Hepatoma Disease

BASICS

DESCRIPTION

Primary malignant tumor of liver arising from hepatic parenchymal cells (hepatocytes), blood vessels or cholangioles within the liver, excluding gallbladder and biliary passages. With the exception of fibrolamellar type, 85% associated with an underlying liver disease, usually cirrhosis.

System(s) affected: Gastrointestinal
Genetics: No known genetic pattern
Incidence/Prevalence in USA:
- 1-5 new cases per 100,000 of population per year
- Among known cirrhotics, 2-5 cases per 100/year
Predominant age: 6th-8th decade (mean age 55-62 years) in USA and western countries. Among immigrants from Asia and Africa occurs 2-3 decades earlier.
Predominant sex: Male > Female (3-4:1)

SIGNS AND SYMPTOMS

Early curable stage
- Paraneoplastic syndrome - feminization, precocious puberty
- Palpable nodule on liver
- Age 2 to 6 years - abdominal mass in liver, abdominal pain, irregular hepatomegaly
Usual adult manifestations
- Known cirrhosis or prominent clinical signs of cirrhosis - 80%
- Abdominal pain - 80%, right upper quadrant, dull ache to severe, aggravated by jolting
- Hepatomegaly - 80-90%, irregular, nodular, firm to hard, tender
- Weight loss - 30%
- Hepatic arterial bruit - 20%
- Friction rub - rare, more common in metastatic liver disease
- Nausea, vomiting
- Fever - 10-50%, low grade, intermittent
- Paraneoplastic manifestations - hypertrophic osteoarthropathy, carcinoid syndrome, feminization, polycythemia
- Hemoperitoneum - most common tumor cause
- Unexplained deterioration of stable cirrhosis
- Budd-Chiari syndrome
- Blockage of portal vein, inferior vena cava, renal veins

CAUSES

Cirrhosis - accounts for 60 to 80% of cases. Alcoholic cirrhosis most important in western world. Reported risk of hepatoma in alcoholic cirrhosis is 3-10% with micronodular pattern.
Hepatitis B virus infection - associated with > 70% of cases worldwide. Most important factor in Africa and Asia but less important in western countries. In USA, HBsAg is positive in 20% cases of this tumor.
Hepatitis C virus infection - 50-70% of HBsAg negative patients are positive for anti-HCV antibody, an important factor in hepatoma patients not due to HBV infection. Particular problem in Orientals.
Mycotoxins (aflatoxins) - metabolite of fungus Aspergillus flavus that contaminates foods. Two series, B1 and derivatives and G1 and derivatives. B1 being the most potent carcinogen, important in Sub-Saharan Africa and Southeast Asia, no significant role in USA.
Vinyl polymer, but not the finished product, produces angiosarcoma

RISK FACTORS

Primary liver disease - cirrhosis, chronic active hepatitis
HBsAg positivity, anti-HCV antibody
Chronic use of oral contraceptives
Hemochromatosis
Alpha-1-antitrypsin deficiency
Primary biliary cirrhosis
Metabolic disorders (tyrosinemia, Niemann-Pick disease)
Clonorchiasis, gallstones, choledochal cysts - cholangiocarcinoma

DIAGNOSIS

LABORATORY

Erythrocytosis, elevated Ca, low glucose
Liver function test abnormalities
Tumor markers
- Alpha fetoprotein (AFP) - single most important lab test for screening and diagnosis of hepatoma (70%). Negative in angiosarcoma, cholangiocarcinoma, and fibrolamellar carcinoma. Level > 400 ng/mL (> 400 µg/L) is diagnostic; level does not correlate with prognosis.
- Other markers - des-gamma-carboxyprothrombin, gamma glutamyl transferase, carcinoembryonic antigen (CEA), variant alkaline phosphatase, isoferritins

Drugs that may alter lab results: Hypoglycemic agents, calcitonin, vitamin D
Disorders that may alter lab results: Acute or chronic hepatitis, germ cell tumors, pregnancy. All cause slight elevation of AFP.

PATHOLOGICAL FINDINGS

Nodular - 75%, usually in cirrhotic liver
Massive - common in children and non-cirrhotic livers, more prone to rupture
Diffuse - rare, a large part of liver is involved
Hepatocellular origin - most commonly multicentric, well differentiated, usually superimposed on underlying cirrhosis. Almost always produces bile. Anaplastic form often difficult to be certain of cell of origin or differentiate from metastatic malignancy.
Fibrolamellar - single nodule, non-cirrhotic, extensive fibrous stroma
Cholangiocarcinoma - multicentric, most often mixed with hepatocellular elements
Angiosarcoma

SPECIAL TESTS

N/A

IMAGING

Plain x-ray - useful to demonstrate metastatic involvement to lung and bone
Ultrasound - best diagnostic imaging technique, capable of detecting tumor > 1 cm, and may be positive when AFP is normal. Has been useful in serially following cases of cirrhosis to identify hepatocellular cancer when under 2 cm and curable.
CT scan - valuable in determining extrahepatic spread of the disease
MRI - helpful in delineating the details of tumor, and invasion of vessels
Hepatic arteriography - mostly done to see the anatomy of hepatic vessels and extent of tumor while considering resection, embolization, dearterialization or intra-arterial infusion of cytotoxic agents. Most useful in detecting angiosarcoma, separating benign vs. malignant.
Lipoidal angiography and CT - lipoidal is readily taken up by tumor cells, this technique can detect even millimeter sized lesions. Lipoidal also serves as a vehicle to deliver chemotherapeutic or radioactive agents to the tumor.
Gallium scans - 90% of hepatocellular carcinoma and 60% of other types of liver cell tumors take up and retain gallium for up to 48 hours

DIAGNOSTIC PROCEDURES

Liver biopsy - recommended for all tumors and particularly small nodules detected on serial ultrasound
Fine needle aspiration - under ultrasonography, may be difficult to determine cell origin when anaplastic, unable to diagnose fibrolamellar and angiosarcoma due to too small a sample of tissue
Laparoscopy - to visualize the extent of tumor, to see whether non-tumorous liver is cirrhotic, peritoneal spread, and obtain diagnostic biopsy
Exploratory laparotomy with operative biopsy, commonly used in children

TREATMENT

APPROPRIATE HEALTH CARE

Inpatient initially

GENERAL MEASURES

Precautions to avoid falls, attention to nutrition

SURGICAL MEASURES

Surgery is lobectomy, liver segmentectomy, or whatever required for complete removal
Repeated injections with absolute ethanol or 50% acetic acid under ultrasound guidance shrinks tumor and prolongs survival. Useful for masses up to 5 cm. Radiofrequency thermal and cryoablation have also been used.
Intra-arterial injection of chemotherapy with infarction shrinks tumor size and prolongs survival
Liver transplantation indicated in advanced cirrhosis or with multiple nodule nonmetastatic disease. 15-60% alive at 3 years.

ACTIVITY

As tolerated

DIET

High calorie, low protein diet

PATIENT EDUCATION

Important for prevention; abstinence from alcohol and IV drugs, vaccination against HBV

FOLLOW UP

PREVENTION/AVOIDANCE

Prevention against HBV infection/cirrhosis
- General education regarding risks of exposure to HBV and precautions to avoid this
- Vaccination in high risk individuals - nurses, doctors, dialysis unit staff, lab technicians
- Vaccination of all children
- Abstinence from alcohol, IV drugs, homosexual behavior
- Persistent HBV and HCV infections eradicated with alpha ‘interferon’, ‘lamivudine’
Screening and early diagnosis
- Early diagnosis to detect asymptomatic tumor (< 3 cm) at a potentially curable stage has been emphasized. The only screening test available so far is AFP testing which can detect 70-80% of tumors < 3 cm when used in conjunction with serial high resolution sonography.
- AFP should be done every 6 months in high risk individuals (cirrhosis, chronic active hepatitis) along with annual ultrasound. In moderate risk subjects (HBsAg positive but asymptomatic), AFP should be done yearly followed by ultrasound if it is abnormal with prompt biopsy of any new nodules.
- Patients exposed to 10 or more years of vinyl chloride polymerization should have q 6 months sonography. New nodules should be promptly biopsied.

POSSIBLE COMPLICATIONS

Rupture, hemoperitoneum, liver failure, cachexia, metastases to other organs

EXPECTED COURSE AND PROGNOSIS

Unresectable symptomatic tumors
- Grave prognosis, seldom live more than 6 months
- After liver transplantation - 2 year survival rate 15-20%
- Asymptomatic tumors found on screening - 1/4 live > 3 years. Direct injection or chemoembolization improves this.
Resectable asymptomatic tumors
- Surgery is curative in > 70% of children without cirrhosis and in > 40% of adults without cirrhosis
- Surgery is curative in > 70% of cirrhosis when tumor nodules less than 2 cm; curative < 10% of the time if 3 cm or greater
- Liver transplantation curative in cancer with cirrhosis with > 15% of patients alive at 3 years

MISCELLANEOUS

ASSOCIATED CONDITIONS

Infections
- Chronic hepatitis B
- Hepatitis C
- Delta hepatitis
- Clonorchiasis
- Schistosomiasis
Primary liver diseases
- Alcoholic cirrhosis
- Primary biliary cirrhosis
Metabolic diseases
- Alpha1-antitrypsin deficiency
- Hemochromatosis
- Tyrosinemia

AGE-RELATED FACTORS

Can occur in all age groups

Pediatric: Second most common tumor in first year of life following Wilms' tumor. High cure rate.
Geriatric: N/A
Others: N/A

PREGNANCY

N/A

OTHER NOTES

In Africa and Southeast Asia:
- Incidence of hepatoma is high - 15-20 cases/100,000/year
- Age group is younger - 3rd and 4th decade
- Male to female ratio is high - 6:1 to 7:1
- Aflatoxin and HBV are the major factors and cirrhosis is less important
- Course is more progressive and fulminant
- Tumors are mostly at unresectable stage at first presentation

ABBREVIATIONS

HBsAg = hepatitis B surface antigen
HCV = hepatitis C virus
HBV = hepatitis B virus
AFP = alpha-fetoprotein

Clinical Investigations

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