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