HEPATOCELLULAR CARCINOMA
Rachel A. Freedman, MD
August 1, 2005
Introduction/Epidemiology
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and the
fifth most common malignancy in the world. Men are affected 2-5 times more than women with
the global incidence in 2000 of 316,000 cases in men and 121,100 cases in women. There is a
distinct geographic distribution with some areas having significantly lower rates than others. This
is likely due to the regional variations in exposure to the Hepatitis viruses as well as culprit
environmental toxins. The annual incidence in North and South America, south-central Asia,
Australia, and New Zealand is considered to be in to low range at <3 cases per 100,000. SubSaharan Africa and East Asia have a high annual incidence of disease at 15 cases per 100,000.
Over 40% of the world’s cases are present in China.
Pathogenesis
HCC is caused by multiple environmental elements in a population or an individual that are
synergistic in creating a permissive environment for carcinogenesis. Though a clear order of
gene mutation has not been established, it appears that “multiple hits” are necessary to develop
HCC. The factors that lead to acquisition of mutations include:

Chronic hepatitis and cirrhosis: Chronic inflammation leads to oxidative stress
on cells that may lead to DNA damage. Fibrosis leads to disruption of normal cell-cell
and cell-matrix interactions important in cell growth and regulation. 80% of patients with
HCC have cirrhosis.

Hepatitis B Virus: Infection with Hep B, Hep C, or both is the most common
etiologic cause for HCC in the world. The hallmark of HBV carcinogenesis is the
integration of the HBV genome into the cellular DNA of HCC cells. In chronic infection,
liver cells drop out and new ones regenerate. It is during this regeneration that HBV
genome is integrated, leading to chromosomal rearrangement, deletions, and
translocations. The HBV genome does not contain oncogenes. It is thought that the
effect is through trans-activation or trans-repression of cellular genes.

Hepatitis C Virus: This RNA virus does not integrate its genome into infected
cells. The chronic hepatitis appears to mediate the carcinogenesis. Inflammation allows
normal hepatocytes to come in contact with free radicals as well as enzymes released by
inflammatory cells that can lead to DNA damage. A more direct effect by HCV occurs
through its gene products that may exert influence on the cell cycle by interacting with
host cellular proteins. Of note, the HCV genotype 1b is associated with a worse
prognosis than genotypes 2 and 3.

Chemicals: Aflatoxin B (AFB), OCPs, betal nuts, azathioprine, and ethanol are
all chemicals that may increase risk of developing HCC. AFB induces a mutation in the
p53 gene that leads to genetic repair problems. These substances increase risk of HCC
alone, but in combination with each other or the chronic hepatitides, the risk is
synergistically increased.

Metabolic disorders: Usually these lead to cirrhosis and the associated
oxidative stress, fibrosis, and degeneration and regeneration that increase risk of gene
error and HCC. These include alpha-1 antitrypsin deficiency, porphyria cutanea tarda,
and hemochromatosis. Iron overload and ATT aggregation may directly induce
mutations that lead to HCC.
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Clinical Manifestations
Usually there are no specific symptoms associated with HCC outside of those related to the
underlying condition that predisposed the patient to developing the tumor. It is important to be
concerned about HCC in a patient with stable cirrhosis who develops decompensation in the form
of ascites, jaundice, variceal bleeding, or encephalopathy. Invasion of the hepatic and portal
veins may induce such a presentation. Constitutional symptoms are also frequently reported
such as weight loss, early satiety, and upper abdominal pain. Patients may present with biliary
obstruction, diarrhea, or symptoms caused by metastases. Tumor bleeding may present with
severe, acute abdominal pain and hypotension. On physical exam patients have stigmata of liver
disease. Hepatomegaly or a tumor bruit may be appreciated in some patients. Paraneoplastic
syndromes may accompany the other more organ specific presentation of HCC. These include:

Erythrocytosis: Some patient’s tumors produce erythropoietin. Most patients are
anemic at time of presentation.

Hypercalcemia: Bony mets or PTHrp production

Hypoglycemia: High metabolic needs of tumor. Rarely because of secretion of insulinlike growth factor II

Watery Diarrhea: May be caused to secretion of various peptides: gastrin, VIP, and
others

Rashes: Dermatomyositis, sudden appearance of multiple seborrheic keratoses
(Lesser-Trelat sign), PCT, and others. None are specific.

Electrolyte Abnormalities: often with hyponatremia, hypokalemia, metabolic alkalosis
Diagnosis/Screening
Most HCC are diagnosed in chronic cirrhotics who are noted to have an increase in their alphafetoprotein level and are sent to an imaging study for further evaluation of their liver for a mass.
Hepatocellular carcinoma is usually diagnosed in late stages of the disease given its lack of
specific symptoms and large reserve of the liver. With a suggestive imaging study, permissive
patient history, and an elevated AFP (most say greater than 500 mcg/L), the diagnosis is almost
certain and tissue is less important to obtain. The most common marker used in screening and
diagnosis is AFP with positive predictive value between 25-61% and a negative predictive value
between 90-98% depending on the prevalence of HCC in the screened population. Other
markers like des-gamma-carboxy prothrombin may also increase the sensitivity of tumor marker
testing for diagnosis and screening, but for now is relegated to research protocols. Ultrasound
and CT scan are the preferred image modalities because of cost and should be first line. Often
ultrasounds that reveal a mass are followed by CT scans to better characterize that mass, so it is
not unreasonable to start with a CT. Not surprisingly, MRI provides the best images but is
prohibitively expensive.
The issue of screening is fairly controversial. There is convincing data that screening allows
earlier stage tumors to be picked up. One 16 year trial in Alaska revealed a survival benefit in the
high risk group screened. Though the yield is low and the cost is high per life saved, most
clinicians advocate q 6 month screening with AFP and imaging in at risk patients. Most use
ultrasound over CT because of a cost advantage. Current recommendations are to screen the
following patients who would be candidates for surgical or percutaneous therapy:



Patients with Child-Pugh class A cirrhosis
Patients with “severe chronic active hepatitis” from HCV.
HepBsAg+ patients with or without cirrhosis.
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Staging/Treatment
Median survival after diagnosis is 6-20 months
Staging is by Okuda System (stages 1-3) which stage tumors by size, presence/absence of
ascites, albumin (less than or greater than 3), and bilirubin (less than or greater than 3). There
are also other scoring systems as well as classic TNM staging systems.


Surgical resection when possible is the treatment of choice
Local ablation
o
Hepatic cryosurgery-subzero probe
o
Radiofrequency ablation
o
Percutaneous ablation with ethanol, acetate, cisplatinum gel,
hot saline



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Transarterial embolization (good for bleeding tumors)
Chemoembolization
Chemotherapy (HCC is relatively refractory to chemotherapy)
Radiation therapy
Liver Transplant
o
Single tumor less than 5 cm
o
No greater than 3 tumors <3 cm each
o
Extrahepatic/Nodal spread is absolute contraindication
o
Possible improvement caused by ablative techniques may
allow patients to be candidates.
Bibliography
Plesch, FN. Prevention of HCC in chronic Liver disease: Molecular Markers and Clinical
Implications. Dig Dis 2001: 19: 338-344.
Rocken, C. Pathology and Pathogenesis of Hepatocellular Carcinoma. Dig Dis 2001; 19:269278.
Teo, EK. Hepatocellular Carcinoma: An Asian Perspective. Dig Dis 2001; 19:263-8.
Up to Date, HCC 2005
Wong, L. Current Status of liver transplantation for hepatocellular cancer. The American Journal
of Surgery. 183 (2002)309-316
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