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Hepatocellular Cancer: A Guide for the Internist
Sameer Parikh, MD, David Hyman, MD, MPH
 Department of Medicine, Baylor College of Medicine, Houston, Tex.
Hepatocellular cancer is the third leading cause of cancer-related deaths worldwide. Its incidence hasincreased dramatically in the United States because of the spread of hepatitis C virus infection and isexpected to increase for the next 2 decades. Hepatitis B virus, hepatitis C virus, and chronic heavy alcoholuse leading to cirrhosis of the liver remain the most important causes. The diagnosis of hepatocellularcancer rests on a combination of radiologic, serologic, and histopathologic criteria. Liver transplantationis the only definitive treatment. Resection of the tumor and other percutaneous therapies are morecommonly used in practice, because most hepatocellular cancers are detected at an advanced stage. Patientswho are at high risk for the development of hepatocellular cancer should be screened with an ultrasoundof the liver every 6 months. The prognosis is dependent on both the underlying liver function and the stageat which the tumor is diagnosed. The aim of this review is to familiarize internists in screening, diagnosis,and referral of patients with hepatocellular cancer in an appropriate and timely fashion. © 2007 ElsevierInc. All rights reserved.
Hepatocellular cancer; Hepatitis C; Chronic alcoholism; Cirrhosis; Screening
Hepatocellular cancer is the fifth most common cause of cancer and the third leading cause of cancer-related deathsworldwide.
Its incidence has increased dramatically in thepast few years in the United States and other Westerncountries.
Despite advances in surgical and nonsurgicaltherapies in the treatment of hepatocellular cancer, a numberof controversial issues regarding appropriate screeningmethods, diagnosis, staging, and management continue toevolve. The aim of this review is to help the internistidentify high-risk patients, implement an appropriatescreening strategy, order relevant tests to confirm the diag-nosis, and formulate an appropriate management plan.
Hepatocellular cancer is a major health problem; more thanhalf a million cases are reported yearly worldwide. Thegeographic areas most affected are located in SoutheastAsia and sub-Saharan Africa. More recently, an increasingnumber of cases have been identified in Western countries.A large, retrospective cohort study confirmed an almost2-fold increase in the incidence of hepatocellular cancerfrom 1975 to 1998 in the United States.
This increase isprimarily related to the spread of hepatitis C virus (HCV)infection, which peaked in the United States in the late1980s.
Given the time lag of 2 to 4 decades between theonset of infection and the development of cirrhosis, it hasbeen predicted that the incidence of hepatocellular cancerwill continue to increase over the next 2 decades.
Accord-ing to the American Cancer Society, there will be 19,160new cases diagnosed and 16,780 deaths due to this diseasein the United States in 2007.
Males are more commonly affected than females in theratio of 3:1 to 9:1.
The mean age of presentation of hepa-tocellular cancer in Europe and the United States is approx-imately 60 years.
This is in contrast with patients in Asiaand Africa, where it is between 20 and 50 years.
The major clinical risk factor for the development of hepatocellular cancer is cirrhosis of the liver. Chronic in-fections with hepatitis B virus (HBV) and HCV and chronicheavy alcohol use are the most important risk factors for the
Requests for reprints should be addressed to Sameer Parikh, MD,Assistant Professor of Medicine, One Baylor Plaza, BTGH 2RM 81-001,Houston, TX 77030.E-mail address: parikh@bcm.tmc.edu
AJM Theme Issue: Gastroenterology
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.amjmed.2006.11.020
The American Journal of Medicine (2007) 120, 194-202
development of cirrhosis. HBV accounts for the majority of hepatocellular cancer in China and Africa, where most of the infection is acquired early in life eitherfrom mother tothe offspring or by horizontal transmission.
In contrast,HCV accounts for most of the cases in the Western hemi-sphere. Chronic alcohol use of greater than 80 g per day for morethan 10 years increases the risk of hepatocellular cancer 5-fold.
Furthermore, chronic alcohol usein HBV or HCV infection doublesthe risk of hepatocellularcancerover either infection alone.
The magnitude of risof hepatocellular cancer from cir-rhosis due to other causes is notwell known. There have been re-ports in patientswith hereditaryhemochromatosis,
alpha-1 anti-trypsin deficiency,
and autoim-mune hepatitis. An increased inci-dence hasbeen associated withsmoking
and exposure to afla-toxin, a mycotoxin that contami-nates peanuts and soybeans, andcauses mutations in thep53 tumorsuppressor gene.
Approxi-mately one quarter of all cases di-agnosed in the United States do not have any of these risk factors. There is growing interest in the role of insulinresistance syndrome as a risk factor for these cryptogeniccases. Insulin resistance syndrome is present in virtually allcases of nonalcoholic fatty liver disease; this condition isthought to predispose to nonalcoholic steatohepatitis andcirrhosis in 10% to 20% of cases.
Diabetes and obesity, 2major manifestations of insulin resistance syndrome, havebeen shown to double the risk of hepatocellular cancer
The typical clinical manifestations of hepatocellular cancerare right upper quadrant abdominal pain, early satiety, andweight loss. However, more and more hepatocellular can-cers are now detected at an asymptomatic stage because of the growing awareness of thesetumors in patients withchronic liver disease and cirrhosis.
Other clinical presen-tations, such as spontaneous rupture of the tumor intothe peritoneal cavity, obstructive jaundice, and bony pain from me-tastasis, are extremely uncommon.Various paraneoplastic syndromeshave been associated with hepato-cellularcancer.Theseincludeeryth-rocytosis (erythropoietin), hypogly-cemia (insulin-like growth factor),and hypercalcemia (parathyroid-re-lated protein). Physical findings inpatients with hepatocellular cancergenerally reflect the severity of theunderlying chronic liver disease andcirrhosis. The liver may be enlargedand a vascular bruit is sometimesheard, consistent with hypervascu-larity of the tumor.
A consensus statement from theEuropean Association for theStudy of Liver Diseases (EASL)has been formulatedto help clinicians standardize diag-nostic approaches
Lesions Greater Than 2 Centimetersin Diameter 
In nodules greater than 2 cm diameter in size, a diagnosis of hepatocellular cancer can be made if any 2 imaging studies(including ultrasonography, computed tomography, mag-netic resonance imaging, or hepatic arteriography) showincreased vascularity. Alternatively, only 1 imaging studywith an alpha-fetoprotein level greater than 400 ng/mL isdiagnostic. Our ability to diagnose these tumors nonin-vasively rests on the premise that they are seen on abackground of cirrhosis and enhance with contrast onrapid-sequence imaging secondary to their neovascular-ity. These radiologic criteria for diagnosis have excellentdiagnostic accuracy with reported sensitivity of 100%and specificity of 98.8%.
In cases of indeterminateradiologic findings, fine-needle aspiration biopsy isrecommended.
Lesions Less Than 2Centimeters in Diameter 
Imaging techniques for lesions less than 2 cm do not havesufficient accuracy in distinguishing hepatocellular cancerfrom other conditions. Alpha-fetoprotein levels may be nor-mal or only slightly elevated and thus provide no diagnosticutility. Hepatic lesions less than 1 cm in size have a less than50% chance of being malignant,
and serial ultrasound
In the US, the incidence of hepatocellu-lar cancer doubled between 1975 and1998 and is expected to continue to in-crease for the next 2 decades.
The American Association for the Studyof Liver Diseases recommends an ultra-sound of the liver every 6 months inhigh-risk patients to screen for hepato-cellular cancer.
Liver transplantation remains the only de-finitive treatment of hepatocellular can-cer, although surgical resection and per-cutaneous therapies are more commonlyapplied in routine clinical practice.
Table 1
Major Causes of Hepatocellular CancerInfections:Chronic hepatitis CChronic hepatitis BChronic hepatitis DToxins:Alcohol AflatoxinMetabolism:Diabetes mellitus, nonalcoholic fatty liver diseaseHereditary hemochromatosisPrimary biliary cirrhosis, autoimmune hepatitis
195Parikh and Hyman Hepatocellular Cancer
(every 3 months) is recommended. On the other hand,fine-needle aspiration biopsy should be performed in lesionsbetween 1 and 2 cm in size.
Role of Liver Biopsy
The role of liver biopsy has been the subject of greatcontroversy. For almost all other types of cancer, his-topathologic confirmation is necessary to make a diag-nosis. However, as elucidated inTable 2,both the EASL and United Network for Organ Sharing criteria
do notrequire a biopsy for the diagnosis of hepatocellular can-cer in lesions greater than 2 cm. For lesions less than 2cm in size where high-quality imaging or expertise inreading these images is not available, a biopsy isrecommended.There is a small but definite risk of tumor seeding froman invasive biopsy. The prevalence rates have been reportedto be anywhere between 0.003% and 5%.
How-ever, it is unclear whether it leads to metastatic disease orworse survival because a majority of patients are treated byexcision of the subcutaneous tumor deposit. Also, the false-negative rate from biopsy of lesions less than 2 cm isapproximately 30% to 40%.
Thus, a negative biopsy doesnot conclusively rule out the diagnosis of hepatocellularcancer.
Role of Serum Markers
The 3 most commonly used serum markers are alpha-feto-protein, Lens culinaris agglutinin-reactive alpha-fetoprotein(alpha-fetoprotein-L3), and protein induced by vitamin Kantagonist-II.
The sensitivity and specificity of thesemarkers to diagnose hepatocellular cancer vary according tothe threshold level used. Total alpha-fetoprotein has a sen-sitivity of 60% and specificity of 90% at cutoff valuesbetween 10 and 20 ng/mL. A systematic review confirmedthe poor diagnostic ability of alpha-fetoprotein alone indetecting hepatocellular cancer at any level of pretest risk.
It is a much better diagnostic test in the presence of ahepatic mass where a cutoff value of greater than 400ng/mL is used in combination with imaging criteria.
Anincrease in the percentage of alpha-fetoprotein-L3 over thetotal alpha-fetoprotein (
10%) is specific for small hepa-tocellular cancer. Protein induced by vitamin K antago-nist-II is also more specific than total alpha-fetoprotein indetecting hepatocellular cancer. However, these are notavailable in most nonresearch laboratories in the UnitedStates at this time.
Although there is no definite evidence that screening inhepatocellular cancer improves survival, many physiciansscreen patients in high-risk groups with either serum alpha-fetoprotein or ultrasound of the liver or both. Two recentrandomized controlled trials completed in China demon-strated a significant reduction in hepatocellular cancer-re-lated mortality in patients who underwent screening.
Ultrasound of the liver is the preferred screening test be-cause it has a sensitivity of 84% and specificity of more than90%.
A combination of alpha-fetoprotein and ultrasoundhas been reported to increase the sensitivity by 5% to 10%over ultrasound alone, but it also increases costs and false-positive rates.
The United States Preventive Services Task Force, Na-tional Comprehensive Cancer Network, and American Can-cer Society do not have any specific guidelines for screeningpatients for hepatocellular cancer. The National Cancer In-stitute recommends against routine screening for lack of asurvival benefit. The American Association for the Study of Liver Diseases and EASL recommend ultrasound of the
Table 2
Diagnostic Criteria for Hepatocellular Cancer1. Histopathologic criteria2. Noninvasive criteria (limited to patients with underlying cirrhosis)(i) European Association for the Study of Liver Diseases Criteria:(a) Radiologic criteria:Two coincident imaging techniques that identify a focal lesion more than 2 cm showing arterial hypervascularization(b) Combined criteria:One imaging modality that identifies a focal lesion more than 2 cm in diameter showing arterial hypervascularizationAND serum AFP levels greater than 400 ng/mL(ii) United Network for Organ Sharing Criteria (for listing patients on transplant list):(a) A prelisting biopsy is not necessary(b) US of the liver, a CT or MRI scan of the abdomen that documents the tumor, and a CT of the chest that rules outmetastatic disease with any 1 of the following:
a vascular blush corresponding to the area of suspicion seen on the above imaging studies
an alpha-fetoprotein level of 
200 ng/mL
an arteriogram confirming a tumor
a biopsy confirming hepatocellular cancer, prior chemoembolization of lesion, radiofrequency, cryoablation,or chemical ablation of the lesion
alpha-fetoprotein; US
ultrasound; CT
computed tomography; MRI
magnetic resonance imaging.
196 The American Journal of Medicine, Vol 120, No 3, March 2007

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