Primary carcinoma of the liver
Introduction/epidemiology
Primary carcinoma of the liver (Hepatocellular carcinoma) is one of the common cancers in China with high mortality
It may either originate from hepatocytes or bile duct epithelium
There is a geographic distribution with high incidence in Asia, South part of African, whilst low incidence in North American, North European
It also varies even in one country
Sex distribution
Male predominance is more obvious in populations at high risk (ratio 3.7:1) than in those whose risk is low or intermediate (2.4:1)
However, in patients in developed countries who have hepatocellular carcinoma but not cirrhosis, the sex distribution is approximately equal
Age distribution
Middle aged man in predominance
It rises progressively with age, although it tends to level off in
the oldest age group
In some sub-Saharan countries, there is a definite shift toward
younger age
It is rare in children
Etiology & Pathogenesis
Hepatocarcinogenesis is a complex incremental process that
evolved over many years
Four major (and several minor) causal associations of the
tumor have been identified
The etiologic agents differs in different parts of the world, an
d this may explain the diverse biologic characteristics of hepatocellular carcinoma in different world
Risk factors
Major
Chronic HBV infection Chronic HCV infection Repeated exposure to aflatoxin β 1
Cirrhosis
Risk factors
Minor Oral contraceptive steroids cigarette smoking Hereditary hemochromatosis Wilson disease α1 –antitrypsin deficiency
Type 1 hereditary tyrosinemia Glycogen stroge disease (types 1 and 2) Hypercitrullinemia Ataxia telangiectasia Membranous obstruction of the inferior vena cava
Hepatitis B virus
Chronic infection with HBV may cause as much as 80%
of human hepatocellular carcinoma It is closest in ethnic Chinese and black Africans As many as 80% of whom are still infected when they
develop hepatocellular carcinoma Early infection carries a greater risk than does infection in
adulthood
Hepatitis B Virus
HBV DNA is integrated into cellular DNA in about 95% of patients with HBV-related tumors
The site of integration is random
Integration perturbing the function of cellular oncogenes or tumor suppressor genes, which may contribute to hepatocellular carcinogenesis
Hepatitis C Virus
HCV is carcinogenic in human
In Japan, Italy, Spain, chronic HCV infection is the major risk factor for hepatocellular carcinoma
A far smaller percentage of ethnic Chinese and black African have HCV-induced tumors
HCV does not integrate into host DNA, its mechanism diff
ers from that of HBV
Cirrhosis
HCC frequently coexists with cirrhosis In ethnic Chinese and black Africans, it is usually of the m
acronodular variety and is the result of chronic HBV infection
In other populations, it is commonly of the mixed micro-macronodular or micronodular variety and is usually caused by chronic HCV infection, alcohol abuse, or both
Male sex, age, duration of cirrhosis are the main risk factors for HCC
Aflatoxin β 1
It is a major risk factor for HCC in certain geographic regions
Epidemiologic studies have shown a positive correlation betweeen exposure to aflatoxin β 1 and the incidence of HCC
Minor risk factors
As many as 45% of persons who suffer from hereditary hemochromatosis develop hepatocellular carcinoma
This complication was thought to occur only in the presence of cirrhosis
Patients with Wilson disease occasionally develop HCC, although only in the presence of cirrhosis
Other inherited metabolic disturbances that predispose to HCC may also cause cirrhosis(α1 –antitrypsin deficiency
Type 1 hereditary tyrosinemia)
Minor Risk Factors
In patients with the use of contraceptive steroids, the risk
is related directly to the duration of use
Controversy exists over whether cigarette smoking
Pathology
Gross appearance
Microscopic appearance Well-Differentiated appearance
Moderate-Differentiated appearance
Undifferentiated appearance
Fibrolamellar hepatocellular carcinoma
Gross appearance
Hepatocellular carcinoma may take three forms Nodular <5cm, usually coexists with cirrhosis
If <3cm (either single or two)
Massive > or =5cm, most common form
most prone to rupture
Diffuse It is rare, may be difficult to distinguish
from regenerating nodules of cirrhosis
Small HCC
<3cm It is based on the histologic finding and biological char
acteristic Well differentiated, low grade malignancy Usually encapsulated cancer embolism rate is low with relative good liver
function
Microscopic appearance
Fibrolamellar hepatocellular carcinoma
Typically occurs in young patients Equal sex distribution Does not secrete alpha-fetoprotein It is not caused by HBV or HCV infection Almost always arises in a noncirrhotic liver It is more often amenable to resection and has a
good prognosis
Metastasis of HCC
Intrahepatic metastasis
Extrahepetic metastasis
Five most common sites of HCC metastasis are:
regional lymph nodes
lung
adrenal glands
bone
peritoneal surface
Clinical manifestation
Symptoms Prevalence(%)
Abdominal pain 59-95
Weight loss 34-71
Weakness 22-53
Abdominal swelling 28-43
Nonspecific 25-28
Gastrointestinal symptoms
Clinical manifestation
Physical signs Prevalence(%)
Hepatomegaly 54-98
Hepatic bruit 6-25
Ascites 35-61
Splenomegaly 27-42
Jaundice 4-35
Wasting 25-41
Fever 11-54
Paraneoplastic syndromes associated with hepatocellular carcinoma
Hypoglycemia
Polycythemia (erythrocytosis)
Hypercalcemia
Sexual changes:
isosexual precocity
gynecomastia
feminization
Systemic arterial hypertension
Watery diarrhea syndrome
Porphyria
Carcinoid syndrome
Osteoporosis
Hypertrophic osteoarthropathy
Thyrotoxicosis
Thrombophlebitis migrans
Polymyositis
Neuropathy
Clinical stages
Stage I (subclinical stage) The outcome of screening to high risk population, hepatitis hi
story more than 5 years or HbsAg positive
No specific symptoms Elevated AFP Single or multiple nodules, <=5cm size No vascular invasion
Clinical stages
Stage IIa Present some symptoms or signs of HCC Abnormal laboratory findings Single or double nodules >5~10cm No portal vein cancerous embolism No lymph nodes enlargement No distant metastasis
Clinical stages
Stage IIb Single or double nodules >=10cm or triple <=10cm
in one hepatic lobule Single or double nodules 5~10 cm in two hepatic
lobule Portal vein cancerous embolism
Clinical stages
Stage III More advanced than stage IIb Or with vascular invasion/intrahepatic or peritoneal l
ymph nodes enlargement or distant metastasis
Complications
Hepatic encephalopsy
end stage deadly complication, 1/3 death cause
Gastrointestinal bleeding
esophageal varices, erosive GI mucosa
Rupture of hepatic cancer mass
accounts for 9~14%
Secondary infection
Laboratory tests and others
Tumor markers of HCC
Radiologic investigations
Needle biopsy
Tumor markers
Alpha-Fetoprotein
γ –Glutamyl Transferase
α –L-Fucosidase
Des- γ-Carboxy Prothrombin
Alpha-Fetoprotein
Alpha-Fetoprotein is an α 1-globulin normally present in high
concentration in fetal serum but in only minute amounts thereafter
(<20μg/L) Reappearance of high serum levels of alpha-fetoprotein in serum
(>500 μg/L) is a strong pointer to the diagnosis of HCC Below this level may be found in patients with variety of
acute and chronic benign hepatic disease or GI tumor with lever
metastasis In patients with pregnancy, neonatal, testis tumor or ovarian tumor,
the serum alpha-fetoprotein may also elevated
Fucosylated Alpha-Fetoprotein
Reactivity of alpha-fetoprotein with Lens culinaris agglutinin A in
the differentiation between HCC and benign hepatic parenchymal
disease
Reactivity with concanavalin A in distinguishing HCC from other
tumor capable of producing this protein
To measure fucosylated alpha-fetoprotein is rather complex
γ –Glutamyl Transferase
Normal serum contains as many as 10 isoenzymes of γ –Glutamyl Transferase
As many as three tumor-associated isoenzymes may be present in serum from patients with HCC
I’ 60% I’’ 27% II’ 30%
Des- γ-Carboxy Prothrombin
It is raised in the majority of patients with HCC
≥ 250μg /L is considered positive
In populations where incidence of this tumor is low, the abnormal prothrombin may prove to be a better marker than alpha-fetoprotein
α–L-Fucosidase
It was first reported to have a sensitivity of 75% and specificity 90% in HCC
In a subsequent study, it failed to distinguish between cirrhosis and HCC
In black Africans, this marker is less sensitive,less specific and has lower predictive value than alpha-fetoprotein
Tumor markers
Sensitivity(%) Specificity (%) Advantages Disadvantages
Alpha-fetoprotein 80~90(high) 90 Relatively quick Relative
50~70(low) easy to measure expansive DES-γ –carboxy 58-91 84 Easy and quick Far more
prothrombin to measure expansive
α –L-fucosidase 75 70-90 Easy and quick
to measure, relative
inexpansive
Isoenzymes of γ- 60 96 Relatively easy and Expansive
Glutamyl transferase quick to measure
Hepatic imaging
Ultrasonography
Computed Tomography
Magnetic Resonance Imaging
Hepatic Arteriography
Position emission computed tomography
Ultrasonography
Detects tumor which size >2cm
Shows the size, sharp, site and its relationship with vessel
Identifies the hepatic vein, portal vein cancerous embolism
Doppler sonography are useful
CT
It usually shows the tumor size greater than 2 cm
It may detect small HCC by using contrast materials
It is the best method for detecting small and micro HCC
MRI
Useful for detecting both primary and tumor spread
Useful in distinguishing between small HCC and small hemangiomas uncovered during surveillance
Hepatic arteriography
It is the best modality for detecting the tumor site
It may show tumor with 0.5~1.0cm tumor
CTCT Hepatic arteriography
Hepatic arteriography
Diagnosis
AFP >400μg/L, exclude chronic active liver disease,
pregnancy, congenital tumors or metastatic liver tumor,
signs suggesting the hepatic tumor AFP <400μg/L, two of the radiologic investigations
indicating the liver tumor or two tumor markers are
positive Manifestations of HCC with confirmed extrahepatic
sighs
Differential Diagnosis
Hepatic cirrhosis/hepatitis
Secondary liver cancer
Benign hepatic tumors
Liver abscess
Treatment
Surgical resection
Alcohol injection
Liver transplantation
Embolization and chemoembolization
Chemotherapy
Surgical resection
Offers the best chance of cure of HCC
For this treatment to be contemplated
The tumor must be confined to one hepatic lobe
Ideally, the nontumorous liver tissue should not be cirrhotic
The recurrence rate after resection is high
Alcohol injection
It is also called percutaneous ethanol injection (PEI)
Small tumor not suitable for resection
Either because they are multiple or because theirposition in the liver or because of severe hepatic dysfunction
It carries the risk of disseminating the tumor
Liver transplatation
It has been performed in patients whose tumors was not
amenable to resection, but not spread beyond the liver
The early results were characterized by an unacceptable high recurrence rate (around 70%), and this was accompanied by a surprisingly short survival after the recurrence
Embolization/Chemoembolization
In selected patients, bland embolization or embolization
with simultaneous administration of lipiodol and
anticancer drugs has been used to reduce the viable
tumor mass before surgery It has not yet been clearly established that the advantage
gained is offset by the disadvantage Patients receiving transarterial chemoembolization may
survival longer than untreated patients
Chemotherapy
A large number of anticancer agents can be employed
The predictable response rate has always been less than
20%
Current trials are investigating the use of agents that
reverse multidrug resistance
Prognosis
In general, the prognosis is poor