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REVIEW

Hepatocellular Cancer: A Guide for the InternistSameer Parikh, MD, David Hyman, MD, MPH

Department of Medicine, Baylor College of Medicine, Houston, Tex.

ABSTRACT

Hepatocellular cancer is the third leading cause of cancer-related deaths worldwide. Its incidence has

increased dramatically in the United States because of the spread of hepatitis C virus infection and is

expected to increase for the next 2 decades. Hepatitis B virus, hepatitis C virus, and chronic heavy alcohol

use leading to cirrhosis of the liver remain the most important causes. The diagnosis of hepatocellular

cancer 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 more

commonly used in practice, because most hepatocellular cancers are detected at an advanced stage. Patients

who are at high risk for the development of hepatocellular cancer should be screened with an ultrasound

of the liver every 6 months. The prognosis is dependent on both the underlying liver function and the stage

at 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 Elsevier

Inc. All rights reserved.

KEYWORDS: 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.1 Its incidence has increased dramatically in the

past few years in the United States and other Western

countries.2 Despite advances in surgical and nonsurgical

therapies in the treatment of hepatocellular cancer, a number

of controversial issues regarding appropriate screening

methods, diagnosis, staging, and management continue to

evolve. The aim of this review is to help the internist

identify high-risk patients, implement an appropriate

screening strategy, order relevant tests to confirm the diag-

nosis, and formulate an appropriate management plan.

EPIDEMIOLOGYHepatocellular cancer is a major health problem; more than

half a million cases are reported yearly worldwide. The

geographic areas most affected are located in Southeast

Asia and sub-Saharan Africa. More recently, an increasing

number of cases have been identified in Western countries.

A large, retrospective cohort study confirmed an almost

2-fold increase in the incidence of hepatocellular cancerfrom 1975 to 1998 in the United States.2,3 This increase is

primarily related to the spread of hepatitis C virus (HCV)

infection, which peaked in the United States in the late

1980s.4 Given the time lag of 2 to 4 decades between the

onset of infection and the development of cirrhosis, it has

been predicted that the incidence of hepatocellular cancer

will continue to increase over the next 2 decades.4 Accord-

ing to the American Cancer Society, there will be 19,160

new cases diagnosed and 16,780 deaths due to this disease

in the United States in 2007.5

Males are more commonly affected than females in the

ratio of 3:1 to 9:1.6 The mean age of presentation of hepa-tocellular cancer in Europe and the United States is approx-

imately 60 years.7 This is in contrast with patients in Asia

and Africa, where it is between 20 and 50 years.

CAUSEThe 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 chronic

heavy 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: [email protected]

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

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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 either from mother to

the offspring or by horizontal transmission.8,9 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 more

than 10 years increases the risk of hepatocellular cancer 5-fold.10

Furthermore, chronic alcohol use

in HBV or HCV infection doubles

the risk of hepatocellular cancer

over either infection alone.11

The magnitude of risk

of hepatocellular cancer from cir-

rhosis due to other causes is not

well known. There have been re-

ports in patients with hereditary

hemochromatosis,12 alpha-1 anti-

trypsin deficiency,13 and autoim-mune hepatitis. An increased inci-

dence has been associated with

smoking14 and exposure to afla-

toxin, a mycotoxin that contami-

nates peanuts and soybeans, and

causes mutations in the p53 tumor

suppressor gene.15,16 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 insulin

resistance syndrome as a risk factor for these cryptogenic

cases. Insulin resistance syndrome is present in virtually allcases of nonalcoholic fatty liver disease; this condition is

thought to predispose to nonalcoholic steatohepatitis and

cirrhosis in 10% to 20% of cases.17 Diabetes and obesity, 2

major manifestations of insulin resistance syndrome, have

been shown to double the risk of hepatocellular cancer18

(Table 1).

CLINICAL FEATURESThe typical clinical manifestations of hepatocellular cancer

are right upper quadrant abdominal pain, early satiety, and

weight loss. However, more and more hepatocellular can-

cers are now detected at an asymptomatic stage because of

the growing awareness of these tumors in patients with

chronic liver disease and cirrhosis.19 Other clinical presen-

tations, such as spontaneous rupture of the tumor into

the peritoneal cavity, obstructive

jaundice, and bony pain from me-

tastasis, are extremely uncommon.Various paraneoplastic syndromes

have been associated with hepato-

cellular cancer. These include eryth-

rocytosis (erythropoietin), hypogly-

cemia (insulin-like growth factor),

and hypercalcemia (parathyroid-re-

lated protein). Physical findings in

patients with hepatocellular cancer

generally reflect the severity of the

underlying chronic liver disease and

cirrhosis. The liver may be enlarged

and a vascular bruit is sometimesheard, consistent with hypervascu-

larity of the tumor.

DIAGNOSISA consensus statement from the

European Association for the

Study of Liver Diseases (EASL)

has been formulated to help clinicians standardize diag-

nostic approaches20 (Table 2).

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) show

increased vascularity. Alternatively, only 1 imaging study

with an alpha-fetoprotein level greater than 400 ng/mL is

diagnostic. Our ability to diagnose these tumors nonin-

vasively rests on the premise that they are seen on a

background of cirrhosis and enhance with contrast on

rapid-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%.21-24 In cases of indeterminate

radiologic findings, fine-needle aspiration biopsy is

recommended.25,26

Lesions Less Than 2Centimeters in Diameter Imaging techniques for lesions less than 2 cm do not have

sufficient accuracy in distinguishing hepatocellular cancer

from other conditions. Alpha-fetoprotein levels may be nor-

mal or only slightly elevated and thus provide no diagnostic

utility. Hepatic lesions less than 1 cm in size have a less than50% chance of being malignant,27 and serial ultrasound

CLINICAL SIGNIFICANCE

● 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 Cancer

Infections:Chronic hepatitis CChronic hepatitis BChronic hepatitis D

Toxins:Alcohol Aflatoxin

Metabolism:Diabetes mellitus, nonalcoholic fatty liver diseaseHereditary hemochromatosis

Primary biliary cirrhosis, autoimmune hepatitis

195Parikh and Hyman Hepatocellular Cancer

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(every 3 months) is recommended. On the other hand,

fine-needle aspiration biopsy should be performed in lesions

between 1 and 2 cm in size.

Role of Liver BiopsyThe role of liver biopsy has been the subject of great

controversy. For almost all other types of cancer, his-

topathologic confirmation is necessary to make a diag-

nosis. However, as elucidated in Table 2, both the EASL

and United Network for Organ Sharing criteria28

do notrequire a biopsy for the diagnosis of hepatocellular can-

cer in lesions greater than 2 cm. For lesions less than 2

cm in size where high-quality imaging or expertise in

reading these images is not available, a biopsy is

recommended.

There is a small but definite risk of tumor seeding from

an invasive biopsy. The prevalence rates have been reported

to be anywhere between 0.003% and 5%.25,29,30-32 How-

ever, it is unclear whether it leads to metastatic disease or

worse survival because a majority of patients are treated by

excision of the subcutaneous tumor deposit. Also, the false-

negative rate from biopsy of lesions less than 2 cm isapproximately 30% to 40%.29 Thus, a negative biopsy does

not conclusively rule out the diagnosis of hepatocellular

cancer.

Role of Serum MarkersThe 3 most commonly used serum markers are alpha-feto-

protein, Lens culinaris agglutinin-reactive alpha-fetoprotein

(alpha-fetoprotein-L3), and protein induced by vitamin K

antagonist-II.33 The sensitivity and specificity of these

markers to diagnose hepatocellular cancer vary according to

the 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 confirmed

the poor diagnostic ability of alpha-fetoprotein alone in

detecting hepatocellular cancer at any level of pretest risk.34

It is a much better diagnostic test in the presence of a

hepatic mass where a cutoff value of greater than 400

ng/mL is used in combination with imaging criteria.35,36 An

increase in the percentage of alpha-fetoprotein-L3 over the

total alpha-fetoprotein (Ͼ10%) is specific for small hepa-

tocellular cancer. Protein induced by vitamin K antago-

nist-II is also more specific than total alpha-fetoprotein in

detecting hepatocellular cancer. However, these are notavailable in most nonresearch laboratories in the United

States at this time.

SCREENINGAlthough there is no definite evidence that screening in

hepatocellular cancer improves survival, many physicians

screen patients in high-risk groups with either serum alpha-

fetoprotein or ultrasound of the liver or both. Two recent

randomized controlled trials completed in China demon-

strated a significant reduction in hepatocellular cancer-re-

lated mortality in patients who underwent screening.

37,38

Ultrasound of the liver is the preferred screening test be-

cause it has a sensitivity of 84% and specificity of more than

90%.39 A combination of alpha-fetoprotein and ultrasound

has been reported to increase the sensitivity by 5% to 10%

over ultrasound alone, but it also increases costs and false-

positive rates.40,41

The United States Preventive Services Task Force, Na-

tional Comprehensive Cancer Network, and American Can-

cer Society do not have any specific guidelines for screening

patients for hepatocellular cancer. The National Cancer In-

stitute recommends against routine screening for lack of a

survival benefit. The American Association for the Study of Liver Diseases and EASL recommend ultrasound of the

Table 2 Diagnostic Criteria for Hepatocellular Cancer

1. Histopathologic criteria

2. 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 hypervascularization

AND 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 out

metastatic 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 Ͻ200 ng/mL

➢ an arteriogram confirming a tumor

➢ a biopsy confirming hepatocellular cancer, prior chemoembolization of lesion, radiofrequency, cryoablation,

or chemical ablation of the lesion

AFPϭ alpha-fetoprotein; USϭ ultrasound; CTϭ computed tomography; MRIϭmagnetic resonance imaging.

196 The American Journal of Medicine, Vol 120, No 3, March 2007

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liver every 6 months for high-risk patients42 (Table 3 and

Figure 1).

NATURAL HISTORY AND PROGNOSISProspective studies have shown that most hepatocellular

cancers develop through a progressive pathway from pre-

malignant nodular lesions to cancerous lesions in the cir-

rhotic liver.43 Progression takes an average of approxi-

mately 2 to 4 decades from the initial time of infection with

HBV or HCV to the development of cirrhosis. Thereafter,

the annual risk of hepatocellular cancer is 2% to 3% for

HBV, 1% to 7% for HCV, and 1% for alcohol-induced

cirrhosis.10,44 Hepatocellular cancer can develop in the ab-

sence of cirrhosis in patients with HBV infection at a rate of 0.26% to 0.6% per year.44 Recent studies have shown that

treatment of chronic HCV infection with interferon mono-

therapy in patients with cirrhosis decreases the risk of hep-

atocellular cancer, and it is expected that combination ther-

apy with pegylated interferon and ribavirin may reduce this

risk even further.45,46

Predicting survival in hepatocellular cancer is compli-

cated by the fact that 2 disease processes, namely, the tumor

and underlying cirrhosis, are present simultaneously. Nu-

merous studies have shown that prognosis is directly pro-

portional to the degree of hepatic function, suggesting that

cirrhosis rather than mass size of the tumor is the main

determinant of outcome. The median survival of untreated

patients with newly diagnosed hepatocellular cancer is

weeks to months.47 A number of factors are associated with

worse outcome: male sex, advanced age, etiologic agent

Table 3 High-Risk Groups for Screening of Hepatocellular

Cancer

Cirrhosis:Hepatitis BHepatitis CAlcoholic cirrhosisHereditary hemochromatosis

Primary biliary cirrhosisNonalcoholic steatohepatitisPatients waiting on the liver transplant list

No cirrhosis: Chronic hepatitis B carriers: males aged Ͼ40 y and

females aged Ͼ50 y, family history of hepatocellular cancer in a

patient with chronic hepatitis B.

Screening for patients with cirrhosis secondary to alpha-1 anti-

trypsin deficiency, autoimmune hepatitis, and Wilson’s disease is con-

sidered low-moderate risk, and there are no recommendations for

screening at this time.

Figure 1 Surveillance of hepatocellular cancer in patients with cirrhosis of the liver. HCC ϭ hepatocellular cancer; AFP ϭ

alpha-fetoprotein.


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(HCV worse than HBV), presence of more than 1 risk

factor, size, number and doubling time of nodules, vascular

invasion, and distant metastasis.

Because of the heterogeneous nature of hepatocellular

cancer with respect to its cause, epidemiologic background,and severity of hepatic dysfunction, a worldwide staging

system is not in place. The most commonly used staging

system for solid tumors, TNM classification, has severe

limitations because it does not include the severity of un-

derlying cirrhosis. Therefore, other staging systems such as

the Barcelona Clinic Liver Cancer staging classification48

(Table 4) and Cancer of Liver Italian Score have been

developed.

MANAGEMENT The definitive treatment of hepatocellular cancer is liver

transplantation; this cures both the cancer and the underly-

ing cancer-prone cirrhotic liver (Figure 2).

Surgical TherapyResection. Resection of the tumor is the treatment of choice

for hepatocellular cancer.49,50 Before using resection, it is

necessary to demonstrate sufficient liver reserve by calcu-

lating the Child-Pugh Score (Table 5). Generally, patients

with Child-Pugh class A can safely undergo resection. How-

ever, not all patients with class A have homogenous liver

function, and therefore, presence of portal hypertension is

assessed to determine feasibility of resection. With thesecriteria, a 5-year survival of approximately 60% to 70% can

be achieved. However, tumor recurrence complicates ap-

proximately 70% of patients at 5 years.51 Adjuvant chemo-

therapy and chemoembolization have not been shown to be

of any added benefit.52,53 Various other adjuvant treatment

approaches, including internal radiation with I-131–labeled

lipiodol,54 adoptive immunotherapy with activated lympho-

cytes,55 and interferon,56,57 have shown promising results

but need further validation.

Liver Transplantation. The indications for liver transplan-

tation as the primary method of treatment continue toevolve. In the 1980s, poor patient selection led to dismal

outcomes with 5-year survival of less than 40%.58 A land-

mark clinical trial in 1996 established the so-called “Milan

Criteria” for selecting ideal candidates for liver transplan-

tation. The investigators included patients with a single

lesion less than 5 cm in size or 3 lesions each less than 3 cmin size. Their 5-year survival exceeded 70%, and the recur-

rence rate was less than 15%.59 Indeed, these results were

duplicated in other studies in which the 5-year survival

exceeded 75%, far greater than survival after resection or

ablation.60 These criteria are still used today for listing

patients on the transplant registry and are listed on the

United Network for Organ Shearing website28 (Table 6).

The assignment of priority scores for liver transplanta-

tion is based on the Model for End-Stage Liver Disease

score, which uses laboratory values of serum creatinine,

total bilirubin, and international normalized ratio. Patients

with hepatocellular cancer are assigned a higher Model forEnd-Stage Liver Disease score and thus, get a priority for

transplant over those with similar degrees of liver dysfunc-

tion, and without hepatocellular cancer, who are waiting for

a transplant. However, a shortage of donors has led to

unacceptably high dropout rates because of deaths or ap-

pearance of contraindications, with survival decreasing to

less than 50% using an intention-to-treat principle.61

Given the difficulties in obtaining a cadaveric liver in a

timely fashion, “bridging” therapies such as surgical resec-

tion, neoadjuvant local ablation, and chemoembolization

have been tried with promising results.62,63 Living-donor

liver transplantation is being increasingly performed in theUnited States with results comparable to those undergoing

cadaveric transplantation.64

Nonsurgical TherapyThe majority of hepatocellular cancers identified at initial

presentation are unresectable and do not qualify to be on the

transplant list. A number of other options are available.

Local Ablation. Local ablation uses image-guided chemi-

cal (ethanol, acetic acid) and thermal (radiofrequency,

cryoablation) techniques. Ablation is commonly used with

curative intent in patients with unresectable tumors, withsurvival similar to resection. Percutaneous ethanol injection

Table 4 Barcelona Clinic Liver Cancer Staging Classification47

Stage Performance Status Test* Tumor Stage Okuda Stage† Liver Function Status

A 0 Single I-II Child Pugh‡ A-BB 0 Large multinodular I-II Child Pugh‡ A-BC 1-2 Vascular invasion, extrahepatic spread I-II Child Pugh‡ A-BD 3-4 Any III Child Pugh‡ C

For Stages A and B: All criteria should be fulfilled. For Stages C and D: At least 1 criterion must be fulfilled.*Performance status test is based on the Eastern Co-Operative Oncology Group performance scale: 0: asymptomatic, 1: symptomatic and fully

ambulatory, 2: symptomatic and in bed Ͻ50% of the day, 3: symptomatic and in bed Ͼ50% of the day, 4: bedridden.

†Okuda staging system (I-III) is another staging system that takes into account the size of the tumor, presence of ascites, and albumin and bilirubin

concentrations.

‡For Child-Pugh Classification, see Table 5.


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was the most commonly applied technique, with a response

rate of 70% to 100%.65,66 However, radiofrequency thermal

ablation is more commonly used now because it can achieve

better control of disease and improve survival compared

with percutaneous ethanol injection.67,68 The major limita-

tion of local ablation is its inability to achieve meaningful

response rates in infiltrative lesions and in tumors larger

than 4 to 5 cm in size.

Transarterial Therapy. Transarterial interventions areavailable for treatment of large unresectable hepatocellular

cancers that are not amenable to resection or percutaneous

therapies. These are generally used with palliative intent

to reduce tumor burden. The most commonly used tech-

niques include transcatheter arterial chemoembolization and

transarterial radioactive iodine with lipiodol. A systematic

review of randomized trials for unresectable hepatocellular

carcinoma showed that in patients with compensated cir-

rhosis and good functional status, arterial embolization im-

proved 2-year survivals.69 Postembolization syndrome, as-

sociated with abdominal pain and fever, can sometimesoccur and precipitate ascites and hepatic encephalopathy.

Figure 2 A simplified approach to the management of newly diagnosed hepatocellular cancer. aResectable lesions—evaluate for liver

transplantation: Surgical resection and liver transplantation compete as first-line therapy for patients with small single tumors and preserved

liver function. bUNOS criteria: See Table 6. c“Bridging therapy” constitutes surgical resection, RFA, or TACE before liver transplantation.

PEIϭpercutaneous ethanol injection; RFAϭ radiofrequency ablation; TACEϭ transcatheter arterial chemoembolization; UNOSϭUnited

Network for Organ Sharing.


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Patients with advanced liver disease (Child-Pugh C) and

portal vein thrombosis should not undergo these therapies

because of the risk of precipitating acute liver failure.

Combination Therapy. Combined therapy with transcath-

eter arterial chemoembolization followed by radiofrequency

thermal ablation has been shown to produce good local

response, especially in tumors less than 5 cm.70 However,the overall usefulness of this procedure needs to be estab-

lished in a larger number of patients.

Systemic Treatment. Numerous systemic therapies, in-

cluding doxorubicin, tamoxifen, megestrol, interferon al-

pha, and anti-androgens, have been tried and compared in

randomized trials. The use of most of these agents is asso-

ciated with significant toxicity without any discernible ben-

efit with regard to survival or complete response.71,72

FUTURE TRENDSProteomics has led to the discovery of new molecular mark-

ers, such as des-gamma carboxyprothrombin and human

hepatocyte growth factor, for screening hepatocellular can-

cer, and these are being validated for clinical use. Antian-

giogenesis agents such as vascular endothelial growth factor

antibodies and thalidomide, nonspecific inhibitors of carci-

nogenesis such as Sandostatin and arsenic, and better means

of delivering radiation such as yttrium microspheres are all

being actively investigated for the treatment of hepatocel-

lular cancer. Expanding the criteria for selecting patients for

liver transplantation, such as the University of California

San Francisco criteria, which include a single tumor lessthan 6.5 cm, 3 or less nodules with the largest being less

than 4.5 cm, and total tumor diameter less than 8 cm,

has shown promising results and may replace the Milan

criteria.73

CONCLUSIONThe incidence of hepatocellular cancer is increasing in the

Western world, including the United States. Although HBV,

HCV, and alcohol use constitute the most important risk

factors for the development of hepatocellular cancer, diabe-

tes and obesity may contribute to increased carcinogenicity.

Primary care physicians taking care of patients with chronic

viral hepatitis and cirrhosis will need to have a heightened

awareness of hepatocellular cancer, because the translation

of bench research into clinical practice will lead to newer

diagnostic tests, better therapeutic options, and improved

survival of these patients. Finally, an important frontier inthe battle against hepatocellular cancer will be the applica-

tion of effective preventive strategies aimed at decreasing

the risk of transmission of HBV and HCV, and the devel-

opment of safe and effective medications for the treatment

of chronic HBV and HCV.

ACKNOWLEDGMENTSWe are indebted to Drs Richard Goodgame, Hashem El-

Serag, and Prashant Kapoor for their critical review of this

article.

References1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer

burden: Globocan 2000. Int J Cancer. 2001;94:153-156.

2. El-Serag HB, Mason AC. Rising incidence of hepatocellular cancer in

the United States. N Engl J Med. 1999;340:745-750.

3. El-Serag HB, Davila JA, Petersen NJ, et al. The continuing increase in

the incidence of Hepatocellular carcinoma in the United States: an

update. Ann Intern Med . 2003;39(10):817-823.

4. Tanaka Y, Hanada K, Mizokami M. A comparison of the molecular

clock of hepatitis C virus in the United States and Japan predicts that

hepatocellular carcinoma incidence will increase in the next two de-

cades. Proc Natl Acad Sci U S A. 2002;99:15584-15589.5. American Cancer Society. Cancer Facts and Figures 2007. Available

at: http://www.cancer.org/downloads. Accessed January 27, 2007.

6. Carr BI, Bartlett D, Marsh JW. Cancers of the Liver. Cancer:

Principles and Practice of Oncology. Edition 7. Philadelphia, PA:

Lippincott; 2004.

7. Tsukuma H, Hiyama T, Tanaka S, et al. Risk factors for hepatocellular

carcinoma among patients with chronic liver disease. N Engl J Med .

1993;328(25):1797-1801.

8. Yeh FS, Yu MC, Mo CC, et al. Hepatitis B virus, aflatoxins, and

hepatocellular carcinoma in southern Guangxi, China. Cancer Res.

1989;49:2506-2509.

9. Kew MC, Yu MC, Kedda MA, et al. The relative roles of hepatitis B

and C viruses in the etiology of hepatocellular carcinoma in southern

African blacks. Gastroenterology. 1997;112:184-187.

10. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular

carcinoma. Gastroenterology. 2004;127:S87-S96.

Table 5 Child-Pugh Score

Chemical and

Biochemical Parameters

Points for Increasing

Abnormality

1 2 3

Encephalopathy (grade) None 1-2 3-4Ascites None Slight ModerateAlbumin (g/dL) Ͼ3.5 2.8-3.5 Ͻ3.5Prothrombin time

prolonged (sec)

1-4 4-6 Ͼ6

Bilirubin (mg/dL) 1-2 2-3 Ͼ3

Class A: 5-6 points (good operative risk); Class B: 7-9 points

(moderate operative risk); Class C: 10-15 points (poor operative risk).

Table 6 United Network for Organ Sharing Criteria for

Cadaveric Liver Transplant for Hepatocellular Cancer with

Underlying Cirrhosis

➢ Patient is not a liver resection candidate➢ Patient has a tumor Ͼ5 cm in diameter or 2 to 3 tumors

each Ͼ3 cm➢ No macrovascular involvement➢ No extrahepatic spread of tumor to surrounding lymph

nodes, lungs, abdominal organs, or bone


7/29/2019 AmJMedHCC


11. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological

studies on the combined effect of hepatitis B and C virus infections in

causing hepatocellular carcinoma. Int J Cancer. 1998;75:347-354.

12. Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with

hereditary hemochromatosis and in their first degree relatives. Gastro-

enterology. 2003;125:1733-1741.

13. Elzouki AN, Eriksson S. Risk of hepatobiliary disease in adults with

severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis

B or C an additional risk factor for cirrhosis and hepatocellular carci-

noma? Eur J Gastroenterol Hepatol. 1996;8:989-994.

14. Kuper H, Tzonou A, Kaklamani E, et al. Tobacco smoking, alcohol

consumption and their interaction in the causation of hepatocellular

carcinoma. Int J Cancer. 2000;85(4):498-502.

15. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of

p53 gene in hepatocellular carcinoma from southern Africa. Nature.

1991;350(6317):429-431.

16. Unsal H, Yakicier C, Marcais C, et al. Genetic heterogeneity of

hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1994;91(2):

822-826.

17. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of

nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocel-

lular carcinoma. Gastroenterology. 2002;123:134-140.

18. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of

chronic liver disease and hepatocellular carcinoma. Gastroenterology.2004;126:460-468.

19. Di Bisceglie AM. Epidemiology and clinical presentation of hepato-

cellular carcinoma. J Vasc Interv Radiol. 2002;13:S169-S171.

20. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepa-

tocellular carcinoma. Conclusions of the Barcelona 2000 EASL Con-

ference. J Hepatol. 2001;35:421-430.

21. Torzilli G, Minagawa M, Takayama T, et al. Accurate preoperative

evaluation of liver mass lesions without fine-needle biopsy. Hepatol-

ogy. 1999;30(4):889-893.

22. Yu JS, Kim KW, Kim EK, et al. Contrast enhancement of small

hepatocellular carcinoma: usefulness of three successive early image

acquisitions during multiphase dynamic MR imaging. Am J Roentge-

nol. 1999;173:597-604.

23. Lim JH, Kim CK, Lee WJ, et al. Detection of hepatocellular carcino-mas and dysplastic nodules in cirrhotic livers: accuracy of helical CT

in transplant patients. Am J Roentgenol. 2000;175:693-698.

24. Kim T, Murakami T, Takahashi S, et al. Optimal phases of dynamic

CT for detecting hepatocellular carcinoma: evaluation of unenhanced

and triple-phase images. Abdom Imaging. 1999;24:473-480.

25. Huang G, Sheu JC, Yang PM, et al. Ultrasound guided cutting biopsy

for the diagnosis of hepatocellular carcinoma—a study based on 420

patients. J Hepatol. 1996;25:334-338.

26. Bru C, Maroto A, Bruix J, et al. Diagnostic accuracy of fine-needle

aspiration biopsy in patients with hepatocellular carcinoma. Dig Dis

Sci. 1989;34:1765-1769.

27. Nakashima T, Kojiro M. Hepatocellular Carcinoma. Tokyo: Springer-

Verlag; 1987.

28. Policy 3.6.4.4 on Organ Distribution: Allocation of Livers. Availableat: www.unos.org. Accessed June 27, 2006

29. Durand F, Regimbeau JM, Belghiti J, et al. Assessment of the benefits

and risks of percutaneous biopsy before surgical resection of hepato-

cellular carcinoma. J Hepatol. 2001;35:254-258.

30. Takamori R, Wong LL, Dang C, Wong L. Needle-tract implantation

from hepatocellular cancer: is needle biopsy of the liver always nec-

essary? Liver Transpl. 2000;6:67-72.

31. Smith EH. Complications of percutaneous abdominal fine-needle bi-

opsy. Rev Radiol. 1991;178:253-258.

32. Schotman SN, De Man RA, Stoker J, et al. Subcutaneous seeding of

hepatocellular carcinoma after percutaneous needle biopsy. Gut. 1999;

45:626-627.

33. Yuen MF, Lai CL. Serological markers of liver cancer. Best Pract Res

Clin Gastroenterol. 2005;19(1):91-99.

34. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein

for detecting hepatocellular carcinoma in patients with hepatitis C.

A systematic review and critical analysis. Ann Intern Med. 2003;

139:46-50.

35. Soresi M, Magliarisi C, Campagna P, et al. Usefulness of alpha

fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer

Res. 2003;23:1747-1753.

36. Maringhini A, Cottone M, Sciarrino E, et al. Ultrasonography and

alpha-fetoprotein in diagnosis of hepatocellular carcinoma in cirrhosis.

Dig Dis Sci. 1988;33:47-51.

37. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol.

2004;130(7):417-422.

38. Chen JG, Parkin DM, Chen QG, et al. Screening for liver cancer:

results of a randomised controlled trial in Qidong, China. J Med

Screen. 2003;10(4):204-209.

39. Peterson MS, Baron RL. Radiologic diagnosis of hepatocellular car-

cinoma. Clin Liver Dis. 2001;5:123-144.

40. Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonog-

raphy as a screening test for primary liver cancer. J Med Screen.

1999;6:108-110.

41. Kang JY, Lee TP, Yap I, Lun KC. Analysis of cost-effectiveness of

different strategies for hepatocellular carcinoma screening in hepatitis

B virus carriers. J Gastroenterol Hepatol. 1992;7:463-468.

42. Bruix J, Sherman M. Practice Guidelines Committee, American As-sociation for the Study of Liver Diseases. Management of hepatocel-

lular carcinoma. Hepatology. 2005;42:1208-1236.

43. Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic

nodules. Semin Liver Dis. 2005;25:133-142.

44. Bialecki ES, Di Bisceglie AM. Clinical presentation and natural course

of hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2005;17:

485-489.

45. Ikeda K, Arase Y, Saitoh S, et al. Anticarcinogenic impact of inter-

feron on patients with chronic hepatitis C: a large-scale long-term

study in a single center. Intervirology. 2006;49(1-2):82-90.

46. Omata M, Yoshida H, Shiratori Y. Prevention of hepatocellular car-

cinoma and its recurrence in chronic hepatitis C patients by interferon

therapy. Clin Gastroenterol Hepatol. 2005;3(10 Suppl 2):S141-3.

47. Okuda K. Natural history of hepatocellular carcinoma including

fibrolamellar and hepato-cholangiocarcinoma variants. J Gastroen-

terol Hepatol. 2002;17:401-405.

48. Llovet J, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the

BCLC staging classification. Semin Liver Dis. 1999;19(3):329-338.

49. Belghiti J, Hiramatsu K, Benoist S. Seven hundred forty seven hepa-

tectomies in the 1990s: an update to evaluate the actual risk of liver

resection. J Am Coll Surg. 2000;191:38-46.

50. Bralet MP, Regimbeau JM, Pineau P, et al. Hepatocellular carcinoma

occurring in nonfibrotic liver: epidemiologic and histopathologic anal-

ysis of 80 French cases. Hepatology. 2000;32:200-204.

51. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing

to early and late intrahepatic recurrence of hepatocellular carcinoma

after hepatectomy. J Hepatol. 2003;38:200-207.

52. Ono T, Nagasue N, Kohno H, et al. Adjuvant chemotherapy with

epirubicin and carmofur after radical resection of hepatocellular

carcinoma: a prospective randomized study. Semin Oncol. 1997;

24(suppl 6):S6-18.

53. Yamamoto M, Arii S, Sughara K, et al. Adjuvant oral chemotherapy

after curative resection of hepatocellular carcinoma. Br J Surg. 1996;

83:336-340.

54. Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine-131-

labelled lipiodol for resectable hepatocellular carcinoma: a prospective

randomized trial. Lancet. 1999;353:797-801.

55. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy

to lower postsurgical recurrence rates of hepatocellular carcinoma: a

randomized trial. Lancet. 2000;356:802-807.

56. Kubo S, Nishiguchi S, Hirohashi K, et al. Effects of long term post-

operative interferon-alpha therapy on intrahepatic recurrence after re-

section of hepatitis C virus-related hepatocellular carcinoma. Ann

Intern Med . 2001;134:963-967.


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57. Lin SM, Lin CJ, Hsu CW, et al. Prospective randomized controlled

study of interferon-alpha in preventing hepatocellular carcinoma re-

currence after medical ablation therapy for primary tumors. Cancer.

2004;100:376-382.

58. Bismuth H, Chiche L, Adam R, et al. Liver resection versus transplan-

tation for hepatocellular carcinoma in cirrhosis. Ann Surg. 1993;218:

145-151.

59. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the

treatment of small hepatocellular carcinomas in patients with cirrhosis.

N Engl J Med. 1996;334:693-699.

60. Regalia E, Coppa J, Pulvirenti A, et al. Liver transplantation for small

hepatocellular carcinoma in cirrhosis: analysis of our experience.

Transplant Proc. 2001;33:1442-1444.

61. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical

treatment for early hepatocellular carcinoma: resection versus trans-

plantation. Hepatology. 1999;30:1434-1440.

62. Lu DS, Yu NC, Raman SS, et al. Percutaneous radiofrequency ablation

of hepatocellular carcinoma as a bridge to liver transplantation. Hepa-

tology. 2005;41:1130-1137.

63. Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoemboli-

zation followed by liver transplantation for hepatocellular carcinoma

impedes tumor progression while on the waiting list and leads to

excellent outcome. Liver Transpl. 2003;9:557-563.

64. Gondolesi GE, Roayaie S, Munoz L, et al. Adult living donor livertransplantation for patients with hepatocellular carcinoma: extending

UNOS priority criteria. Ann Surg. 2004;239:142-149.

65. Hasegawa S, Yamasaki N, Hiwaki T, et al. Factors that predict

intrahepatic recurrence of hepatocellular carcinoma in 81 patients

initially treated by percutaneous ethanol injection. Cancer . 1999;

86:1682-1690.

66. Shiina S, Tagawa K, Niwa Y, et al. Percutaneous ethanol injection

therapy for hepatocellular carcinoma: results in 146 patients. Am J

Roentgenol. 1993;160:1023-1028.

67. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carci-

noma in cirrhosis: randomized comparison of radiofrequency thermal

ablation versus percutaneous ethanol injection. Radiology. 2003;228:

235-240.

68. Lin SM, Lin CJ, Lin CC, et al. Radiofrequency ablation improves

prognosis compared with ethanol injection for hepatocellular carci-

noma Ͻ or equal to 4 cm. Gastroenterology. 2004;127:1714-1723.

69. Llovet JM, Bruix J. Systematic review of randomized trials for unre-

sectable hepatocellular carcinoma: chemoembolization improves sur-

vival. Hepatology. 2003;37:429-442.

70. Veltri A, Moretto P, Doriguzzi A, et al. Radiofrequency thermal

ablation after transarterial chemoembolization as a combined therapy

for unresectable non-early hepatocellular carcinoma. Eur Radiol.

2006;16(3):661-669.

71. Burroughs A, Hochhauser D, Meyer T. Systemic treatment and liver

transplantation for hepatocellular carcinoma: two ends of the thera-

peutic spectrum. Lancet Oncol. 2004;5:409-418.

72. Mathurin P, Rixe O, Carbonell N, et al. Review article: overview of

medical treatments in unresectable hepatocellular carcinoma—an im-possible meta-analysis? Aliment Pharmacol Ther. 1998;12:111-126.

73. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepato-

cellular carcinoma: expansion of the tumor size limits does not ad-

versely impact survival. Hepatology. 2001;33:1394-1403.


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