less sensitive
and less specific and had lower predictive values than
alpha-fetoprotein (Bukofzer et al., 1989).
5- Carcinoembrvonic antigen:
Serum concentrations of carcinoembryonic antigen
are raised in 32 to 79% of patients with HCC. The degree
of elevation in these patients is slight or moderate and may
result from existing chronic benign hepatic disease
especially that caused by alcohol rather than synthesis by
the tumour. No correlation between serum levels of alphafetoprotein and carcinoembryonic antigen is noted in
individual patient with HCC (Kew, 1997).
6- Isoferritins:
Serum ferritin concentrations are often raised in
patients with HCC. Production of an acidic isoferritin by
HCC occurs in a few patients and serum from patients with
this tumour may contain acidic as well as the usual basic
isoferritin (Wu et al., 1997). An isoferritin similar to that
developed in HCC tissue has been isolated from fetal liver.
A weak inverse correlation has been reported between
alpha-fetoprotein and ferritin concentrations (Ohta et al.,
1995).
95
Diagnosis of HCC
7- HCC specific alkaline phosphatase;
A specific ALP variant has been identified in
patients with HCC and demonstrated electrophoretically
by differential rates of inhibition of heat and Lphenylalanine. It is distinguished from that of normal liver
by being more sensitive to heat and to L-phenylalanine
inhibition. It is most sensitive in non-cirrhotic group; it is
of value in low incidence areas, as it is present in up to
30% of patients (Ohta et al., 1995).
III-Radiological diagnosis:
A- Ultrasound features of hepatocellular carcinoma:
1. Small HCC:
Morphologically, small HCC tumours less than 3 cm
in greatest dimension usually show a nodular configuration
and may be divided into four types: single nodular type,
single nodular type with extranodular growth, contiguous
multinodular type, and poorly demarcated nodular type
(Buscarini et al., 1996).
The Capsule: Small, classical, nodular type HCC is a
sharply demarcated lesion, which may or may not be
capsulated. On U/S, the shape of the tumour appears round
or oval, and its boundary is sharp and smooth. The fibrous
capsule is seen as a peripheral hypoechoic halo. However,
depiction of peripheral halo may also be due to compressed
96
Diagnosis of HCC
liver tissue at the periphery of the tumour (pseudocapsule).
The presence of the fibrous capsule is commonly said to
produce a typical U/S feature of HCC, represented by
lateral shadows. The single nodular type with extranodular
growth, the contiguous multinodular type, and the poorly
demarcated type show a nodular configuration with an
irregular or blurred margin on U/S images (Lencioni and
Menu, 1999).
Echogenicity: There are three types of internal
echogenicity in HCC: hypoechoic, isoechoic, and
hyperechoic. When the nodule is small, the internal echo
pattern tends to be hypoechoic. Small HCC may exhibit a
hyperechoic pattern, which is indicative of fatty changes,
clear cell changes, pseudoglandular arrangement of the
tumour cells, peliotic changes of vascular spaces in the
tumour, or sclerotic changes in the tumour. More than half
of small HCC nodules present with a hypoechoic pattern,
about one third present with a hyperechoic pattern,
whereas a minority of lesions present with an isoechoic
pattern, frequently with a peripheral hypoechoic halo.
Many HCCs are homogenous, but some are found to be
heterogeneous and consists of a mosaic. Internal mosaic
architecture is a typical feature of large HCCs and is
characterized by components separated by thin septa. This
occurs if areas of different degrees of differentiation or
different degrees of fatty changes are present (Sakaguchi
et al., 1992).
97
Diagnosis of HCC
Posterior enhancement: Another characteristic U/S
feature of HCC is posterior echo enhancement, which is
produced by the softness of the tumour compared with the
surrounding cirrhotic tissue. This feature may serve to
detect isoechoic lesions (Sakaguchi et al., 1992).
2-Advanced HCC:
Advanced HCC lesions are classified into three major
types: expansive nodular type, infiltrative type, and diffuse
type (Buscarini et al., 1996).
a. The typical expansive nodular type of HCC: is a
sharply demarcated lesion, which may be unifocal or
multifocal. Most expansive HCC lesions have a we 11 developed fibrous capsule. The capsule may be detected by
U/S in up to 70% of large, encapsulated lesions on
macroscopic pathologic examination. Internal architecture
is typically characterized by mosaic pattern, with
components of different echogenicity separated by thin
septa. In large lesions, mosaic architecture should not be
confused with uneven U/S appearance caused by
degeneration, necrosis, or bleeding (Buscarini et al.,
1996).
b. The infiltrative type HCC: is characterized by an
irregular and indistinct tumour-non-tumour boundary. This
type is demonstrated as a mainly uneven area with unclear
margins. The tumour forms strands into surrounding
98
Diagnosis of HCC
tissues, which frequently invade vascular structures,
particularly portal vein branches. HCC, in fact, has great
tendency for invading and growing into the portal vein
eliciting tumour thrombi. Infiltrative HCC may create a
massive involvement of the liver, replacing large parts of
the parenchyma (Buscarini et al., 1996).
c. The diffuse type: is by far the most unusual presentation
of HCC. This type is characterized by numerous nodules of
small size scattered throughout the liver. The nodules do
not fuse with each other and are visualized as diffusely
distributed hypoechoic lesions (Honda et al., 1992).
d. Satellites: HCC has the typical tendency to give small or
minute satellite nodules. These nodules represent
intrahepatic metastases developed via the portal vein
branches and are frequently located in the surrounding area
of the main tumour. Identification of these satellite lesions
is of the most importance for therapeutic planning, and
represents one of the most challenging issues in HCC
patients (Honda et al., 1992)
B- Doppler ultrasound features of HCC:
On color Doppler U/S, HCC is usually displayed as a
vascular-rich region containing intratumoural signals with
a pulsatile arterial Doppler spectrum, corresponding to the
characteristic findings of hypervascularity on angiography.
A basket pattern, which is fine blood-flow network
99
Diagnosis of HCC
surrounding the tumour nodule, and tumour vessels
flowing into the tumour and branching within it, are the
characteristic findings of HCC (Choi et al., 1996).
These findings are almost always detected in large
HCCs lesions, and are frequently associated with very high
Doppler shift. The specificity may be as high as 95%, and
the sensitivity is also rather high at 70%. In small HCC
lesions; however, the sensitivity of such findings is
substantially lower. Color signals may be detected in no
more than 70% of HCC 3 cm or less in diameter. The
observed features were those of vessels running toward the
center of the tumour or along its periphery (Reinhold et
al., 1995).
A study was done In order to improve the
differentiation between hepatocellular carcinomas and
regenerative nodules in patients with liver cirrhosis;
Doppler-sonographic criteria for the tumours were
evaluated. The results showed that hepatocellular
carcinomas and regenerative nodules showed different
contrast behavior with echo-enhanced power-Doppler
sonography. The following features of hepatocellular
carcinomas were frequently found: peritumoural signal
detection in the early arterial phase, disorganized and
centripetal contrast enhancement in the arterial phase,
hypervascularization in the capillary phase, and loss of
portal venous blood flow. So they concluded that
100
Diagnosis of HCC
hepatocellular carcinomas and regenerative nodules display
different vascularization patterns in the echo-enhanced
power Doppler sonography. These characteristics can be
useful for their differential diagnosis (Chen et al., 2002).
Power Doppler U/S is proved to be significantly
more accurate than color Doppler U/S in assessing
vascularity of HCC. Intratumoural pulsatile flow was
detected in 92% of cases by power Doppler U/S and in
73% of cases by conventional Doppler imaging. This
proves that power Doppler U/S is more sensitive than color
Doppler U/S in detection of weak signals coming from tiny
or remotely located nodules. The detectability rate of power
Doppler signals is not affected by the size or the site of the
lesion within the liver (Choi et al., 1996).
The use of U/S contrast agents may add further
information to the color and power Doppler studies. After
administration of U/S contrast agent, hypervascular HCCs
show strong, rapid intratumoural enhancement in the
arterial phase (Albrecht et al., 1998).
The observable features included the evidence of
several well-defined intratumoural vessels running toward
the center and along its periphery or multiple internal
vascular pedicles (Kim et al., 1998). It provided
information similar to that obtained with dual phase spiral
CT, dynamic MRI or angiography (Bartolozzi et al., 1998).
101
Diagnosis of HCC
Portal vein thrombosis: Color Doppler U/S studies
are very useful in evaluating portal vein thrombosis. As
patients with cirrhosis are at high risk of developing portal
vein thrombosis, this phenomenon cannot be immediately
related to the presence of HCC despite the well-known
propensity of this tumour of invading the portal vein
branches. With color Doppler U/S, the peculiar aspect seen
in cases of malignant thrombosis is the presence of
pulsatile flow within the thrombus. The sensitivity of
Doppler U/S in detecting pulsatile flow within tumour
thrombi may be increased by using the power Doppler
mode in combination with contrast agents: enhancement of
the thrombus in the arterial phase will indicate malignant
thrombosis (Albrecht et al., 1998).
C- Computed tomography (CT) features of HCC:
Computed tomography (CT) currently plays a
fundamental role in the screening, differential diagnosis,
staging, and evaluation of response to treatment of
hepatocellular carcinoma.
1- Triphasic spiral CT features of HCC:
a. Small HCC:
Macroregenerative and dysplastic nodules, as well as
early HCC, have a predominantly portal blood supply,
102
Diagnosis of HCC
while overt HCC lesions are supplied almost exclusively
by hepatic arterial branches (Lencioni et al., 1996).
The different blood supply to the lesion is the single
most important CT feature that may help to differentiate
among small hepatocellular lesions, which have emerged
in a cirrhotic liver (Lee et al., 1997). In fact, while small,
overt HCC tumours show a typical hypervascular pattern,
with clear-cut enhancement in the predominantly arterial
phase and rapid washout in the portal venous phase, earlystage HCC and regenerative or dysplastic lesions fail to
exhibit this feature and appear isoattenuating or
hypoattenuating with respect to surrounding liver
parenchyma on spiral CT images (Choi et al., 1996)
Morphologically, small HCC tumours less than 3 cm
in greatest dimension usually show a nodular configuration
and may be divided into four types: single nodular type,
single nodular type with extranodular growth, contiguous
multinodular type, and poorly demarcated nodular type
(Hollett et al., 1995).
In the classic small nodular type, sharply demarcated
lesion, which may or may not be encapsulated. The CT
detection rate of the capsule is low in small tumours
because the capsule is thin and poorly developed. The
capsule in the spiral CT appears as a peripheral rim that is
hypoattenuating in unenhanced and arterial phase contrastenhanced images and enhances on portal contrast103
Diagnosis of HCC
enhanced images (Ros et al., 1990). The remaining types
of small nodular HCC show nodular configuration with an
irregular or unclear margin on CT images (Oliver et al.,
1996).
b. Advanced HCC:
Advanced HCC lesions are classified into three major
types: expansive nodular type, infiltrative type, and diffuse
type. The typical expansive type of HCC is a sharply
demarcated lesion, which may be unifocal or multifocal.
Typical features of expansive type HCC include tumour
capsule and internal mosaic architecture. The latter is
characterized by components separated by thin septa; these
different components may show various attenuation on
precontrast CT images, particularly if areas of welldifferentiated tumour with different degree of fatty
metamorphosis are present (Ros et al., 1990).
The infiltrative type HCC is characterized by an
irregular and indistinct tumour-non-tumour boundary. This
type is demonstrated as a mainly uneven area of unclear
margin. The tumour strands into surrounding tissue, and
frequently invades vascular structures, particularly the
portal vein branches. Infiltrative HCC may create a
massive involvement of the liver, replacing large parts of
the parenchyma. The diffuse type is the most unusual type
of HCC. It is characterized by numerous small sized
scattered nodules throughout the liver. HCC has the typical
104
Diagnosis of HCC
tendency of giving small or minute satellite nodules,
frequently located in the surrounding area of the main
tumour (Kemmerer et al., 1998).
Helmy et al. (2002) studied the role of spiral CT in
the diagnosis of hepatic focal lesions and they concluded
that the peripheral puddles, complete ring and abnormal
internal vessels or variegated enhancement patterns in the
arterial phase are associated with the diagnosis of
hemangiomas, metastases and HCC, respectively, with
positive predictive value (PPV) of 75-95% and specificity
of 94.83-96.88%. Thus, the appearance of hepatic lesions
in the arterial phase of enhancement has potential use in
the determination of specific diagnosis to help the clinician
to manage die case accurately.
2- CT Arteriographv (CTA):
CTA is based on the fact that most of HCC tumours
are fed from the hepatic artery. On CTA images, HCC
lesions show high-attenuation blushes compared with the
surrounding normal liver and stand out against the faintly
enhanced normal parenchyma. Therefore, even small but
overt HCC tumours may be well depicted. With CTA,
however, early-stage, well-differentiated HCC tumours
with immature neovascularity fail to enhance and are not
distinguished from liver parenchyma (Takayasu et al.,
1995).
105
Diagnosis of HCC
3- CT Arterioportography (CTAP):
CTAP is based on the reverse pathologic substratum
with respect to CTA, that is, on the fact that almost no HCC
tumours are fed by the portal vein. This procedure produces
dense enhancement of portal venous blood, so that the
arterially supplied overt HCC lesions are highlighted as
negative defects. The liver is markedly increased in
attenuation, and even small tumour deposits may be
depicted as definitely hypodense areas. Well-differentiated,
early-stage HCC tumours, however, maintain a portal blood
supply (although usually decreased with respect to that of
normal liver or regenerative nodules) and may exhibit a
faint hypodensity with respect to liver parenchyma, being
hardly detectable (Takayasu et al., 1995).
Many reports have shown that this technique has a
very high detectability rate for small, overt HCC tumours.
However, CTAP lacks specificity, as almost every focal
lesion in the liver, including benign lesions such as
hemangiomas and small cysts, assumes the same
hypoattenuating appearance and therefore may simulate
tumour (Matsui et al., 1994). Moreover, this technique has
the drawback that nontumourous portal vein perfusion
defects, unrelated to tumour deposits, can occur due to
altered hemodynamics, particularly in the presence of liver
cirrhosis. False-positive rates as high as 20 to 30% for
patient analysis, in fact have been reported, making CTAP
106
Diagnosis of HCC
unreliable for the correct prediction of positive tumour
involvement (Hori et al., 1998).
4- Lipiodol CT:
Lipiodol is the iodinated ethyl ester of the fatty acid
of poppy seed oil and contains 37 to 38% iodine by weight.
When lipiodol is injected into the hepatic artery, most of
the iodized oil droplets flow into HCC lesions by virtue of
the increased blood supply to the tumour. Once deposited
in the tumour, the lipiodol droplets disappear at a far slower
rate compared with those deposited in the normal liver
tissue. In fact, while iodized oil undergoes rapid washout
from the noncancerous liver parenchyma, usually leaving
an unappreciable amount 3-4 weeks after the intra-arterial
injection, it remains for months or years within HCC
nodules. The reason for the selective and prolonged
retention of lipiodol in HCC lesions has not yet to be mlly
clarified. Some authors suggested that trapping of the oil in
the irregular, tortuous, and poorly contractile vessels of the
tumour, as well as the abnormally increased permeability of
these vessels, may be involved. Moreover, it has been
hypothesized that the slow disappearance of lipiodol from
HCC lesions may be explained with the absence of
lymphatic vessels and Kupffer cells in the tumour tissue
(Kanematsu et al., 1999).
On CT scans acquired 3-4 weeks after intra-arterial
injection of lipiodol, HCC lesions appear as highly
107
Diagnosis of HCC
hyperattenuating areas compared with nontumourous liver
tissue. Many published reports have shown that lipiodol
CT has a high detectability rate for tiny HCC nodules
(Lencioni et al., 1997a).
Finding on lipiodol CT are quite specific for th
ediagnosi sof HCc, provided that correct diagnostic criteria
are used. Small, rounded, circumscribed areas of dense
liiodol retention on CT scans obtained 3-4 weeks after the
intra-arterial injection of the iodized oil have a 90%
positive predictive value for being true satellite neoplstic
foci in the clinical setting of a cirrhotic patient with HCC
(Bisollon et al., 1998).
D- Magnetic resonance imaging
Hepatocellular carcinoma is usually hypo-intenseisointense to the liver. Areas of increased intensity may be
due to fat, protein, or copper in the tumor. Similar to
computed tomography, magnetic resonance imaging (MRI)
plays a role in staging, in the detection and number of
lesions, their size, and vascular and biliary involvement.
MR imaging also plays a critical role in postoperative
treatment surveillance as recurrent tumor will demonstrate
early enhancement and washout on the delayed phase. MRI
can be used as a modality to guide the treatment of HCCs
not visualized by other modalities (Huppertz et al., 2005).
108
Diagnosis of HCC
IV- Liver biopsy
Liver biopsy is the most important procedure to
consider when HCC is suspected. Needle biopsies are
generally not recommended, especially in the setting of
cirrhosis, because overlooking the findings of malignantly
transformed hepatocytes in a small specimen may be easy,
and the diagnosis may be missed. If definitive tumor
resection is possible, this procedure should be undertaken
by a qualified surgeon.
Histologic Findings:
Histologic examination of tumor tissue in children
with classic HCC shows large, polygonal cells with central
nuclei, frequent mitotic figures, and, often, invasion into
surrounding hepatic tissue or adjacent abdominal
structures. Areas of hemorrhage and necrosis, which may
complicate the interpretation of needle biopsy specimen,
are common.
A distinct histologic variation, termed fibrolamellar
carcinoma, occurs with relatively high frequency in
children and young adults. Tumor cells in this subtype are
circumscribed characteristically by bundles of acellular
collagen, creating either trabeculae or large nodules of
tumor islands. Interestingly, in the fibrolamellar variant,
levels of B12 binding protein are elevated significantly and
rise and fall concomitantly with successful or unsuccessful
109
Diagnosis of HCC
disease control. The fibrolamellar variant is generally
associated with a more favorable prognosis (Stuart Winter,
2006).
Complications of liver biopsy:
Although liver biopsy is a remarkably safe procedure,
several complications can occur that may require
immediate attention. These include pain, bleeding, bile
leakage, and pneumothorax. The complications are more
likely to occur when the operator is inexperienced. There is
a possibility that biopsy will facilitate spread
along the needle tract exists but is rare. The mortality from
various large combined series is about 0.01%.
Complications are reported in 0.06% to 0.32% of patients
(Tobkes and Nord, 1995).
All the complications can occur with any needle,
although the frequency appears to be lowest, but not zero,
with the fine needle aspiration technique. The size of the
needle did not make a difference in some series. Many
complications can be avoided by not doing biopsies in
persons with bleeding tendencies resulting from low levels
of or missing clotting factors or myeloproliferative
disorders, hemangiomas, vascular tumours, cystic masses,
and extrahepatic biliary obstruction, especially if bile ducts
are noted to be dilated by ultrasonography (Fenton and
Swan, 1995).
110
Diagnosis of HCC
Staging:
Although no staging system has been uniformly
adopted, a staging method proposed by the Children's
Cancer Group and Southwest Oncology Group incorporates
tumor bulk with surgical resection. The staging and
classification for HCC draw upon location, resectability,
and response to any presurgical therapy given to the
affected patient.
 Clinical group 1-Complete resection of the tumor.
 Clinical
group IIa-Completely resectable
presurgical irradiation and/or chemotherapy.
after
 Clinical group IIb-Residual disease confined to either
left or right lobes of the liver after presurgical irradiation
or chemotherapy.
 Clinical group III-Residual or unresectable tumor
involves both left and right lobes of the liver.
 Clinical group IIIb-Regional node involvement.
 Clinical group IV-Distant metastatic spread (usually to
the lungs and/or bone).
(Stuart Winter, 2006)
Evaluation and treatment of patients with
hepatocellular carcinoma is dependent on accurate staging.
Major vascular and microvascular invasion act as
111
Diagnosis of HCC
independent predictors of death. Severe fibrosis and
cirrhosis is a negative predictor of survival following
resection of HCC (Pawlik et al., 2005). There are a few
classification systems: CLIP (Cancer of the Liver Italian
Program), BCLC (Barcelona Clinic Liver Cancer), and JIS
(Japan Integrated Staging). Tables 6 and 7 present the latest
tumor staging by the AJCC (American Joint Committee on
Cancer).
Table (5): TNM staging system devised by the American
Joint Committee on Cancer
Stage I
T1 N0 M0
Stage II
T2 N0 M0
Stage IIIA
T3 N0 M0
Stage IIIB
T4 N0 M0 or any T1 N1 M0
Stage IIIC
Any T N0 M1
Stage IV
Any T—any NM1
(Pawlik et al., 2005)
112
Diagnosis of HCC
Table (6): TNM staging system devised by the American
Joint Committee on Cancer
T1 Solitary without vascular invasion
T2 Solitary with vascular invasion
Multiple <5cm
T3 Multiple <5cm
Invades major branch of portal or hepatic vein(s)
T4 Invades adjacent organs other than gallbladder
Perforates visceral peritoneum
N1 Regional lymph nodes
M
Distant metastasis
(Pawlik et al., 2005)
Table (7): Definition of the Okuda staging system for
hepatocellular carcinoma
Points
0
<50% of liver
1
>50% of liver
Ascites
No
Yes
Albumin (g/dl)
3
<3
Bilirubin (mg/dl)
<3
3
Tumour size
Okuda stage 1, 0 points; okuda stage II, 1 or 2 points; Okuda stage III, 3 or
4 points.
(Gut, 2005)
113
Diagnosis of HCC
New staging systems for HCC have recently been
reported from Italy and France. The newer classifications
have included prognostic factors including portal vein
thrombosis, multifocal tumour, diffuse or massive disease
high AFP level, and performance status. The Italian
(Cancer Liver Italian Programs, CLIP) (Table 4) and
French (Barcelona Clinic Liver Cancer, BCLC) (Table 5)
classifications have been shown to have a better predictive
power than the Okuda or Child Pugh classification (The
Cancer of the Liver Italian Program (CLIP)
Investigation, 2000).
Table (8): CLIP staging system for hepatoellular
carcinoma.
Variables
Points
0
1
2
Child-Pugh class
A
B
C
Tumour
morphology
Single nodule and
extension
< 50%
Multiple nodules
and extension
< 50%
Massive or
> 50%
AFP (ng/ml)
400
> 400
Portal vein
thrombosis
No
Yes
CLIP score is the sum of points of the 4 variables
(Quoted From Befeler and Di Bisceglie, 2002)
114
Diagnosis of HCC
Table (9): BCLC staging system for hepatocellular
carcinoma.
Stage
Stage A: early
HCC
A1
A2
A3
A4
Stage B
intermediate
HCC
Stage C:
advanced HCC
Stage D: end
stage HCC
Performance
status
Tumour stage
Liver function
0
0
0
0
Single, < 5 cm
Single, < 5 cm
Single, < 5 cm
3 tumours < 3 cm
No portal HTN and normal bili.
Portal HTN an normal bili
Portal HTN and elevated bili
Child pugh class A-B
0
Large multinodular
Child Pugh class A-B
1-2
Vascular invasion or
extrahepatic spread
Child Pugh class A-B
3-4
Any
Child-Pugh class C
N.B. HTN, hypertension
(Quoted From Llovet et al., 2004)
METASTASIS FROM HEPATOCELLULAR CARCINOMA
The most frequent site of metastasis from HCC is the
lung, followed by bone (vertebral body and ribs), lymph
nodes, and adrenal glands. Metastases are seldom seen in
the peritoneum, brain, skin, or muscles. Most frequently
encountered nodal metastasis is within the celiac axis. The
other sites of nodal metastasis, in the order of decreasing
frequency, occur along the portahepatis, para-aortic,
portocaval, mediastinal and cardiophrenic lymphatic chains
(Katyal et al., 2000).
115
Treatment of HCC
TREATMENT OF HCC
T
herapies for HCC can be divided into different
categories: surgical interventions (tumour resection and
liver transplantation), percutaneous interventions (ethanol
injection, radiofrequency thermal ablation, microwave
coagulation, laser ablation, cryoablation), transarterial
interventions
(embolisation,
chemo-perfusion,
or
chemoembolisation) and drugs, including gene and immune
therapy. Potentially curative therapies are tumour resection,
liver transplantation, and percutaneous interventions that can
result in complete responses and improved survival in a high
proportion of patients. In selected cases transarterial
interventions results in palliation with in some case good
response rates and improved survival. To date, surgical,
percutaneous and transarterial interventions have not been
compared in randomised controlled trials. Tumour resection
and transplantation result in selected patient populations in 5year survival rates of 60-70%, with transplantation being the
best treatment for patients with single lesions and advanced
liver disease, e.g. decompensated cirrhosis, or multicentric
small tumours. Percutaneous interventions, again in
selected patient populations, result in 5-year survival rates
of 40-50%. In the following the different therapeutic
options will be discussed in some details (Blum, 2005).
116
Treatment of HCC
I-Surgical interventions of HCC:
A-Resection of HCC
In patients without concomitant liver cirrhosis (5%
in Western countries, 40% in Sub-Saharan Africa and
Asia) HCC resection is the treatment of choice with low
rates of life-threatening complications. By comparison, in
the majority of patients with cirrhosis, strict selection is
required to avoid resection-related complications,
especially postoperative liver failure (Kubo et al., 1999).
Partial hepatectomy with curative intent can be
performed for patients with disease confined to the liver,
patients with adequate hepatic reserve, and patients with
disease anatomically disposed so as to allow adequate
residual liver after resection (Fong et al., 2002).
Patients with extrahepatic metastases are excluded
from partial hepatectomy. The search for extrahepatic
disease must include the locations at greatest risk for
metastases as the lungs, peritoneum, adrenal glands, and
bones (Fong et al., 2002).
Assessment of the extent of liver involvement allows
selection of patients and surgical planning. Triphasic CT
scanning permits evaluation of number and distribution of
liver tumours, and proximity of tumours to vascular
structures. Tumour thrombosis in portal vein, hepatic veins
117
Treatment of HCC
or vena cava can be readily seen on CT. Patients with
intravascular extension of tumour have very poor
prognosis. Even though tumour thrombosis can be treated
with liver resection and thrombus extraction, the risk of
disseminated disease is extremely high and few are cured.
Most surgeons consider tumour thrombus involving main
portal vein or the vena cava to be a relative
contraindication for liver resection (Little and Fong,
2001).
The patient's underlying liver reserve and
regenerative capacity are the most important determinants
of the risk of postoperative hepatic failure. Portal
hypertension and cirrhosis may result in a number of
complications that may compromise a safer intra
postoperative course (Fong et al., 2002).
The Child-Pugh classification system is the bestknown system for assessment of liver function. Child-Pugh
class A indicates functionally well-compensated cirrhosis,
Child-Pugh class B indicates decompensating cirrhosis,
and Child-Pugh class C is decompensated cirrhosis.
Surgical resection generally offered to patients with ChildPugh class A and those at the upper end of class B
spectrum (Little and Fong, 2001).
Surgery of HCC often requires an extensive hepatic
resection, which accompanies a marked reduction in
functional hepatic mass and is associated with a significant
118
Treatment of HCC
postoperative risk of liver failure. The concern is more
serious when patients have a limited reserve of hepatic
functions. Preoperative portal vein embolization (PVE)
aims at atrophy of the part to be resected along with a
compensatory hypertrophy of remnant liver in the future.
PVF is performed via either the percutaneous transhepatic
or transileocolic route (Madoff et al., 2002).
If the volume of the non-cancerous liver to be
resected exceeds 60% of the whole liver, exclusive of the
tumour, PVE of the area to be resected is indicated. When
liver function is impaired, PVE is indicated provided that
the portion of the liver to be resected exceeds 40%.
Complications of PVE are rare; fever, pain and elevated
liver
enzymes
are
milder
than
transarterial
chemoembolization (TACE) (Makuuchi et al., 2002).
Partial hepatectomy remains the main stay of
treatment for HCC with curative intent. In the past decade,
advances in anesthesia, preoperative care, nutrition, and
surgical techniques have meant that the mortality for this
procedure is now less than 5% in specialized centers (Little
and Fong, 2001).
In non-cirrhotic liver, up to two thirds of functional
parenchyma can be removed safely with a good recovery
expected, and resection can provide 5 -year survival in
greater than 30% of patients (Fong et al., 2002).
119
Treatment of HCC
Even in experienced centers in liver resection, partial
hepatectomy in patients with cirrhosis is associated with a
mortality of 1 0% or more (Little and Fong, 2001).
Two major changes in operative technique have
contributed to the improvement of perioperative mortality.
The first is the resection across non- anatomical
boundaries for cirrhotic patients. The second is the
acceptance that inflow occlusion of the hepatic artery and
portal vein is a safe procedure in cirrhotic patients.
Intraoperative ultrasound is also now employed, and aids
in delineating tumours and resection margins (Little and
Fong, 2001).
The long-term prognosis after resection of HCC
remains unsatisfactory as a result of a high incidence of
recurrence. Prevention and effective management of
recurrence are the most important strategies to improve the
long-term survival results. Pathologic factors indicative of
tumour invasiveness such as venous invasion, presence of
satellite nodules, large tumour sizes and advanced TNM
staging, are the best-established risk factors for recurrence
(Poon et al., 2000).
B- Liver transplantation:
Liver transplantation is in principle the optimal
therapeutic option for HCCs because it simultaneously
removes the tumour and the underlying cirrhosis, including
120
Treatment of HCC
the risk of HCC recurrence. While broad selection criteria
applied previously led to poor results with recurrence rates
of about 50% and 5-year survival rates <40%, the current
criteria for liver transplantation in patients with HCC. The
criteria used at most transplant centers are: absence of
extrahepatic metastases, absence of lymph node metastases,
absence of vascular invasion, and tumour size less than 5
cm if single, or less than 3 cm if multiple provided that the
total number of tumours does not exceed three. Result in 5year survival rates of 70% and more and recurrence rates
<15% (Shetty et al., 2004).
Adjuvant chemotherapy and antiviral therapy have
been used to prevent recurrence after transplantation
(Matsunami et al., 2002).
Liver transplantation was originally attempted to treat
patients with extensive unresectable HCC (Starzl et al.,
1967b). Liver transplantation was recently performed for
patients with small HCC lesions arising from cirrhotic
livers and excellent short and long term results have been
achieved (Hemming et al., 2001).
Specifically, patients with cirhrosis and HCC lesion
less than 5 cm in diameter or three or fewer lesions the
largest of which is less than 3 cm in diameter which
compromises the Milan criteria (Mazzaferro et al., 1996)
have 4 year survival rates in excess of 80% which are
comparable to liver transplant recipients with non
121
Treatment of HCC
malignant primary liver disease (Hemming et al., 2001)
and better than those undergoing surgical resection
(Figueras et al., 2000).
Latter on in 2001 the group from University of
California, San Francisco proved that solitary tumor < or =
6.5 cm, or < or = 3 nodules with the largest lesion < or =
4.5 cm and total tumor diameter < or = 8 cm, had survival
rates of 90% and 75.2%, at 1 and 5 years, respectively,
after OLT. And concluded that Milan criteria may be
modestly expanded while still preserving excellent survival
(Yao et al., 2001).
The time spent waiting for a deceased donor liver
was the most important determinant of HCC progression
beyond Milan criteria (Llovet et al., 1999), which is of
course not the case with LDLT. On the other hand,
application of adjuvant local treatment to HCC for patients
waiting for transplantation more than 1 year is a cost
effective strategy for maintaining these patients within
Milan criteria (Llovet et al., 2002). Progression beyond
Milan criteria within 1 year is approximately 10% for HCC
less then 3 cm in size and approximately 60% for large
tumors (Yao et al., 2002).
Most authors advise surgical resection or ablation as
a first line treatment of HCC in patients with well
compensated liver disease (El-Serag et al., 2005b;
Yamamoto et al., 2007a) even though tit was proved that
122
Treatment of HCC
long term patient survival rates are improved with liver
trnasplatnation compared with liver resection (Bigourdan
et al., 2003) and this is because of reasonable success of
resection (Jaeck et al., 2004; Andriulli et al., 2006) and
scarcity of organ donors, which is surely not a problem
with LDLT.
Liver transplantation for patients with false positive
diagnosis of HCC exposes them and their donors to risks as
well as diverts scarce organs away from those who could
benefit more. Therefore, diagnostic accuracy is very
important. CT or MRI can achieve sensitivity and
specificity up to 70% or 8% (Maciel et al., 2006). Liver
biopsy can be needed at some occasions (Durand et al.,
2001).
Tumor size, AFP level, the presence of vascular or
capsular invasion, bi lobar location, and the number of
nodules are all poor prognostic factors and independently
predic mortality and recurrence of HCC. AFP is also a
predictor of recurrence and AFP level greater than 300
ng/dL indicates a high chance of recurrence (Lerut, 2007).
II-Percutaneous interventions:
Percutaneous interventions are the best options for
small unresectable HCCs. Tumour ablations can be
achieved chemically by percutaneous ethanol injection
(PEI) or acetic acid injection (PAI) or hot saline or
123
Treatment of HCC
thermally by radiofrequency thermal ablation (RFTA),
microwave-heat induced thermotherapy (HiTT), laser
induced thermotherapy (LiTT), or cryoablation. Apart from
percutaneous interventions, these techniques can be applied
also laparoscopically or with open laparotomy (Liveraghi
et al., 2004).
A-Percutaneous ethanol injection (PEI):
PEI is the technique most widely used. It is safe, easy
to perform, inexpensive and achieves complete tumour
response rates of t 90-100% in HCCs smaller than 2 cm in
diameter, 70% in HCCs of 3 cm diameter and 50% in
HCCs of 5 cm in diameter. Patients with liver cirrhosis
Child A with complete responses can achieve 5-year
survival rates of 50% and more. Therefore, PEI is the
procedure of choice for patients with a single HCC lesion
smaller than 5 cm in diameter or with up to three lesions
smaller than 3 cm in diameter (Lencioni et al., 1997b).
Worldwide, ultrasound-guided percutaneous ethanol
injection (PEI) is the most commonly used minimally
invasive method for treating HCC. The mechanism of
tumouricidal action is cytoplasmic dehydration with
subsequent coagulation necrosis and fibrosis reaction.
Within neoplastic vessels, ethanol induces necrosis of
endothelial cells and platelet aggregation, thus causing
thrombosis and tissue ischemia. The size and shape of the
induced necrosis is not always reproducible it varies with
124
Treatment of HCC
histological characteristics, degree of vascularization,
presence of capsule or septa, and tissue consistency
(Barnett and Curley, 2001).
PEI is generally applied to treat HCC in cirrhotic
patients. For this treatment must have tumour volumes
less than 30% of the total liver volume. It is
contraindicated in patients with extrahepatic disease,
portal vein thrombosis, Child-Pugh class C cirrhosis,
prothrombin time less than 40% of normal, or platelet
count of less than 40,000/mm3. Other absolute
contraindications include ascetic patients, in whom the
risk of hemorrhage is high, and tumours at the dome of
the liver. In addition, the tumour to treat by PEI must be a
nodular lesion with well-defined borders (Lencioni et al.,
1999).
According to the size and number of the lesions,
ethanol ablation is performed either as outpatient multisession technique or as an inpatient one-shot technique
under general anesthesia. In most instances, HCCs that are
smaller than 5 cm are treated on an outpatient basis but
larger tumours are treated with the one-shot inpatient
technique. For both, ethanol is injected percutaneously
under sonographic guidance. In general, multi-session
procedures using only local anesthesia involve twiceweekly injection of 8 to 10 ml of absolute ethanol for a
total of 4 to 12 sessions. An inpatient procedure involves
125
Treatment of HCC
one session under general anesthesia of approximately 60
to 150 ml delivered via multiple injections over 30 minutes
(Liveraghi et al., 1999).
May be multiple injections are required and these
cause significant local pain associated with the treatment.
Serious complications such as, hemorrhage, hepatic
insufficiency, abscess, bile duct necrosis or biliary fistula,
hepatic infarction, and hypotension are rare, occurring in
less than 5% of patients. Local recurrence after PEI is
common in tumours that are greater than 5 cm in diameter
(Barnett and Curley, 2001).
B-Percutaneous microwave coagulation therapy (PMFT):
In microwave ablation, molecular dipoles are
vibrated and rotated, resulting in thermal coagulation of
the target tissue. The basic mechanism of heat generation
consists of rotation of water molecules. The rotation
follows the alternating electric field components of the
ultra-high-speed (2,450 MHz) microwave. Microwaves
emitted from the distal segment of a percutaneous probe
cause the thermal coagulation of the adjacent tissue (Dodd
et al., 2000).
Potential candidates for microwave ablation include
patients with inoperable tumours that cannot be
chemoembolized due to severe liver dysfunction or
hypovascularity and patients with tumours that failed
126
Treatment of HCC
chemoembolization or alcohol ablation. Generally, the
therapy is limited to patients with four or fewer tumours
that are each less than 5 cm in diameter. Single ablation
produces an elliptical coagulated area with a maximal
diameter slightly greater than 2 cm near the tip of the
electrode. Thus ideal lesions for microwave therapy should
be less than 3 cm in diameter (Dodd et al., 2000).
C- Laser ablation:
From a single, bare 400-um-laser fiber, light at
optical or near-infrared wavelength will scatter within
tissue and be convened into heat. Light energy of 2.0-2.5
Watt will produce a spherical volume of coagulation
necrosis 2 cm in diameter. The use of higher power result
in charring and vaporization around the fiber tip. Two
methods have been developed for producing larger
volumes of necrosis. The first consists of firing multiple
bare fibers arrayed at 2 cm spacing throughout a target
lesion. The second is cooled-tip diffuser fibers that can
deposit up to 30 Wait over a larger surface area, thus
diminishing local overheating (Nolsoe et al., 1995).
Laser ablation can be done after percutaneous ethanol
injection or before transcatheter arterial chemoembolization as a combination therapy (Pacella et al., 2001).
127
Treatment of HCC
D- Cryoablation:
Cryoablation is a method of in situ tumour ablation in
which subfreezing temperatures are delivered by
penetrating the hepatic surface by cryoprobe. Thermally
conductive material is used to cool tissues to irreversible
tissue destruction at temperature below -20 to -35°c. Cell
death is caused by direct freezing, denaturation of cellular
proteins, cell membrane rapture, cell dehydration, and
ischemic hypoxia. Cryolesions as large as 6-8 cm in
diameter can be created safely (Barnett and Curley, 2001).
Patients with unresectable HCC are candidates for
this therapy; however, it is generally limited to patients
with four or fewer lesions. Cryotherapy is performed
routinely during open laparotomy, but may be performed
by
minilaparotomy,
laparoscopically,
or
even
percutaneously. Contraindications include extrahepatic
disease and inability to undergo general anesthesia and
laparotomy (Pistorius et al., 2000).
E- Radiofrequency ablation:
Radiofrequency ablation (RFA) is an evolving
technology being used to treat patients with unresectable
primary and metastatic hepatic cancers. RFA produces
coagulative necrosis of tumour through local tissue heating.
Liver tumours are treated percutaneously, laparoscopically,
or during laparotomy using ultrasonography to identify
128
Treatment of HCC
tumours and guide placement of the RFA needle electrode.
In general, RFA is a safe, well-tolerated, effective
treatment for unresectable hepatic malignancies less than
6.0 cm in diameter. Effective treatment of larger tumours
awaits the development of more powerful, large array
monopolar or bipolar RFA technologies (Curley, 2001).
Radio frequency ablation (RFA) is a localized thermal
treatment technique designed to produce tumour
destruction by heating tumour tissue to temperatures that
exceed 60°C, intracellular proteins are denatured and cell
membranes are destroyed through dissolution and melting
of lipid bilayers (Curley, 2001).
Radiofrequency energy is an alternating current with
a frequency between 10 kHz and 900 MHz, and is a portion
of the electromagnetic spectrum. RF waves have relatively
long, wavelength and are of a very low energy. RF waves
applied for tissue thermal ablation have a frequency of 480500 kHz (Scudamore, 2000).
Patients must have some general characteristics to be
considered eligible for treatment by radio frequency
ablation. First, because RF ablation is a local treatment,
disease ideally should be confined to the liver, without
evidence of vascular invasions or extrahepatic metastases.
In addition, the tumour must be focal, and of a nodular
type. The presence of a clear and easy-to-detect target for
129
Treatment of HCC
needle placement is crucial for an optimal outcome
(Lencioni et al., 2000).
The tumour must be either uninodular or, when
multinodular, have a maximum of four lesions. Tumour
size should be ideally smaller than 4 cm in the greatest
dimension, as the goal of RF thermal ablation is to kill all
of the tumour and circumferential cuff of normal liver
surrounding the tumour, i.e., adequate free margin 1 cm
thick (Rhim and Dodd, 1999).
Nevertheless, larger lesion, especially HCC, can also
be treated by using newer RF generators and multiple
needle insertions or by performing RFA after transcatheter
hepatic arterial occlusion embolization (Lencioni et al.,
2001).
The main aim of thermal tumour ablation therapy is to
destroy an entire tumour by using heat to kill malignant
cells without damaging adjacent vital structures. This
therapy often includes the treatment of 0.5-1 cm safety
margin of apparently healthy tissue adjacent to the lesion.
As long as adequate cytotoxic heat can he generated
throughout the tumour, eradication of the tumour will be
accomplished (Goldberg et al., 2000).
Treatment of lesions adjacent to the gall bladder or to
the hepatic hilum may cause thermal injury to the biliary
tract. In contrast, treatment of lesions located in the vicinity
130
Treatment of HCC
of hepatic vessels is possible because flowing blood
usually cools the vascular wall, protecting it from thermal
injury; in these cases, however, the risk of incomplete
ablation of the lesion adjacent to the vessel may increase
because of the heat loss caused by the vessel itself. Lesions
located along the hepatic surface can be considered for RF
ablation, although their treatment requires experienced
hands and may be associated with a higher risk of
complications (Lencioni et al., 2000).
Other exclusion criteria include in addition to what
are mentioned before, active infection, uncorrectable
coagulopathy and pregnancy (Rhim and Dodd, 1999).
So the most important complications of
radiofrequency ablation are: bleeding infection, biliary
tract damage, liver failure visceral damage and hepatic
vessels injury (Torres et al., 2001).
Also other complications like pneumothorax
vasovagal reactions, ventricular fibrillation and electrode
track seeding may occur (Bowles et al., 2001).
III-Transarterial interventions:
Transarterial embolization and chemoemBotization
(TACE) are the most widely used treatments for HCCs that
are unresectable or cannot be effectively treated by
percutaneous interventions. Embolization agents may be
131
Treatment of HCC
administered alone (embolization) or after selective intraarterial chemotherapy (generally doxorubicin, mitomycin
or cisplatin) mixed with lipiodol (chemoembolization).
Transarterial embolization delays tumour progression and
vascular invasion and results in a survival benefit compared
with conservative management. The most important aspect
is the selection of patients, i.e. patients should have
preserved liver function (Child A) and asymptomatic
multinodular tumours without vascular invasion or
extrahepatic spread (Llovet and Bruix, 2004).
The main goals of TACE are: (1) tumour necrosis
after ischemia induce by embolization; (2) increased drug
concentration into the tumour by selective arterial
injection intensified by the arterial flow slow-down
induced by embolization; (3) increased efficacy of certain
drugs in ischemic tumours, and (4) better hepatic
clearance of the drug resulting in diminution of systemic
concentrations (Lee et al., 2002).
TACE should not be performed in patients with
predominant or extensive extrahepatic disease. Because
TACE causes some damage to the hepatic parenchyma not
included with tumour, significant baseline liver dysfunction
is contraindication. Tumour burden more than 50% of the
liver volume, LDH level of more than 425 IU/L, AST level
more than 100 IU/L, a total Bilirubin of 2 mg/dl or more,
and cardiac and renal insufficiency, have been shown to
132
Treatment of HCC
correspond to a high risk of acute hepatic failure following
TACE. Refractory ascites, absence of hepatic portal blood
flow, encephalopathy, and biliary obstruction are other
contraindications (Barnett and Curley, 2001).
Post-embolization syndrome consisting of pain,
fever, nausea and vomiting, leucocytosis and transient
elevation of liver enzymes is the rule, but supportive
therapy typically suffices. Major complications occur in
3% to 4% of patients and include hepatic failure, hepatic
infarction, hepatic abscess, tumour rupture, hepatic arterial
occlusion, and non-target embolization (Roche, 1999).
In different series, TACE treatments lead to about
50% of complete response and 25% of partial response
depending on elevated AFP. Complete plus partial
morphological responses are reported in about 45% of
cases (25-60%) and, interestingly, most of the responses
occur before the 3 session of treatment (Roche, 1999).
A meta-analysis of survival among patients with
HCC indicated that the survival rates of patients
underwent chemoembolization were 70% at 1 year, 40% at
3 years, and 10% at 5 years. The range of reported survival
rates at each interval is substantial, because these rates are
strongly influenced by various prognostic factors: tumour
burden, tumour stage, underlying cirrhosis, and uptake and
retention of the chemoembolic materials (Chung, 1998).
133
Treatment of HCC
IV-Drugs:
1-Systemic chemotherapy:
For a number of reasons, systemic chemotherapy may
appear to be ineffective against HCC. Inherent drug
resistance may be present, because hepatocytes
constitutively express the multidrugs resistance gene. The
underlying hepatic dysfunction may also be problematic,
requiring dosage adjustments of chemotherapeutics to
avoid drug toxicity. Drug delivery to the tumour may be
compromised due to portal hypertension or blood shunting
(Fong et al., 2002).
2- Interferon and combinations with cytotoxic drugs
Interferon-a (IFN-a) has antiviral, antiangiogenesis,
and antitumour activities and has been shown significantly
to reduce the rate of HCC in patients with viral hepatitis.
The use of interferon as single-agent therapy for HCC was
popular in 1930s. It seems that interferon-a may have some
activities in HCC, but high dose is required. It may be best
used in lower dosage and in combination with cytotoxic
drugs (Leung and Johnson, 2001).
Chung and Song (2000) reported that the combined
therapy consisting of intra-arterial cisplatin infusion and
systemic IFN-a may be useful as palliative treatment for
134
Treatment of HCC
HCC patients with major
extrahepatic metastases.
vascular
thrombosis
or
For IFN-P to play a truly significant role as an
adjuvant to local treatment, it should have antitumour
activity against intrahepatic metastasis unrecognized at
the initial treatment. However, this effect has not been
evaluated clinically and was never established in clinical
setting (Okada et al., 2001).
3- Hormonal therapy:
As HCC occurs more commonly in males and HCC
cells have been shown to express estrogen receptors in
35%, it was hypothesized that the growth of HCC might
be hormone related. Compared with placebo, tamoxifen
does no extend the survival of patients with cirrhosis and
advanced HCC. The combination of tamoxifen with
etoposide showed mild activity and acceptable toxicity in
advanced HCC and was a useful palliative treatment in
25% of these patients. Combining tamoxifen with
cytotoxic drugs as doxorubicin was also effective
(Schachschol et al., 2000).
Somatostatin receptors have been demonstrated in
40% of HCC, and octreotide, a somatostatin analogue, has
been shown to treat unresectable HCC. The effect of
octreotide was compared versus no treatment; treated
patients had longer median survival and an increased
135
Treatment of HCC
cumulative survival rate at 6 and 12 months (Kouroumalis
et al., 1998).
4- Viscum in the treatment of HCC:
Mistletoe (viscum album L.) is a semi-parasitic plant
that draws water minerals and a small amount of sugar and
amino acids from a variety of host trees (apple, oak, birch,
hawthorn, fir pine and ash etc.) It is the most widely
known species of mistletoe growing in Europe (Becker,
1986).
Steiner first proposed mistletoe treatment for cancer
in 1920. The liquid extract from mistletoe plant has been
used for over 75 years to treat tumours with active
ingredients being viscotoxins, lectins and others (Franz,
1986 and Baudina, 1987).
Viscum album extract contains liposomes due to a
high sophisticated technology. This technique of liposome
ensures:
- Long action of the drug.
- Targeting of the active ingredients to specific organs.
The mechanism by which Viscum reaches blood
from liposomes is dependent on free fraction inside
intracellular subcutaneous tissue. Viscum is used
subcutaneously, intralesional or in special situation
intravenously (infusion) (Gabius et al., 1992).
136
Treatment of HCC
Mode of Action:
Different mechanisms of action related to different
active component of viscum album L. extract work in
synergy in order to maximize the therapeutic efficacy of
viscum fraxini.
The following table (10) show the different active
component and their mechanism of action.
Table (10): Pharmacodynamics
Material type and
components
Effect on tumour
cells
Effect on immune
system
Other effects
Glycoproteins:
Mistletoe lectin-I, II,
III
Inhibition of
ribosomal protein
synthesis, induction of
apoptosis
Release of TNF-, IL1, IL-2, IL-6,
stimulation of NKcells activity,
immunoglobulin
production
Release of endorphins
Polypeptide:
Viscotoxins
Cytotoxicity by
increased cell
membrane
permeability
Activation of
macrophages, T
lymphocyte and their
cytotoxic effect
Interactions with
lectins
Increased Tlymphocytes
synergistic activity
Effect with lectins
Vesicles:
Lipids and proteins of
the membranes
Amino acids:
Arginine
Arrest of tumour
induction in animal
experiments
Activation of
macrophages
Proliferation and
stimulation of NKcells
Polysaccharides:
Arabinogalactan
Galaturonan
Oligosaccharides
Arrest of tumour
induction in animal
experiments
Flavonoids:
Quercetin
Inhibition of
collagenase-IV and
arrest of tumour
induction in vivo
Interferon release,
stimulation of NKcells
(Fischer et al., 1997)
137
Treatment of HCC
5-Targeted immunotherapy:
This involves the use of monoclonal antibodies
against cells as I131 labeled antiferritin and a -fetoprotein
antibodies (Williams et al., 1987).
Transinterleukin-2 emulsified in a lipiodol-urografin
mixture as a promising therapeutic approach in patients
suffering from advanced unresectable HCC (Lygidakis et
al., 1995).
Immunoliposomes represent a promising approach
in treatment strategies for HCC. Liposomes are safe
delivery vehicles that can carry a variety of substance as
doxorubicin in their inner aqueous space. To increase the
efficiency of delivery, liposomes have been targeted to
specific cell types using monoclonal antibodies (Moadpour
et al., 1995).
6. Radiotherapy:
The use of radiotherapy for HCC has been limited
because, it has not been capable of curing HCC and
because the radiation tolerance of the normal liver is far
lower than the tumouricidal dose. In addition excessive
radiation provokes so called radiation hepatitiss There is
direct relationship between the radiation dose and the
tumouricidal effect, so that irradiation below the threshold
138
Treatment of HCC
of tolerance cannot stop the tumour growth (Llovet et al.,
2000).
Proton irradiation is a modality for the treatment of
HCC that is safe and effective for local tumour control,
Matsuzaki et al. (1995) experience had demonstrated
excellent local tumour control for 6 years or longer, as well
as maintenance of good quality of life. It could be used
even for patients for whom conventional therapies were
not available. The only major limitation is that the HCC
should be nodular not diffuse. No serious adverse effects
have been observed.
139
Summary
SUMMARY
H
CC is the most common primary malignant tumour
of the liver. HCC accounts for 90% of primary liver
cancers and causes at least 1 million deaths worldwide per
year. It is the 51 most common cancer in the world and the
4 in annual mortality rare. The annular mortality rare from
the HCC is virtually the same as its annular incidence,
which attests to its rapid course, and grave prognosis.
Post-hepatitic cirrhosis due to HCV infection is one
of the most important hepatic affection among Egyptian
patients. Hepatocellular carcinoma is one of the most
serious complications of post hepatitic C cirrhosis.
In addition, prevalence of HCC among residents of
urban areas proved to be relatively higher than rural areas.
The aetiology of HCC proved to be multifactorial.
Chronic liver diseases namely HCV, HBV and bilharziasis
infections proved to be the most important risk factors
judging by their high prevalence among HCC cases and
their alarming prevalence among the Egyptian community
as a whole.
It is worth mentioning that the presence of liver
cirrhosis paves the way for risk factors making HCC
almost always inevitable.
140
Summary
Agricultural and industrial pollutant exposure has
proved to be worthy of a high rank among the conventional
risk factors of HCC.
Smokers, alcoholics and drug addicts proved to be at
a relatively higher risk of developing HCC than other
individuals abstaining from such hazardous habits.
AFP levels alone are controversial regarding the
diagnosis and follow-up of HCC. However, when
radiological imaging by U/S and/or C.T. is correlated with
AFP levels diagnosis and follow-up become more
conclusive.
Screening often permits the diagnosis of HCC at a
stage when it is small and limited to the liver. Such
tumours are frequently amenable for resection, or to other
local treatment measures, resulting in a prolonged diseasefree survival.
Surgical resection remains the only potentially
curative treatment of hepatic malignancies. Unfortunately,
most primary hepatic malignancies are unresectable.
Approximately 35% of patients with HCC have resectable
disease at the time of diagnosis. Patients with HCC are
often poor surgical candidates because of the lake of
hepatic reserve resulting from coexisting liver cirrhosis, the
presence of multiple lesions at the time of diagnosis, or
proximity of tumour to key vascular jar biliary structures,
141
Summary
additionally, because of the underlying cirrhosis, this
patients are high risk for the development of new tumour
nodules.
Radiofrequency thermal ablation (RFA) is a more
recently developed method for local tissue ablation. In this
technology radiofrequency energy at a frequency of 400 to
500 kHz is delivered into the tissues. A resistive heating
occurs as a result of the vibrations of the electrons within
the tissues caused by this high frequency current. Once
cells are heated above 50°C, their cell membranes melt
and fuse, and with continuous heating, proteins
denaturation and irreversible cell death occurs.
Biologic therapy is a model of cancer treatment that
produces antitumor effects primarily through action of
natural host defense mechanism.
Viscum fraxini is an aqueous extract of mistletoe
plant that has got an immunomodulatory effects as release
ofIL-2, 6, 12, activates NK cells and cytotoxic Tlymphocytes. Also it has got other effects as induction of
apoptosis and release of endorphins and encephalin. It is
considered as an example of non-specific active
immunotherapy.
142
References
REFERENCES
Abdel-Ghaffar Y and Khalil A (1984): Hepatitis B
surface antigen and hepatocellular carcinoma.
Egypt J Gastroenterol 10: 21.
Abdel-Wahab MF, Zakaria S, Kamal M et al. (1994):
High seroprevalence of hepatitis C infection
among risk groups in Egypt. Am J Trop Med
Hyg 51: 563-567.
Adams LA, Sanderson S, Lindor KD, Angulo P (2005):
The histological course of nonalcoholic fatty
liver disease: a longitudinal study of 103
patients with sequential liver biopsies. J
Hepatol 42: 132-8.
Albrecht T, Urbank A, Mahler M et al. (1998):
Prolongation and optimization of Doppler
enhancement with a microbubbles U/S contrast
agent by using continuous infusion: preliminary
experience. Radiology 207: 339-347.
Alison M, Poulsom R, Jeffery R et al. (2000):
Hepatocytes from non hepatic adult stem cells.
Nature 406: 257-260.
American Society of Clinical Oncology (2005): Annual
meeting, Abstracts on Hepatobiliary carcinoma.
143
References
Andriulli A, De Sio I, Brunello F et al. (2006): Survival
of patients with early hepatocellular carcinoma
treated by percutaneous alcohol injection.
Aliment Pharmacol Ther 23(9): 1329-1335.
Angulo P (2002): Nonalcoholic fatty liver disease. N Engl
J Med 346: 1221-31.
Anthony P and Bannasch P (1994): Tumors and tumor
like lesions of the liver and biliary tract. In:
Pathology of the liver, edited by MacSween R,
Anthony P, Scheuer P et al. Churchill
Livingstone, Edinburgh 635-657.
Anthony PP (1987): Tumor and tumor like lesions of the
liver and biliary tract. In: Pathology of the liver,
2nd edition, MacSween RNM, Anthony PP,
Scheuer PJ, Churchill Livingstone, Edinburgh,
London, Melbourne and New York: 17: 574-645.
Anthony PP (2001): Primary carcinoma of the liver. A
study of 282 cases in Ugandan Africans. J
Pathol 110: 37-48.
Armstrong GL, Alter MJ, McQ Villan GM and
Margolis HS (2000): The past incidence of
hepatitis C virus infection: implications for the
future burden of chronic liver disease in the
United States. Hepatology 31: 777-782.
144
References
Austin A (1991): The role of tobacco use and alcohol
consumption. In: Etiology, Pathology and
treatment of HCC in North America: Review of
cigarette smoking as a minor risk factor for
HCC, edited by Tabor, E., and Di Bisceglie,
A.M., Purcell R.H. Gulf Publishing Company,
Houston, pp. 57-76.
Barnett B and Curley SA (2001): Ablative techniques for
hepatocellular carcinoma. Semin in Oncology,
28(5): 487-496.
Barrett J (2000): Mycotoxins: of molds and maladies.
Environ Health Perspect 108: A20-A23.
Bartolozzi C, Lencioni R, Caramella D et al. (1998):
Detection of small hepatocellular carcinoma:
prospective comparison of U/S, CT, MR
imaging, DSA and Lipiodol-CT. Acta. Radiol
(in press).
Baserga R, Yoko H, Henegar GC (1960): Thorotrast
induced cancer in man. Cancer 13: 1021-31.
Baudina S (1987): The active substances of mistletoe.
Pharmacological properties and therapeutic
application. Annals des. Sciences Naturals
Botanique 13: 45-72.
145
References
Bayman P, Baker JL, Doster MA et al. (2002):
Ochratoxin production by the aspergillus
ochraceus group and aspergillus alliaceus. Appl
Environ Microbiol 68: 2326-2329.
Beasley RP, Hwang L, Lin C et al. (2001): Hepatocellular
carcinoma and hepatitis B virus: a prospective
study of 22,707 men in Taiwan. Lancet, ii:
1129-1133.
Becker H (1986): European Mistletoe. Oncology 43: 2-7.
Befeler AS and Di Bisceglie AM (2002): Hepatocellular
carcinoma:
Diagnosis
and
treatment.
Gastroenterology 122: 1609-1619.
Bennett JW and Klich M (2003): Mycotoxins. Clinical
Microbiology Reviews; 16(3): 497-516.
Bergstrand G and Czar B (1957): Paper electrophoresis
study of human fetal serum protein with
demonstration of a new protein fraction. Scand
J Clin Lab Invest 9: 277-280.
Berman MM, Libbey NP and Foster JH (2001):
Hepatocellular carcinoma; polygonal cell type
with fibrous stroma; an atypical variant with a
favourable prognosis. Cancer; 46: 1448-55.
146
References
Bianchi L (1993): Glycogen storage disease and
hepatocellular tumors. Eur J Pediatr 152: 6370.
Bigourdan JM, Jaeck D, Meyer N et al. (2003): Small
hepatocellular carcinoma in Child A cirrhotic
patients: hepatic resection versus transplantation.
Liver Transpl 9(5): 513-520.
Bisollon T, Rode A, Baricel B et al. (1998): Diagnostic
value and tolerance of Lipiodol CT for the
detection of small HCC: correlation with
pathologic examination of explanted livers. J
Hepatol 28: 491-496.
Bjersing L, Andersson C and Lithner F (1996): HCC in
patients from northern Sweden with acute
intermittent porphyria: morphology and
mutations. Cancer Epidemiol Biomarkers Prev
5: 393-397.
Blumgart L and Fong Y (2000): Computed tomography
and magnetic resonance imaging of liver and
biliary tract. In: Surgery of the liver and biliary
tract, 3rd edition, 309-358.
Bock CT, Tillmann HL, Manns MP and Trautwein C
(1999): The pre-S region determines the
intracellular localization and appearance of
hepatitis B virus. Hepatology 30: 517-525.
147
References
Bolondi L, Sofia S, Siringo S, GAiani S, Casali A, Zironi
G, Piscaglia F, Gramantieri L, Zanetti M and
Sherman M (2001): Surveillance programme of
cirrhotic patients for early diagnosis and
treatment of hepatocellular carcinoma: a cost
effectiveness analysis. Gut 251-259.
Borowski P, Oehlmann K, Heiland M and Laufs R
(1997): Nonstructural protein 3 of hepatitis C
virus blocks the distribution of the free catalytic
subunit of cyclic AMP dependent protein
kinase. J Virol 71: 2838-2843.
Bosch FX, Ribes J, Diaz M and Cleries R (2004):
Primary liver cancer. Worldwide incidence and
trends. Gastroenterology 127: S5-S16.
Bowels B, Machi J, Lim W et al. (2001): Safety and
efficacy of radiofrequency thermal ablation in
advanced liver tumors. Arch. Surg 136: 864-869.
Boyd SA, Jones A, Knaus and McGrath C (eds.) (2001):
Drinking water: a community action guide.
Concern, Inc., Washington, D.C.
Brechot C, Pourcel C, Louise A, Rain B, Tiollais P
(1980): Presence of integrated hepatitis B virus
DNA sequence in cellular DNA of human
hepatocellular carcinoma. Nature, 286: 533-5.
148
References
Brechot C, Thiers V, Kremsdorf D, et al (2001):
Persistent hepatitis B virus infection in subjects
without hepatitis B surface antigen: Clinically
significant or purely occult. Hepatology Jul 34
(1):194-203.
Browning J, Szczepaniak L, Dobbins R, Nuremberg P,
Horton J, Cohen J et al. (2004): Prevalence of
hepatic steatosis in an urban population in the
United States: Impact of ethnicity. Hepatology
40: 1387-95.
Brugwra M, Cremades M, Salinas R, Costa J, Grau M
and Sans J (1992): Impaired response to
recombinant hepatitis B vaccine in HIVinfected persons. J Clin Gastroenterol 14:27-30.
Bruix J, Barrera JM, Galvet X et al. (2001): Prevalence
of antibodies to hepatitis C virus in Spanish
patients with hepatocellular carcinoma and
hepatic cirrhosis. Lancet ii: 1004-1006.
Bruix J, Sherman M, Liovet JM, Beaugrand M, Lencioni
R, Burroughs AK, Christensen E, Pagliaro L,
Colombo M and Rodes J (2001): Clinical
management of hepatocellular carcinoma.
Conclusions of the Barcelona-2000 EASL
Conference. European Association for the study
of the liver, J Hepatol; 35: 421-430.
149
References
Brummund W, Arvan D, Mennuti M et al. (1980): Alpha
fetoprotein in the routine clinical laboratory:
evaluation of a simple radioimmunoassay and
review of current concepts in its clinical
application. Clin Chem Acta, 105: 25-30.
Bukofzer S, Stass P, Kew M et al. (1989): Alpha Lfucosidase as a serum marker of HCC. Br J
Cancer 54: 417-420.
Buscarini L, Di Stasi M, Buscarini E et al. (1996):
Clinical presentation, diagnostic work up and
therapeutic choices in two consecutive series of
patients with HCC. Oncology 53: 204-209.
Byrd DR (2001): Hepatobiliary anatomy. In: Surgery
scientific principles and practice, 3rd ed., edited
by Greenfield L, Oldham K, Mulholland M et
al., Philadelphia, Lippincott Williams and
Wilkins, 915-927.
Cacciola I, Pollicino T, Squadrito G, Cerenzia G,
Orlando ME and Raimondo G (1999):
Occult hepatitis B virus infection in patients
with chronic hepatitis C liver disease. N Engl J
Med 341:22-6.
Calvo AM, Bok J, Brooks W et al. (2004): VeA is
required for toxin and sclerotial production in
Aspergillus
parasiticus.
Applied
and
Environmental Microbiology; 70(8): 47334739.
150
References
Cheever A (1988): Schistosomiasis and neoplasms. J Nat
Cancer Inst 61: 13-18.
Chen MF, Jan YY, Jeng LB et al. (1994): Obstructive
jaundice secondary to ruptured hepatocellular
carcinoma into the common bile duct. Cancer
73: 1335-1338.
Chen RC, Chen LY, Liao NY et al. (2002): Intravenous
contrast enhanced Doppler sonography and
intraarterial
carbon
dioxide
enhanced
sonography in the assessment of hepatocellular
carcinoma vascularity before and after
treatment. Acta Radiological 43: 411-414.
Cheng WSC, Govindarajan S and Redeker AG (1992):
HCC in a case of Wilson's disease. Liver 12:
42-45.
Chiesa R, Donato F, Tagger A et al. (2000): Etiology of
hepatocellular carcinoma in Italian patients
with and without cirrhosis. Cancer Epid Bio
Prev 9(2): 213-216.
Choi BI, Kim TK, Han JK et al. (1996): Power versus
conventional color Doppler sonography:
comparison in the detection of vasculature in
liver tumors. Radiology, 200: 55-58.
151
References
Chung J (1998): Transcatheter arterial chemoembolization
of hepatocellular carcinoma. Hepatogastroenterology, 45: 1236-1241.
Chung YH and Song BC (2000): Combined therapy
consisting of hepatocellular
carcinoma.
Hepatogastroenterology, 45: 1236-1241.
Chung YH and Song BC (2000): Combined therapy
consisting of intraarterial cisplatin infusion and
systemic interferon- for hepatocellular
carcinoma patients with major portal vein
thrombosis or distant metastases. Cancer 88:
1986-1991.
Collier J and Sherman M (1998): Screening for hepatocellular carcinoma. Hepatology 27: 273-278.
Craig J, Peters R and Edmonson H (1989): Tumors of the
liver and intrahepatic bile ducts, 2nd edition,
Washington, DC: Armed forces Institute of
Pathology, 422: 430.
Craig JR (1997): Fibrolamellar carcinoma: clinical and
pathological features. In: Liver cancer, edited
by Okuda K and Tabor E, New York Churchill
Livingstone, 255-262.
152
References
Crawford M (1999): The liver and the biliary tract. In:
Pathologic basis of disease, 6th edition, edited by
Cotran R, Kumar V and Collins T, W.B. Saunders
Company, Philadelphia, 845-901.
Curley SA (2001): Radiofrequency ablation of liver tumours.
The Oncologist, 6: 14-23.
Deugnier YM, charalambous P, Le Quilleuc D et al.
(1993): Preneoplastic significance of hepatic iron
free foci in genetic hemochromatosis: a study of
185 patients. Hepatology, 18: 1363-1369.
Di Bisceglie AM (1999): Malignant neoplasms of the liver. In
Schiff's diseases of the Liver, 8th edition, edited by
Schiff ER, Sorrell MF and Maddrey WC,
Lippincott-Raven Publishers, Philadelphia, pp.
1281-1303.
Dodd GD, Soulen MC, Kane RA et al. (2000): Minimally
invasive treatment of malignant hepatic tumours:
At the threshold of major break through.
Radiographics, 9: 20-27.
Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P,
Albertini A, Decarli A, Trevisi P, Ribero ML,
Martelli C, Porru S and Nardi G (2002):
Alcohol and hepatocellular carcinoma: The effect
of lifetime intake and hepatitis virus infection in
men and women. Am J Epidemiol, 155: 323331.
153
References
Dorner
JW (2002): Simultaneous quantitation of
aspergillus flavus/ A. parasiticus and aflatoxins
in peanuts. J AOAC Int 85(4): 911-916.
Durand F, REgimbeau JM, Belghiti J et al. (2001):
Assessment of the benefits and risks of
percutaneous biopsy before surgical resection
of hepatocellular carcinoma. J Hepatol 35(2):
254-258.
Edington GM (1979): Schistosomiasis and primary liver
cancer. Trans R Soc Trop Med Hyg 351-352.
Edmondson H and Steiner P (1954): Primary carcinoma
of the liver. A study of 100 cases among 48.900
necropsies. Cancer, 7: 462-503. Sited in Saul
SH (1999): Masses of the liver. In: Diagnostic
surgical pathology, 3rd edition, edited by
Sternberg SS, Lippincott Williams and Wilkins,
Philadelphia, 1553-1628.
El-Serag HB, Davila JA, Petersen NJ and McGlynn KA
(2003): The continuing increase in the incidence
of hepatocellular carcinoma in the United States:
an update. Ann Intern Med, 139: 817-823.
Evans AA, O'Connell AP, Pugh JC et al. (1998):
Geographic variation in viral load among
hepatitis B carriers with differing risks of
hepatocellular carcinoma. Cancer Epidemiol
Biomarkers Prev 7: 559-565.
154
References
EXTOXNET primary files maintained and achieved at
Oregon State University, Revised June
(1996): A pesticide information project of
cooperative extension offices of Cornell
University, Oregon State University, the
University of Idaho, and the University of
California at Davis. The Institute for
Environmental Toxicology, Michigan State
University. U.S. National Agricultural Pesticide
Impact Assessment Program.
Farag RS, RAshed MM and Abo-Hager AA (1996):
Aflatoxin destruction by microwave heating.
Int J Food Sci Nutr 47(3):197-208.
Fenton S and Swan N (1995): Liver biopsy. In Bockus
Gastroenterology, 5th edition, edited by
Haubrich W, Schaffner F and Berk J, W.B.
Saunders Company, Philadelphia, 1832-1848.
Fen-YU Ren, Xi-Ku Piao and Ai-Lian Jin (2006):
Efficacy of ultrasonography and alphafetoprotein on early detection of hepatocellular
carcinoma. World J Gastroenterol 12 (29):
4656-4659.
Ferlay J, Bray F, Pisani P and Parkin DM. Globocan
(2000): Cancer Incidence. Mortality and
Prevalence worldwide.
155
References
Figueras J, Jaurrieta E, Valls C et al. (2000):
or transplantation for hepatocellular
in cirrhotic patients: outcomes
indicated treatment strategy. J Am
190(5): 580-587.
Resection
carcinoma
based on
Coll Surg
Fink-Gremmels J (1999): Mycotoxins: their implications
for human and animal health. Vet Q 21: 115120.
Fischer S, Scheffler A and Kabelitez D (1997):
Stimulation of the specific immune system by
mistletoe extracts. Anticancer drugs 8(1): 533539.
Fong
Y,
Venook R and Lawrence T (2002):
Hepatocellular cancer: clinical management In:
Gastrointestinal Oncology: Principle and
Practice, edited by Kelsen D, Daly J, Levin B,
et al., Philadelphia, Lippincott Williams and
Wilkins, 579-600.
Francisco A Durazo, Lawrence M Blatt, William G
Corey, Jiing-Huey Lin, Steven Han and
Sammy
Saab
(2008):
Des-gammacarboxyprothro-mbin, Alpha-fetoprotein and
AFP-L3 in patient hepatocellular carcinoma. J
Gastro-enterol Hepatol Apr 19.
156
References
Franz H (1986): Mistletoe lectins and their A and B
chains. Oncology, 1: 23-34.
Fujiyama S, Tanaka M, Maeda S et al. (2002): Tumour
markers in early diagnosis, follow up, and
management of patients with hepatocellular.
Oncology 62(1): 57-63.
Gabius H, Walzel H, Joshiss K et al. (1992): The
immunomodulatory beta-galactoside specific
lectin from mistletoe partial sequence analysis,
cell and tissue binding, and impact on
intracellular biosignalling of monocytic
leukemia cells. Anticancer Research 12(3): 669675.
Garcia-Samaniego J, Rodriguez M, Berenguer J,
Rodriguez-Rosado, Carbo J, Asensi V and
Soriano V (2001): Am J Gastroenterol, 96:
179-183.
Garcio-Tsao G (2001): Current management of the
complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites and
spontaneous bacterial peritonitis. Gastroenterolgy 120:726-748.
157
References
Goldberg SN, Gazelle GS, Campteri CC et al. (2000):
Treatment of intraheptaic malignancy with
radiofrequency ablation: Radiological pathologic
correlation. Cancer 88: 2452-2463.
Goodman ZD (2001): Benign tumors of the liver. In:
Neoplasms of the Liver, edited by Okuda, K
and Ishak KG, Springer Verlag, Tokyo pp. 105125.
Goodman ZD, Ishak KG, Longlos JM et al. (1998):
Combined hepatocellular cholangiocarcinoma:
a histologic and immunohistochemical study.
Cancer 55: 124.
Gore RM and Remer EM (2000): Normal anatomy and
examination techniques. In: Gastrointestinal
Radiology, 2nd ed., Edited by Gore RM and
Levine MS, Philadelphia, W.B. Saunders,
1416-1441.
Gupte
P,
Amarapurkar D, Agal S, Baijal R,
Kulshrestha P, Pramanik S et al. (2004): Non
alcoholic steatohepatitis in type 2 diabetes
mellitus. J Gastroenterol Hepatol 19: 854-8.
Gut (2005): Definition of the Okuda staging system for
hepatocellular carcinoma. Gut 54(3): 411-418.
158
References
Haagsma EB, Smit GP, Niezen-Koning KE et al. (1997):
Type III b glycogen storage disease associated
with end stage cirrhosis and HCC. Hepatology,
25: 37-540.
Hardell L, Bengtsson NO, Jonsson U et al. (1984):
Aetiological aspects of primary liver cancer with
special regard to alcohol, organic solvents and
acute intermittent porphyira. An Epidemiological
Investigation. Br J Cancer 50: 389.
Hass JE, Mucryznski KA, Krailo M et al. (2003):
Histology and prognosis in childhood
hepatoblastoma and hepatocarcinoma. Cancer
54: 1082.
Hassan MM, Zaghloul AS, EL-Serag HB, Soliman O,
Patt YZ, Chappell CL, Beasley RP and
Hwang LY (2001): The role of hepatitis C in
hepatocellular carcinoma: a case control study
among Egyptian patients. J Clin Gastroenterol
33: 123-126.
Helmy A, Dabbous H, Hetta O et al. (2002): The value of
triphasic spiral C Tin comparison to other
conventional modalities in diagnosis of hepatocellular carcinoma. Sci Med J 14(2): 6781.
159
References
Hemming AW, Catral MS, reed AI et al. (2001): Liver
transplantation for hepatocellular carcinoma.
Ann Surg 233(5): 652-659.
Hicks JK, Shimizu K and Keller NP (2002): Genetics and
biosynthesis of aflatoxins and sterigmatocystin.
In: The mycota, Agricultural applications.
Kempken F (ed), Springer-0Verlag, Berlin,
Germany; Vol. XI: 55-69.
Hirayama T (1981): A large scale cohort study on the
relation ship between diet and selected cancers
of digestive organs. In: Banburg Report 7.
Gastrointestinal Cancer. Endogneous Factors.
Cold Spring. Harbor Laboratory, 198: 409-29.
Hollett M, Jeffry R, Nino-Murcia M et al. (1995): Dual
phase helical CT of the liver: value of arterial
phase scans in the detection of small (< cm)
malignant hepatic neoplasm. Am J Radiol
164:879-884.
Honda H, Onitsuka H, Murakami J et al. (1992):
Characteristic findings of HCC: an evaluation
with comparative study of U/S, CT, and MRI.
Gastrointestinal Radiology 17: 245-249.
160
References
Hori M, Murakami T, Kim T et al. (1998): Sensitivity of
double phase helical CT during arterial
portography for detection of hypervascular
HCC. J Comput Assist Tomogr 22: 861-867.
Huppertz A, Haraida, Kraus A, Zech CJ, Scheidler J,
Breuer J, et al. (2005): Enhancement of focal
liver lesions at gadoxetic acid-enhanced MR
imaging: Correlation with histopathological
findings and spiral CT-initial observations.
Radiology 234: 468-78.
Idilman R, De Maria N, Colantoni A and Van Thiel DH
(1998): Pathogenesis of hepatitis B and Cinduced hepatocellular carcinoma. J Virol
Hepat 5: 285-299.
International Agency for Research on Cancer (1994):
Monogrphs on the evaluation of carcinogenic
risks to humans. IARC Lyon, Vol. 61.
Ishak KG (1991): Hepatocellular carcinoma associated
with the inherited metabolic disease. In
Etiology, Pathology, and Treatment of
Hepatocellular carcinoma in North America,
edited by Tabor, E., Gulf Publishing Company,
Houston, pp. 91-103.
161
References
Ishak KG (2002): Benign tumors and pseudotumors of the
live. Appl. Pathol 6: 82-104. A review oriented
toward histopathology drawn from the uniquely
rich experience of the armed forces institute of
pathology.
Isselbacher KY and Dienstage JL (1998): Tumors of the
liver and biliary tract. IN Harrison S principles
of internal medicine; Fauci AS (ed); Mc Graw
Hill. Inc. USA, 14th edition: 578-81.
Ito Y, Kojiro M, Nakashima T et al. (1998):
Pathomorphologic characteristics of 102 cases
of thorotrast related HCc, cholangiocarcinoma,
and hepatic angiosarcoma. Cancer 62: 11531162.
Ito Y, Petersno SW, Wicklow DT et al. (2001):
Aspergillus pseudotamarii, a new aflatoxin
producing species in Aspergillus section Flavi.
Mycol Res 105: 233-239.
Iwama S, Ohnishi K, Nakajima Y et al. (1982): A
clinical study of hepatocellular carcinoma in
relation to hepatitis B sero markers. Implication
of non A non B hepatitis. Hepatology, 2: 117.
162
References
Izzotti A, Scatolini L, Lewtas J et al. (1995): Enhanced
levels of DNA adducts in the liver of
woodchucks infected with hepatitis virus.
Chem Biol Interact 97(3): 273-285.
Jepsen P, Vilstrup H, Mellemkjaer L, Thulstrup AM,
Olsen JH, Baron JA et al. (2003): Prognosis
of patients with a diagnosis of fatty liver a
registry based cohort study. Hepatogastroenterology 2003; 50: 2101-4.
Johansson AS, Whitaker TB, Hagler WM et al. (2000):
Testing shelled corn for aflatoxin, Part I:
Estimation of variance components. J AOAC
Int 83: 1264-1269.
Johnson PJ (2000): Malignant tumors of the liver. IN
Comprehensive Clinical Hepatology, 1st
edition, edited by O'Grady JG, Lake JR and
Howdle PD, Harcourt Publishers, London, pp.
25, 1-25, 18.
Kaenematsu M, Hoshi H, Yamawaki Y et al. (1999):
Angiographically assisted helical CT of the
liver Am J Radiol 172: 97-105.
Kamel M, Miller F, El Masry A, Zakaria S, Khattab M,
Essmat G and Ghaffar Y (1983): The
epidemiology of schitosoma mansoni. Hepatitis
B and hepatitis Cinfection in Egypt. Ann Trop
Med Parasitol 88: 501-509.
163
References
Kamo E and Ebato T (1992): A clinical analysis of
primary carcinoma of the liver in relation with
schistosomiasis Japonica. J Yamanashi Med
Assoc 9: 23-37.
Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr
BS and Baron RL (2000): extrahepatic
metastasis of hepatocellular carcinoma.
Radiology 216: 698-703.
Kawai HF, Kaneko S, Honda M et al. (2001): Alpha
fetoprotein producing hepatoma celllines share
common expression profiles of genes in various
categories demonstrated by cDNA miroarrya
analysis. Hepatology 33(3): 676-691.
Kelleher MB, Iwatsuki S, Sheahar DG (2003):
Epithelioid hemangioendothelioma of the liver.
Clinicopathological correlation of 10 cases
treated by orthotopic liver transplantation. Am
J Surg Path 13: 999.
Kemmerer SR, Mortele KJ and Ros PR (1998): CT scan
of the liver, Red Clin North Am 36(2): 247260.
164
References
Ke-Qin KE (2002): Occult hepatitis B virus infection and
its clinical implication.J Viral Hepatitis 9:243257.
Kew MC (1995): Hepatocellular carcinoma. Postgrad Med
J 59: 78-87.
Kew MC (1996): Hepatitis delta virus and heptocellular
carcinoma. Viral Hepatitis Rev 2: 285-290.
Kew MC (1997): Clinical and non imaging diagnosis of
hepatocellular carcinoma. In Liver Cancer, 20th
edition, edited by Okuda K and Tabor E,
Churchill Livingstone, London, pp. 315.
Kew MC (1997): Clinical and non imaging diagnosis of
hepatocellular carcinoma. In: Liver Cancer, 20th
edition, edited by Okuda K and Tabor E,
Churchill Livingstone, London, 315-322.
Kew MC (1998): Hepatitis viruses and hepatocellular
carcinoma. Res Virol 149: 257-262.
Kew MC (1999): Clinical and non imaging diagnosis of
hepatocellular
carcinoma.
IN:
Liver
malignancies, edited by Okuda K and Tabor T,
New York, Churchill Livingstone, 315-329.
165
References
Kew MC (2002): Hepatocellular carcinoma: Epidemiology
and risk factors. In: Gastrointestinal Oncology,
Principle and practice, edited by Kelsen D,
Daly J, Levin B, et al., Philadelphia, Lippincott
Williams and Wilkins, 529-538.
Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, Lim SK
et al. (2004): Metabolic significance of
nonalcoholic fatty liver disease in nonobese,
nondiabetic adults. Arch Intern Med 164: 216975.
Kiyosawa K, Sodeyama T, Tanaka E et al. (2000):
Interrelationship of blood transfusion, non A,
non B hepatitis and hepatocellular carcinoma:
analysis by detection of antibody to hepatitis C
virus. Hepatology 12: 671-675.
Klaassen CD (2001): Chemical carcinogenesis. In:
Casarett and Doull's toxicology: the basic
science of poisons, 6th ed. Seils A, Susan R,
Noujaim, et al. (editors) McGraw-Hill, 8: 240265.
Klich MA, Mullaney EJ, Daly CB et al. (2000):
Molecular and physiological aspects of
aflatoxin and sterigmatocystin biosynthesis by
A. tamari and A. ochraceoroseus. In: Appl.
Microbiol Biotechnol 53: 605-609.
166
References
Koike Y, Shiratori Y, Sato S, et al. (2001): Des-gammacarboxy prothrombin as a useful predis-posing
factor for the development of portal venous
invasion in patients with hepatocellular
carcinoma: A prospective analysis of 227
patients. Cancer 91: 561-569.
Kojiro M (2003): Hepatocellular carcinoma presenting as
intrabile duct tumor growth; a clinicopathologic
study of 24 cases. Cancer 9: 2144.
Kouroumalis E, Skordilis P, Thermos K et al. (1998):
Treatmetn of hepatocellualr carcinoma with
octreotide: a randomized controlled study. Gut
42: 442-447.
Kuang SY, Lekawanvijit S, Maneekarn N et al. (2005):
Hepatitis B 1762T/1764A mutations,hepatitis C
infection, and codon 249 p53 mutations in
heptocellular carcinomas from Thailand.
Cancer
Epidemiology
Biomarkers
and
Prevention; 14: 380-384.
Kubo S, Nishiguchi S, Hirohashi K et al. (1999): Cl
inical significance of prior hepatitis B virus
infection in patients with hepatitis C virus
related hepatocellular carcinoma. Cancer 86:
793-798.
167
References
Kubo S, Nishiguchi S, Hirohashi K et al. (1999): Clinical
significance of prior hepatitis B virus infection
in patients with hepatitis C virus related
hepatocellular carcinoma. Cancer 86: 793-798.
Kubosawa H, Ishige H, Kondo Y (1998): Hepatocellular
carcinoma with rhabdomyoblastic differentiation.
Cancer 62: 781-6.
Kuiper Goodman T (1998): Food safety: mycotoxins and
phycotoxins in perspective. In: Mycotoxins and
phycotoxins development sin chemistry,
toxicology and food safety. Miraglia M, van
Edmond H, Brera C, et al. (ed.). Alaken Inc.,
Fort Collins, Colo, 25-48.
Kumada T, Nakano S, Takada I et al. (1999): Clinical
utility of alpha fetoprotein L3 in small
hepatocellular carcinoma: special reference to
imaging diagnosis. J Hepatol 30: 125-30.
Kumar V, Fausto N and Abbas A (2003): Robbins and
Caotran Pathologic Basis of Disease, 7th,
Saunders, pp.914-7.
Kunio O, Toshiro N (1985): Primary carcinomas of the
liver. Bockus Gastroenterol 4: 3315-3376.
168
References
Law MG, Roberts SK, Dore GJ and Kaldor JM (2000):
Primary hepatocellular carcinoma in Australia,
1978-1997: increasing incidence and mortality.
Med J Aust, 173: 403-405.
Lee HS, Kim JS, Choi IJ et al. (1997): The safety and
efficacy
of
transcatheter
arterial
chemoembolization in the treatment of patients
with hepatocellular carcinoma and main portal
vein obstruction: a prospective controlled
study. Cancer 79: 2087-2094.
Lee KH, Lu DS, Krasny RM et al. (2002): Transcatheter
arterial chemoembolization for hepatocellular
carcinoma: anatomic and hemodynamics
considerations in the hepatic artery and portal
vein. Radio Graphics 22L 1077-1091.
Leeuwen M, Noordzij J, Fernandez M et al. (1994):
Portal veins segmental anatomy of right hemi
liver; observation based on three dimensional
spiral CT. Am J Radiology 163 1395-1400.
Lemoine A, Azoulay D, Cure JM et al. (1999):
Hepatocellular carcinoma. Pathol Biol 47(9):
903-910.
169
References
Lencioni R, and Menu Y (1999): Ultrasound and Doppler
ultrasound of HCC. In: Liver malignancies
diagnostic and internvetional radiology, 1st
edition, edited by BArtolozzi C Lencioni R
Menu Y et al., Spring Verlag, Serlin
Heidelberg, 47-67.
Lencioni R, bartolozzi C, Caremella D et al. (1996):
Small hepatocellular carcinoma: differentiation
from adenomatous hyperplasia with color
Doppler ultrasound and dynamic MR imaging.
Abd Imaging 21: 41-48.
Lencioni R, Cioni D, Donati F et al. (2001):
Combination of interventional therapies in
heaptocellular
carcinoma.
Hepatogastroenterology 48: 8-14.
Lencioni R, Cioni D, Goletti O et al. (2000):
Radiofrequency thermal ablation of liver
tumors: state of the art. Cancer Journal 6(4):
304-313.
Lencioni R, Cioni D, Paollicchi D et al. (1999):
Percutaneous ethanol injection of heaptocellular
carcinoma. In: Liver malignancies, edited by
Bartolozzi C and Lencioni R, Berlin, Springer
Verlage 275-292.
170
References
Lencioni R, Pinto F, Armillotta N et al. (1997a):
Intrahepatic metastatic nodules of HCC
detected at lipiodol-CT: imaging pathologic
correlation. Abdom. Imaging 22: 253-258.
Lerut J (2007): Hepatic transplantation for hepatocellular
carcinoma: state of the art. J Chir Paris 144(2):
105-110.
Leung TW and Johnson PJ (2001): Systemic therapy for
hepatocellular
carcinoma.
Seminars
in
Oncology 28(5): 514-520.
Leuschner
I, Schmidt D, Harms D (1999):
Undifferentiated sarcoma of the liver in
childhood. Morphology, Flow Cystometry and
literature review. Hum Pathol 21: 28.
Levi F, Lucchini F, Negri E, Boyle P and La Vecchia C
(2004): Cancer Mortality in Europe,1995-1999,
and overview of Trends since 1960.Int J Cancer
110:155-169.
Liaw CC, Ng KT, Chen TJ et al. (1989): HCC presenting
as bone metastases. Cancer 64: 1753-1757.
Little S and Fong Y (2001): Hepatocellular carcinoma:
current surgical management. Semin in
Oncology 28(5): 474-486.
171
References
Liu FJ, Fritsche HA, Trujillo JM et al. (1983): Serum
alpha fetoprotein; beta subunits of human
chorionic
gonadotropine
and
lactate
dehydrogenase 1isoenzyme in patients with germ
cell tumors of the testis. Am J Clin Pathol 80:
120-127.
Liver Cancer Study Group of Japan (1989): The general
rule for the clinical and pathological study of
primary liver cancer. J Surg 19: 98-129.
Liveraghi T, Goldberg N, Lazzaroi S et al. (1999): Small
hepatocellular carcinoma: treatment with
radiofrequency ablation versus percutnaeous
ethanol injection. Radiology 210: 655-661.
Liveraghi T, Meloni F, Morabito A et al. (2004):
Multimodal image guided tailored therapy of
early
and
intermediate
hepatocellular
carcinoma: long term survival in the experience
of a single radiological referral center. Liver
Transpl 10(2): 98-106.
Llovet J and Beaugrad M (2003): Hepatocellular
carcinoma: present status future prospects. J
Hepatol 387: 136-149.
172
References
Llovet J and Bruix J (2004): Unresectable hepatocellular
carcinoma: meta analysis of arterial
embolization radiology 230(1): 300-301.
Llovet J, Sala M, Castells L et al. (2000): Randomized
controlled trial of interferon treatment for
advanced heptaocellular carcinoma. Hepatology
31: 54-58.
Llovet JM, Fuster J and Bruix J (1999): Intention to treat
analysis of surgical treatment for early
heptocellular carcinoma: resection versus
transplantation. Hepatology 30(6): 1434-1440.
Llovet JM, Mas X, Aponte JJ et al. (2002): Cost
effectiveness of adjuvant therapy for
hepatocellular carcinoma during the waiting list
for liver transplantation. Gut 50(1): 123-128.
Luchi M, Hayakawa M, Kitani K et al. (1973):
Hepatocellular
carcinoma
and
chronic
schistosomiasis japonica. Acta Hepatol Jpn 11:
249-252.
Lygidakis N, Pothoulakis J, Konstantinidou A et al.
(1995): Hepatocellular carcinoma: surgical
resection versus surgical resection combined
with pre and post operative locoregional
immunotherapy chemotherapy. A prospective
randomized study. Anticancer Res 15: 543-553.
173
References
MacDonald S and Castle L (1996): A U.K retail survey of
aflatoxins I herbs and species, their fate during
cooking, Food Addit. Contain 13(1): 121-128.
Maciel AC, Cerski CT, Moreira RK et al. (2006):
Hepatocellular carcinoma in patients undergoing
orthotopic liver transplantation: radiological
findings with anatomopathological correlation in
Brazil Arq Gastroenterol 43(1): 24-29.
Madoff D, Hicks M, Vauthey J et al. (2002): Transhepatic
portal vein embolization: anatomy, indication,
and technical consideration Radiographics, 22:
1063-1076.
Madwar M, El TAhawey M and Strickland T (1989):
The relationship between uncomplicated
shcistosomiasis and hepatitis B infection. Trans
Roy Soc Trop Med 83: 233-236.
Magalotti D, Marchesini G, Ramilli S, Berzigotti A,
Bianchi G, Zoli M (2004): Splanchnic
haemodynamics in non alcoholic fatty liver
disease: effect of a dietary/pharmacological
treatment. A pilot study. Dig Liver Dis 36: 40611,
174
References
Makuuchi M, Imamura H, Akayoma T et al. (2002):
Progress in surgical treatment of heaptocellular
carcinoma. Oncology, 67(1): 74-81.
Malagon HD and Graham GS (2001): Hepatocellular
carcinoma: an updated. Ultrastruct. Pathol
25(6): 497-516.
Marrero JA, Fontana RJ, Su GL, Conjeevaram HS,
Emick DM, Lok AS (2002): NAFLD may e a
common underlying liver disease in patients
with hepatocellular carcinoma in the United
States. Hepatology 36: 1349-54.
Marrero JA, Su GL, Wei W, et al. (2003): Des-gamma
carbo-xyprothrombin can differentiate hepatocellular carcinoma from non malignant chronic
liver disease In American patients. Hepatology
37: 1114-1121.
Matsui O, Takahashi S, Kadoya M et al. (1994):
Pseudolesion in segment IV of the live at CT
during arterial portography: correlation with
aberrant gastric venous drainage. Radiology
193: 31-35.
Matsunami H, Shimizu Y, Lynch S et al. (2002): Liver
transplantation as a therapeutic option for
heptocellular carcinoma. Oncology 62(1): 8286.
175
References
Matsuzaki Y, Osuga T, Ciba T et al. (1995): New
effective treatment using proton irradiation for
unresectable hepatocellular carcinoma. Int
Med 34: 302-304,
Matteoni CA, Younossi ZM, gramlich T, Boparai N, Liu
YC, McCullough AJ (1999): Nonalcoholic fatty
liver disease: a spectrum of clinical and
pathological severity. Gastroenterology 116:
1413-9.
Mazzaferro V, Regalia E, Doci R et al. (1996): Liver
transplantation for the treatment of small
hepatocellular carcinomas in patients with
cirrhosis. N Engl J Med 334(11): 693-699.
McMinn RM (1994): Anatomy of the liver. IN: Last's
anatomy regional and applied, edited by
McMinn RM, 9th ed, Edinburgh, Churchill
Livingstone, 297-303.
Menu Y and Lencioni R (1999): Segmental anatomy of
the liver. In: Liver Malignancies, Bartolozzi C
and Lencioni R, Berlin, Spinger Verlage 3-10.
Michael LB, Duben JL and Fody EP (2000): Specialty
areas of
clinical chemistry. In: Clinical
Chemistry, 4th edition, edited by Michael LB,
Duben JL and Fody EP, Lippincott Raven
Publishers, Philadelphia, 526-527.
176
References
Mofrad P, Contos MJ, Haque M, sergeant C, Fisher
RA, Luketic VA et al. (2003): Clinical and
histologic spectrum of nonalcoholic fatty liver
disease associated with normal ALT values.
Hepatology 37: 1286-92.
Moore TA, Ferrante WA, Crowson TD (1996):
Hepatoma occurring two decades after hepatic
irradiation. Gastroenterology 71: 128-32.
Moradpour D, Compagon B, Wilson B et al. (1995):
Specific targeting of human hepatocellular
carcinoma cells by immunoliposomes in vitro.
Hepatology 22: 1527-1537.
Nagorany DM, Aason MA, Weiland LH et al. (1995):
Fibrolamellar heptoma. Am J Surg 149-113.
Nakashima T, Okuda K, Kijoro M (1993): Pathology of
hepatocellular carcinoma in Japan, 232
consecutive cases autopsies in ten years.
Cancer 51: 863-77.
Nakashima T, Sakamoto K, Ikari T, Kumao S and Sato
E (2001): Pathological and morphological
studies of primary liver cancer, hepatocellular
carcinoma and portal hypertension. Kurume
Med J 26: 231-45.
177
References
Niederau C, Fischer R, Sonnenberg A et al. (1985):
Survival and causes of death in cirrhotic and in
non
cirrhotic
patients
with
primary
hemochromatosis. N Engl J Med 313: 1256-1262.
Nolsoe C, Torp Pedersen S, Burcharth F et al. (1995):
Interstitial hyperthermia of liver metastases
with ultrasound guided percutaneous Nd: YAG
laser with a diffuser tip: a pilot clinical study.
Radiology 187: 333-337.
Nouh M, BAshi S, Laajama M, Moflah I and Al-Aska
M (1990): Hepatitis B virus vs. schistosomiasis
and heptocellular carcinoma in Saudi Arabia.
East. Afr. Med J 67: 139-144.
Ohta H, Watanabe H and Sawaba N (1995): Isoenzyme
as tumor marker. Nippon Rinsho 53: 11241128.
Okabe H, Ikai I, Matsuo K et al. (2000): Comprehensive
allelotype study of hepatocellular carcinoma:
potential
differences
in
pathway
to
hepatocellular carcinoma between hepatitis B
virus positive and negative tumors. Hepatology
31(5): 1073-1079.
178
References
Okada S, Sato T and Yamamoto S (2001): Adjuvant
interferon for hepatocellular carcinoma.
Hepatology 33: 481-490.
Okuda H, Nakanishi T, Takatus K et al. (2000): Serum
levels of des--carboxy prothrombin measured
using the revised enzyme immunoassay kit
with increased sensitivity in relation to
clincopathologic features of hepatocellular
carcinoma. Cancer 88: 544-549.
Okuda K and Kondo Y (1995): Primary carcinoma of the
liver. IN Bockus Gastroenterology, 5th edition,
edited by Haubrich WS, Schaffner F and Berk
JE, W.B. Saunders Company, Philadelphia, pp.
2444-2482.
Okuda K and Nakashima T (1995): Primary carcinoma
of the liver. In: Bockus gastroenterology 4th
edition, Berk JE, WB Saunders Company,
London, Philadelphia, Toronto, Mexico City,
Rio De Janeiro, Sydney, Tokyo, Hong Kong;
173: 3315-76.
Okuda K, Kondo Y, Nakano M et al. (1991):
Hepatocellular carcinoma presenting with
pyrexia and leucocytosis: report of five cases.
Hepatology 13: 695-698.
179
References
Oliver JH, Baron RL, Federle MP et al. (1996):
Detecting HCC: value of unenhanced or arterial
phase CT imaging or both. Used in conjunction
with conventional portal venous phase contrast
enhanced CT imaging. Am J Radiol 167: 7177.
Omata M, Peters RL and Tatter D (2001): Sclerosing
hepatic
carcinoma;
relationship
to
hypercalcemia. Liver, 1: 33-49.
Pacella C, Bizzarri G, Cecconi P et al. (2001):
Hepatocellular carcinoma: long term results of
combined treatment with laser thermal ablation
and transcatheter arterial chemoembolization.
Radiology 219: 669-678.
Parkin DM, Bray F, Ferlay 1and Pisani P (2000):
Estimating the world cancer burden:Globocan
2000. Int. J Cancer 2001; 94: 153-156.
Pawlik TM, Delman KA, Vauthey JN, Nagorney DM,
Ng Io, Ikai I, et al. (2005): Tumor size
predicts vascular invasion and histologic grade:
Implications for selection of surgical treatment
for hepatocellular carcinoma. Liver Transpl
11:1086-92.
180
References
Peterson SW, Ito Y, Horn BW et al. (2001): Aspergillus
bombycis, a new aflatoxigenic species and
genetic variation in its sibling species, A.
nomius. Mycologia, 93: 689-703.
Pistorius
G, Menger M and Feilel G (2000):
Minilaparotomy vs the percutaneous approach
for minimally invasive hepatic cryosurgery.
Surg Endosc 10(2): 207-209.
Poon R, Fan S and Wong J (2000): Risk factors,
prevention, and management of postoperative
recurrence after resection of hepatocellular
carcinoma. Ann of Surgery 232: 10-24.
Poonawala A, Nair SP, Thuluvath PJ (2000): Prevalence
of obesity and diabetes in patients with
cryoptogenic cirrhosis: a case control study.
Hepatology 32: 689-92.
Poston G and Blumgart L (2003): Surgical anatomy of
the liver and bile ducts. In: Surgical
management of hepatobiliary and pancreatic
disorders, edited by Poson G and Blumart L,
London, Martin Dunitz, 1-18.
Ray RB, Meyer K and Ray R (1996): Suppression of
apoptotic cell death by Klein, G. and
Weinhouse, S, Academic Press, Orlando, 49:
285-401.
181
References
Ray RB, Steele R, Meyer K and Ray R (1998): Hepatitis
C virus core protein represses P21 WAF1/
Cip1/Sid 1 promoter activity. Gene 208: 331336.
Reading NG, Frobes A, Nummerly HB et al. (1998):
Hepatic hemangioma: a critical review of
diagnosis and management. QJ Med 67-431.
An Excellent recent review of these most
common hepatic neoplasm.
Reddy JK, Svobodoba D (1992): Effect of lasiocarpine on
aflatoxin B carcinogenicity in rat liver. Arch
Pathol 93: 55-60.
Reinhodl C, Hammers L, Taylor C et al. (1995):
Characterization of focal hepatic lesions with
duplex sonography. Am J Radiol 164: 11311135.
Rhim H and Dodd G (1999): Radiofrequency thermal
ablation of liver tumors. J Clin Ultrasound 27:
221-229.
Robinson WS (1994): Molecular events in the
pathogenesis
of
hepadnavirus-associated
hepatocellular carcinoma. Annu Rev Med 45:
297-323.
182
References
Roche A (1999): Transcatheter arterial chemoembolization
for hepatocellular carcinoma. In: Liver
malignancies, edited by Bartolozzi C and
Lencioni R, Berlin, Springer-Verlag 255-274.
Ros PR, Goodman ZD et al. (2001): Intrahepatic
cholangiocarcinoma, radiologic pathologic
correlation. Radiology 167-689.
Ros PR, Murphy BJ, buck JL et al. (1990): Encapsulated
HCC: radiological findings and pathologic
correlation. Gastrointetinal Radiology, 190: 853856.
Ross
JS
and Kurian S (1995): Clear cell
hepatocarcinoma;
sudden
death
from
hypoglycemia. Am J Gastroenterol 80: 180.
Roze LV, Miller MJ, Rarick M et al. (2004): A novel
cAMP response element, CRE1, modulates
expression of nor-1 in Aspergillus parasiticus. J
Biol Chem 279(26).
Russo M and Jacobson I (2002): Hepatocellular
carcinoma
screening,
surveillance
and
prevention. In: Gastrointestinal Oncology:
Principles and Practice, edited by Kelsen D,
Daly J, Levin et al., Philadelphia, Lippincott
Williams and Wilkins, 559-568.
183
References
Sakaguchi
S, Tohara N and Oka Y (1992):
Ultrasonographic diagnosis of HCC. In:
Primary Liver cancer in Japan. Edited by Tobe
T, Kameda H, Okudaira M et al., Springer
Verlag Tokyo, 115-123.
Salata H, Cortes JM, De Salamanca RE, et al. (1985):
Porphyria cutanea tarda and HCC: frequency of
occurrence and related factors. J Hepatol 1:
477-487.
Saul SH (1999): Masses of the liver. In Diagnostic surgical
pathology, 3rd edition, edited by Sternberg SS,
Lippincott Williams and Wilkins, Philadelphia,
1553-1628.
Schachshol G, Lochs H and Plauth M (2000): Controlled
clinical trials of doxorubicin and tamoxifen
versus tamoxifen monotherapy in hepatocellular
carcinoma. Eur J Gastroenterolhapatog 12: 281284.
Schaff Z and Nagy P (1997): Pathology techniques and
grading systems in the diagnosis of HCC. In:
Liver Cancer, edited by Okuda K and Tabor E,
Churchill Livingstone, New York, 111-135.
Schaff Z, Lapis K and Henson D (1993): Pathology of
incipient neoplasia. In: Major problems in
Pathology, 2nd edition, edited by Henson DE,
Albores A and Saavedra J, W.B. Saunders,
Philadelphia, 151-166.
184
References
Schiff L and Eugene R (1993): Diseases of the liver.
Hepatocellular carcinoma. Vol. 2, 7th edition,
Publ. JB Lippincott Company, 1243-69.
Scudamore C (2000): Volumetric radiofrequency ablation:
technical considerations. Cancer J 6(4): 316318.
Sen NP, Smith DC, Schwinghamer L (1969): Formation
of N-nitrosamines from secondary amines and
nitrite in human and animal gastric juice. Food
Cosmet Toxicol 7: 305-7.
Shapiro ET, Bell GI, Polonsky KS et al. (1990): Tumor
hypoglycemia: relationship to high molecular
weight insulin like growth factor II. J Clin
Invest 85: 1672-1677.
Sherlock S and Dooley J (1997): Hepatic tumors. In
diseases of the liver and biliary system.
Blackwell Science Ltd 10th edition, 531-59.
Sherlock S and Dooley J (2002): Sherlock and Dooley,
diseases of the liver and biliary system. 11th
edition,
Oxford,
Blackwell
scientific
publications, Ch. 3, 10, 19, 28.
Sherman M (2001): Alphafetoprotein: an obituary. J
Hepatol; 34: 603-605.
185
References
Sherman M (2001): Surveillance of hepatocellular
carcinoma. Semin in Oncol 28(5): 450-459.
Shetty K, timmins K, Brensinger C et al. (2004): Liver
transplantation for hepatocellular carcinoma
validation of present selection criteria in
predicting outcome. Liver Transpl 10(7): 911918.
Simauchi Y, Tanaka M, Ogata R et al. (2000): A
simultaneous monitoring of alpha fetoprotein –
L3 and des--carboxy prothrombin as an early
diagnosis of hepatocellular carcinoma and in
the follow up of cirrhotic patients. Oncol Rep
7: 244-256.
Smela ME, Currier SS, Bailey EA et al. (2001): The
chemistry and biology of aflatoxin B1: from
mutational spectrometry to carcinogenesis.
Carcinogenesis; 22(4): 535-545.
Squadrito G, Orlando ME, Pollicini T, Raffa G,
Restuccia et al. (2002): Virological profiles in
patients with chronic hepatitis C and overt or
occult HBV infection.Am J Gastroenterol 97
(6):1518-1523.
Starzl TE, Marchioro TL, Porter KA et al. (1967b):
Homotransplantation of the liver. Transplantation
5(4): 790-803.
186
References
Stuart S Winter (2006): Hepatocellular carcinoma. April 13.
Sweeney MJ and Dobson AD (1999): Molecular biology of
mycotoxin production. Microbiol Lett 175: 149163.
Sweeney MJ, White S and Dobson AD (2000): Mycotoxins
in agriculture and food safety. Irish J Agric Food
Res 39: 235-244.
Tai DI, Tsai SL, Chen YM, Chuang YL, Kuo GC and
Liaw YF (2000): Activation of nuclear factor
Kappa B in hepatitis C virus infection:
implications for pathogenesis and hepatocarcinogenesis. Hepatology; 31: 656-664.
Takayasu K, Muramatsu Y, Furukawa H et al. (1995):
HCC: Appearance at CT during arterial
portography and CT arteriography with
pathologic correlation. Radiology, 194: 101-105.
Tanaka Y, Hanada K, Mizokami M, Yeo AE, Shih JW,
Gojobori T and Alter HJ (2002): A comparison
of the molecular Clock of hepatitis C virus in the
United States and Japan Predicts that
hepatocellular carcinoma incidence in the United
States will increase over the next two
decades.Proc Natl Acad Sci USA, 99: 1558415589.
187
References
Tavani A, Negri E, Parazzini F et al. (2003): Female
hormone utilization and risk of HCC. Br J
Cancer 67: 635-639.
Taylor DR, Shi ST, Romano PR, Barber GN and Lai
MM (1999): Inhibition of the interferoninducible protein kinase PKR by HCV E2
protein. Science; 285: 107-110.
Teli MR, James OF, Burt AD, Bennett MK, Day CP
(1995): The natural history of nonalcoholic
fatty liver: a follow up study. Hepatology
22:1714-9.
Terada T, Nanaknumo Y and Kawai K (1989); Small
hepatocellular carcinoma presenting as
intrabiliary pedunculated polyp and obstructive
jaundice. J Clin Gastroenterol 11: 587-590.
The Cancer of the Liver Italian Program (CLIP)
Investigation (2000): A new prognostic system
for patients with cirrhosis and heptocellular
carcinoma. Hepatology 31: 840-845.
Thimme R, Bukh J, Spangenberg HC, et al. (2002):
Viral and immunological determinants of
hepatitis C virus clearance, persistence, and
disease. Proc Natl Acad Sci USA. 99: 1566115668.
188
References
Tobkes AI and Nord HJ (1995): Liver biopsy review of
methodology and complications. Digestion, 13:
267-270.
Tong MJ, El-Farra NS, Reikes AR et al. (1995):
Clinical outcome after transfusion associated
hepatitis. CN Engl J Med 332: 1463-1466.
Trail F, Mahanti N and Linz J (1995): Molecular biology
of aflatoxin biosynthesis. Microbiology 141:
755-765.
U.S.
Council of Environmental Quality (2001):
Contamination of Ground water by toxic
organic chemicals. U.S. Government Printing
Office, Washington, D.C. http://hermes.ecn.
purdue.edu/cgi/convwqtest?fs-2.me.ascii.
U.S. National Primary Drinking Water Regulations
(1997):
Synthetic
organic
chemicals;
monitoring for unregulated contaminatns.
Federal Register 52(130): 25690-25734.
U.S. Safe Drinking Water Committee, U.S. National
Academy of Scineces, U.S. National
Research Council (1996): Drinking water and
health, volume 6. National Academy Pres,
Washington, D.C. http://hermes.ecn.purdue.
edu/cgi/convwqtest?fs-2.me.ascii.
189
References
Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L,
Feitelson MA and Jay G (1995): Functional
inacti-vation but not structural mutation of p53
causes liver cancer.Nat Genet 1995; 9: 41-47.
Verme G, Brunetto MR, Oliveri F, Baldi M, Forzani B,
Piantino P, Ponzetto A and Bonino F (1991):
Role of hepatitis delta virus infection in hepatocellular carcinoma. Dig Dis Sci, 36: 1134-1136.
Wang JS and Groopman JD (1999): DNA damage by
mycotoxins. Mutat Res 424: 167-181.
Wang LY, Hatch M, Chen CJ et al. (1996): Aflatoxin
exposure and risk of hepatocellular carcinoma
in Taiwan. Int. J Cancer 67: 620-625.
Wanless IR, Lentz JS (1990): Fatty liver hepatitis
(steatohepatitis) and obesity: an autopsy: an
autopsy study with analysis of risk factors.
Hepatology 12: 1106-10.
Water test corporation (2002): Manual, 6th edition.
Manchester, NH. http://hermes.ecn.purdue.
eduwqtest?fs-2.me.ascii/ cgi/conv.
Weinberg AG, Mize CE and Worthen HG (1976): The
occurrence of hepatoma in the chronic form of
hereditary tyrosinemia. J Pediatr 88: 434-438.
190
References
Welch HG, Schwartz LM and Woloshin S (2000): Do
increased 5- year survival rates in prostate
cancer indicate better outcomes? JAMA
284:2053-2055.
Wheeler DA, Edmondson HA (2003): Cystadenoma with
mesenchymal stroma (CMS) in the liver and
bile ducts: a clinicopathologic study of 17
cases, 4 with malignant change. Cancer, 561434.
Williams JH, Phillips TD, Jolly PE et al. (2004): Human
aflatoxicosis in developing countries: a review
of toxicology, exposure, potential health
consequences, and interventions. In: American
Journal of Clinical Nutrition; 80(5): 1106-1122.
Williams PL, Bannister LH, Berry MM et al. (1987):
Use of monoclonal antibodies for diagnosis and
treatment
of
liver
tumors.
Clinical
Gastroenterology 1: 115-123.
Williams PL, Bannister LH, Berry MM, et al. (1999):
Anatomy of the liver. In: Gray's anatomy,
edited by Williams PL, Bannister LH, Berry
MM, et al., 38th ed., London. Churchill
Livingstone, 1799-1809.
Wing JR, Panz VR, Joffe BI (1991): Hypoglycemia in
HCC, failure of short term growth hormone
administration to reduce enhanced glucose
requirement. Metabolism, 40: 508-511.
191
References
Wogan GN (1992): Aflatoxins as risk factors for
hepatocellular carcinoma in humans. Cancer
Research 52: 2114s-2118s.
Wogan GN, Cameron HM, Linsell DA, Warwick GP
(2001): The induction of liver cell cancer by
chemicals. In: Eds. Liver cell cancer.
Amsterdam: Elsevier, 121-152.
Wogan GN, Hecht SS, Felton JS et al. (2004):
Environmental and chemical carcinogenesis.
Semin Cancer Biol 14(6): 743-486.
Wu C, Groenik M, Bosma A et al. (1997): Rat ferritin H,
C DNA cloning, differential expression and colocalization
during
hepatocarcinogenesis.
Carcinogenesis, 18: 47-52.
Yamamoto J, Kosuge T, Saiura A et al. (2007a):
Effectiveness of hepatic resection for early
stage hepatocellular carcinoma in cirrhotic
patients: subgroup analysis according to Milan
Criteria. Jpn J Clin Oncol 37(4): 287-295.
Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K,
Inoue O, Hashimoto E, Lefkowitch JH,
Ludwig J and Okuda K (1996): The longterm pathological evolution of chronic hepatitis
C. Hepatology 23: 1334-1340.
192
References
Yao FY, Bass NM, Nikolai B et al. (2002): Liver
transplantation for hepatocellular carcinoma:
analysis of survival according to the intention
to treat principle and dropout from the waiting
list. Liver Transpl 8(10): 873-883.
Yao FY, Ferrell L, Bass NM, et al. (2001): Liver
transplantation for hepatocellular carcinoma:
expansion of the tumor size limits does not
adversely impact survival. Hepatology 33(6):
1394-1403.
Yoo YD, Ueda H, Park K, Flanders KC, Lee YI, Jay G
and Kim SJ (1996): Regulation of
Transforming growth factor-beta1 expression
by the hepatitis B virus (HBV) X
Transactivator. Role in HBV pathogenesis.J
Clin Invest 97: 388-395.
Yoshizawa H (2002): Hepatocellular Carcinoma associated
with hepatitis C virus infection in Japan:
Projection to other countries in the foreseeable
future. Oncology 62 (suppl 1): 8-17.
Yu MC, Yuan J and Ross RK (1997): Presence of
antibodies ot the hepatitis B surface antigen is
associated with an excess risk of hepatocellular
carcinoma among non Asians in Los Angeles
Country, California. Hepatology 25: 226-228.
193
References
Zafrani ES (1998): Update on vascular tumors of the liver.
J Hepatol 9: 125.
Zayadi A (1986): Hepatocellular carcinoma in Egypt.
Islamic World Med J 2: 50.
194
LIST OF ABBREVIATIONS
AFP
: Alpha-fetoprotein
ALP
: Alkaline phosphatase
ALT
: Alanine transaminase
AST
: Aspartate transaminase
B-endorphin: Beta-endorphin
CT
: Computed tomography
CTA
: Computed tomography arteriography
CTAP
: Computed tomography arterioportography
D.BIL
: Direct bilirubin
DEP
: Des-gamma carboxy prothrombin
DNA
: Deoxyribonucleic acid
HBsAg
: Hepatitis B surface antigen
HBV
: Hepatiti B virus
HCC
: Hepatocellular carcinoma
HCV Ab
: Hepatitis C antibody
HCV
: Hepatitis C virus
HDV
: Hepatitis D virus
HiTT
: Microwave heat induced thermotherapy
IFN
: Interferon
IGF-II
: Insulin growth factor II
IL
: Interleukin
IVC
: Inferiro vena cava
LDH
: Lactate dehydrogenase
LiTT
: Laser heat induced thermotherapy
MRI
: Magnetic resonant image
NK
: Natural killer
PAI
: Percutaneous acetic acid injection
PEI
: Percutaneous ethanol injection
PT
: Prothormbin time
PVE
: Portal vein embolization
RFA
: Radiofreuqency ablation
RITA
: Radiofrequency interstitial thermal ablation
RIVKA
: Prothrombin induce by vitamin K absence or antagonism
RNA
: Ribonuclic acid
TACE
: Transarterial chemoembolization
TGF
: Tumour growth factor
TNF
: Tissue necrosis factor
U/S
: Ultrasonography
WHO
: World Health Organization
ACKNOWLEDGMENT
Before all, Thanks to GOD.
I would like to express my profound gratitude to
Professor Doctor/ Amr Fateen, Professor of Internal
Medicine, Faculty of Medicine, Ain Shams University for his
most valuable advises and support all through the whole work
and for dedicating much of his precious time to accomplish this
work.
I am also grateful to Professor Doctor/ Sayed
Shalaby, Professor of Internal Medicine, Faculty of
Medicine, Ain Shams University for his unique effort,
considerable help, assistance and knowledge he offered me
through out the performance of this work.
My special thanks and deep obligation to Professor
Doctor/ Osama Hetta, Profesor of Radiology, Faculty of
Medicine, Ain Shams University for his continuous
encouragement and supervision and kind care.
Last but not least I would like to express my deepest
thanks and gratitude to all members in my family especially to
my Father, for supporting, understanding and pushing me
forward all the time.
‫الملخص العربى‬
‫أورام الكبد السرطانية تعتبر من أكثر األورام الخبيثة أنتشا اًر فى العالم‪.‬‬
‫وفيرو‬
‫سب‬
‫م ننن أا ننم العوامن ن المس ننبسة لن ن ورام الس ننرطانية الكبدي ننة ا ننى في ننرو‬
‫والكحوليات واألفالتوكسين وسعض األمراض الميتابولزمية‪.‬‬
‫لكن وضح أن تليف الكبد الناتج من التها‬
‫لزيادة األورام السرطانية فى المجتمع المصرى‪.‬‬
‫الفيروسات الكبدية او أام‬
‫يعتمن ن نند تشن ن ننخيد سن ن ننرطان الكبن ن نند ملن ن ننى ين ن ننا‬
‫نسن ن ننسة د‬
‫ت األورام‬
‫(الفافيتوبروتين) ووجود الصفات المميزة ل ورام فى األشعة المقطعينة الحلزونينة‬
‫وكذلك أخذ مينة من الكبد أما من طرق العالج المتاحة فهى تعتمد ملى حجم‬
‫الورم ومكانه التشريحى فى الكبد و الحالة العامة للمريض‪.‬‬
‫مننازاا األستاصنناا الج ارحننى اننو العننالج األمث ن لننورم الكبنند ولكننن أكثننر‬
‫اذه األورام‬
‫يمكن استاصالها جراحياً‪ .‬حيث تص نسسة الحنا ت التنى يمكنن‬
‫مالجها ساألستاصاا الجراحى إلى ‪ %53‬فقط‪.‬‬
‫يعتبننر العننالج سننالتردد الحن اررى اننو أحنندى الطننرق األكثننر اسننتخداماً فننى‬
‫السنوات األخيرة وفى اذه التكنولوجيا يتم توليد موجات ترددية تصن إلنى ‪355‬‬
‫ميجاارتز فى األنسنجة ونتيجنة لهنذه التنرددات تحندث أات ازمنات واحتكاكنات فنى‬
‫األيوننات ومنن ثنم تننتج منن ذلننك حن اررة موضنعية تصن إلنى ‪ 055‬درجنة ماويننة‬
‫وذه الح اررة تكفى لقت الخاليا فى األنسجة المعرضة للتردد‪.‬‬
‫الع ننالج البيرول ننوجى ا ننو طريق ننة م ننن ط ننرق الع ننالج الت ننى تح نناوا تنبي ننه‬
‫الجهاز المنامى للجسم لمهاجمة الخاليا السرطانية ومقار الفيسكم يعد من أحند‬
‫أسالي‬
‫العالج البيولوجى‪.‬‬
LIST OF CONTENTS
Title
Page No.
Introduction .................... Error! Bookmark not defined.
Anatomy of the liver ............................................................ 4
Histology of the liver ......................................................... 10
Tumors of the liver ........ Error! Bookmark not defined.
Epidemiology and risk factors of
hepatocellular carcinoma (HCC) ....................................... 16
Risk factors of HCC ............................................................ 22
Pathology of HCC ................................................................. 72
Diagnosis of HCC ................................................................. 87
Treatment of HCC ..............................................................116
Summary .............................................................................. 140
References .......................................................................... 143
Arabic summary ........................................................................
LIST OF TABLES
Tab. No.
Title
Page No.
Table (1):
Synthetic organic compound: Herbicides,
pesticides, insecticides .................................................. 47
Table (2):
Volatile organic compounds: household cleaning
compounds, industrial wastes, insecticides .................... 48
Table (3):
Inorganics .................................................................... 64
Table (4):
Organics ....................................................................... 65
Table (5):
TNM staging system devised by the American
Joint Committee on Cancer ....................................... 112
Table (6):
TNM staging system devised by the American
Joint Committee on Cancer ....................................... 113
Table (7):
Definition of the Okuda staging system for
hepatocellular carcinoma ........................................... 113
Table (8):
CLIP staging system for hepatoellular
carcinoma ................................................................... 114
Table (9):
BCLC staging system for hepatocellular
carcinoma ................................................................... 115
Table (10): Pharmacodynamics .................................................... 137
LIST OF FIGURES
Fig. No.
Title
Page No.
Figure (1): Functional anatomy of the liver ...............................................9
Figure (2): Chemical structures of aflatoxins ...........................................55
Figure (3): Aflatoxin B1 ............................................................................56
Figure (4): Gross picture of advanced HCC .............................................72
Figure (5): Stromal invasion in Well-differentiated early-stage HCCs ...76

Introduction

Anatomy fo the Liver

Histology of the Liver

Tumors of the Liver

Epidemiology of
Hepatocellular Carcinoma

Risk factors of HCC

Pathology of HCC

Diagnosis of HCC

Treatment of HCC

Summary

References

Arabic Summary
STUDY OF RISK FACTORS OF
HEPATOCELLULAR CARCINOMA IN EGYPT AND
DIFFERENT MODALITIES OF MANAGEMENT
Essay
Submitted for Partial Fulfillment of
M.Sc Degree in Internal Medicine
Presented By
MOUMEN MOHSEN MOSTAFA MOHAMED MAHER
M.B., B.Ch.
Supervised By
Professor Doctor/ Amr Fateen
Professor of Internal Medicine
Faculty of Medicine, Ain Shams University
Professor Doctor/ Sayed Shalaby
Professor of Internal Medicine
Faculty of Medicine, Ain Shams University
Professor Doctor/ Osama Hetta
Professor of Radiology
Faculty of Medicine, Ain Shams University
Faculty of Medicine
Ain Shams University
2009
‫دراسة عوامل الخطورة المؤدية‬
‫لسرطان خاليا الكبد فى مصر‬
‫وطرق العالج المختلفة‬
‫رسالة‬
‫توطئة للحصول على درجة الماجستير‬
‫فى األمراض الباطنة العامة‬
‫مقدمة من‬
‫الطبيب ‪ /‬مؤمن محسن مصطفى محمد ماهر‬
‫تحت إشراف‬
‫األستاذ الدكتور ‪ /‬عمــرو فطيــن‬
‫أستاذ الباطنة العامة‬
‫كلية الطب – جامعة عين شمس‬
‫األستاذ الدكتور ‪ /‬سيد شلبى‬
‫أستاذ الباطنة العامة‬
‫كلية الطب – جامعة عين شمس‬
‫األستاذ الدكتور ‪ /‬أسامة حتة‬
‫أستاذ األشعة‬
‫كلية الطب – جامعة عين شمس‬
‫كلية الطب‬
‫جامعة عين شمس‬
9552