A section of a liver removed at liver transplantation showing a massive HCC (in white) and multiple satellite nodules. Treatments Available for HCC

What is Hepatocellular Carcinoma (HCC)?
HCC is a type of cancer that originates from hepatocytes – the specialized epithelial cells of the liver. (Epithelial cells perform most of the functions of the liver.) HCC is therefore a primary liver cancer because it starts in this organ. Other types of cancers usually start elsewhere and then metastasize, or spread, to the liver.

Hepatocellular carcinomas (HCC) are also known as “primary liver cancers” or “hepatomas.” These terms can be used interchangeably.

What causes HCC?
In about 20% of people with HCC, there is no evidence of a disease causing it. However, most patients with HCC develop it after several years of cirrhosis due to chronic alcohol consumption or chronic infection with hepatitis B or C. Most patients with hepatitis C develop cirrhosis and then HCC; however, many patients with hepatitis B can often develop HCC without first developing cirrhosis. Thus, the main risk factors for HCC are:

• Chronic alcohol consumption
• Chronic hepatitis C
• Chronic hepatitis B
• Increasingly, obesity – which can lead to nonalcoholic steatohepatitis (NASH)
• Cirrhosis from any cause

In addition, there are other diseases sometimes associated with HCC. These include hemachromatosis and alpha-1-antitrypsin deficiency; primary biliary cirrhosis; and metabolic disorders, including porphyria cutanea tarda, citrullinemia, glycogen storage disease and tyrosinemia (and Alagille’s syndrome in children).

In some countries outside the United States, HCC has a strong association with chronic exposure to dietary toxins (such as Aspergillus flavus) made by Aspergillus fungi, which grow on grains and food products (such as peanuts) that are stored in humid, non-refrigerated conditions.

Radiation therapy, smoking, birth control pills and anabolic steroids have also been associated with various forms of primary tumors of the liver, but the associations are weak.

What are the signs and symptoms of HCC?
Unfortunately, many people with this type of cancer don’t have any symptoms until the disease becomes advanced. The most common symptom is abdominal (hepatic) pain. In children, abdominal swelling and/or an abdominal mass is also common. Other symptoms of advanced liver cancer include:

• Weight loss
• Diminished energy, general fatigue and malaise (“out-of-sorts” mood)
• Fevers of unclear origin
• Persistent feeling of fullness
• Upset stomach
• Reduced appetite

Rarer symptoms include shoulder pain (this is “referred” pain from the liver) and bone pain.

A doctor may detect certain physical signs that are consequences of the cirrhosis that leads to HCC. Those signs include:

• An enlargement of the liver
• Harsh or “musical” sound in the abdomen
• Enlargement of the spleen
• Accumulation of fluid in the abdominal cavity (ascites)

Abnormal test results (such as on a routine annual physical exam) can frequently be an indicator of HCC. When people have HCC, their blood work will usually show what physicians refer to as “elevated” or “abnormal” liver function tests.

Other individuals – especially ones with a known predisposing disease, such as chronic hepatitis or cirrhosis from any cause – are sometimes diagnosed when their liver function test results suddenly take a turn for the worse, or because they show abnormal blood test results for alpha-fetoprotein (AFP). (Note: If you have chronic hepatitis or cirrhosis, you should probably have liver function tests, an AFP test and an ultrasonogram or CT scan twice a year in order to detect HCC in the early stages.)

Finally, clinicians suspect liver cancer when they see a mass on an ultrasound, CT scan or MRI scan. A follow-up biopsy is needed to provide proof of the existence of liver cancer (although it is strongly suspected from the triad of presence of cirrhosis, a vascular liver lesion on CT or MRI scan, and an elevated and rising AFP blood test).

How do your physicians evaluate HCC tumors and surrounding tissues?
Computed tomography (CT) scans are important tools in evaluating HCC. In addition, blood tests, biopsies and other diagnostic measures help physicians to understand a patient’s general health status, liver function and quality of life. If a patient will be undergoing chemotherapy, this evaluation may also include a hearing test, as well as a MUGA heart scan.

Scans
Following a diagnosis of HCC, CT or MRI scans help determine:

• The size and location of HCC in the liver
• Whether or not the cancer has moved beyond the liver to form metastases
• How close the tumor is to major hepatic blood vessels – including if the tumor has invaded the portal vein (the main vein that leads to the liver)
• Whether or not there are blood clots in any of the major branches of the portal and hepatic veins (portal thrombosis is a poor prognostic sign)
• Whether or not regional lymph nodes are enlarged

A high-speed helical (spiral) triphasic CT scan of the liver helps our specialists to assess the location, number and size of the tumor(s). (An MRI scan of the liver provides the same information.) A CT scan of the chest and pelvis can help them determine if the cancer has spread to other parts of the body. In addition, a bone scan may be performed to exclude or confirm the presence of cancer in bone.

In evaluating CT scans of the tumor, our physicians also look for evidence of cirrhosis and its complications, such as portal hypertension, which often include ascites (buildup of fluid in the abdomen) and an enlarged spleen.

Blood Tests
Blood tests also help our physicians to assess the patient’s general health status – including past exposure to hepatitis B or C and whether or not the hepatitis is active. Blood test results also provide a measure of the patient’s overall liver function.

The physician will order a complete blood count. A white cell or platelet count that is below the normal range can be a sign of an enlarged spleen and/or portal hypertension.

Important blood tests will include:

• Albumin level
• Prothrombin time
• Transaminase level (SGOT, SGPT)
• GGTP and phosphatase alkaline
• Creatinine level

There are also blood tests to detect specific tumor “markers.” These tests include:

• Alpha-fetoprotein (AFP and AFL-L3, a new, more specific variant)
• Des-gamma carboxy prothrombin (DCP, or PIVKA-2)
• Some newer markers that include glypican and cell-cycle proteins
• Neurotensin (for the fibrolamellar variant of hepatoma of young adults)

Biopsies
In addition to a biopsy of the tumor itself, our radiologists perform a biopsy on a specimen of non-cancerous liver tissue. This biopsy helps to determine the presence and/or severity of cirrhosis. A core-needle biopsy (as opposed to a fine-needle aspiration biopsy) is typically required to assess the composition of an HCC tumor.

If the CT scan suggests a blood clot in a major portal vessel, then a fine needle-aspiration biopsy of the portal vein may also be required. This type of biopsy helps our physicians to determine whether or not the tumor is, in fact, invading the portal vein. This type of invasion has profound implications on the long-term outcome of liver transplantation for HCC.

What are the risk factors for HCC?
The following is a list of the risk factors for HCC:

• Cirrhosis from any cause
• Hepatitis B or C chronic infection
• Chronic consumption of ethanol
• Nonalcoholic steatohepatitis (NASH), a disease characterized by elevated blood levels of liver enzymes and the accumulation of fat and scar tissue in the liver in the obese
• Aflatoxin B1 or other mycotoxins, which can be transmitted through nuts and cereals contaminated with fungus
• Primary biliary cirrhosis
• Hemochromatosis, a disease in which the body absorbs too much iron
• α1-antitrypsin deficiency, a cause of cirrhosis
• Glycogen storage diseases
• Citrullinemia, an inherited disorder that causes ammonia and other toxic substances to build up in the blood
• Porphyria cutanea tarda, an inherited or acquired disorder of certain enzymes responsible for heme production
• Hereditary tyroseinemia, a metabolic disorder in which the body can’t break down an amino acid common in animal and plant proteins
• Wilson’s disease, a rare genetic disorder in which copper builds up in the liver and is released into other parts of the body

Please click on the image above for an enlarged view.

Summary: HCC
The most common modes of patient presentation

1. A patient with known history of hepatitis, jaundice or cirrhosis, with an abnormality on US or CT scan, or rising AFP or DCP (PIVKA 2)
2. A patient with abnormal liver function blood tests, as part of a routine examination
3. Radiologic work-up for liver transplant for cirrhosis, with scans showing a liver mass.
4. Non-specific symptoms of HCC including cachexia, abdominal pain or fever

History and physical examination

1. Clinical jaundice, asthenia, itching (scratches), tremors or disorientation
2. Hepatomegaly (enlarged liver), splenomegaly (enlarged spleen), ascites (buildup of fluid in abdominal cavity), peripheral edema (swelling), skin signs of liver failure

Clinical evaluation

1. Blood tests: full blood count (splenomegaly), liver function tests, ammonia levels, electrolytes, alpha-fetoprotein and DCP (PIVKA-2), Ca2+ and Mg2+; hepatitis B, C, and D serology (and quantitative HBV DNA or HCV RNA, if either is positive); neurotensin (specific for fibrolamellar HCC)
2. Triphasic dynamic helical (spiral) CT scan of liver (if inadequate, then follow with an MRI); chest CT scan; upper and lower gastrointestinal endoscopy (for varices, bleeding, ulcers); and brain scan (only if symptoms suggest)
3. Core biopsy: of the tumor and a separate biopsy of the underlying liver

Therapy

1. HCC < 2 cm: radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or liver resection
2. HCC >2 cm, no vascular invasion: liver resection, RFA or liver transplantation
3. Multiple unilobar tumors or tumor with vascular invasion: intrahepatic chemotherapy/chemoembolization (TACE)
4. Bilobar tumors, no vascular invasion: intrahepatic chemotherapy/chemoembolization (TACE) with liver transplantation for patients with tumor response
5. Extra-hepatic HCC or elevated bilirubin: Phase I and II studies

Contact us
To schedule an appointment with a Jefferson physician call 1-800-JEFF-NOW or click here.

To contact the Liver Tumor Program team at the Kimmel Cancer Center at Jefferson, please call 215-503-8752 and/or fax your records to 215-503-8755. We aim to schedule your first clinic visit within two weeks of your diagnosis being made and records being received.

Further Reading

1. Bartlett D, Carr BI and Marsh JW. Cancers of the Liver. In: DeVita VT, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology, Chapter 28, pp 986-1038, Seventh Edition. Lippincott Co., Philadelphia, 2005.
2. Carr BI (ed). Hepatocellular Cancer. Humana Press, 2005 (ISBN 1-59259-844-7).
3. Carr BI. Hepatocellular carcinoma: current management and future trends. Gastroenterology 2004; 127: S218-S224.