The American Journal of Medicine (2007) 120, 194-202

REVIEW

AJM Theme Issue: Gastroenterology

Hepatocellular Cancer: A Guide for the Internist

Sameer 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 transplantation is the only denitive 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 fth most common cause of cancer and the third leading cause of cancer-related deaths worldwide.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 conrm the diagnosis, and formulate an appropriate management plan.

EPIDEMIOLOGY
Hepatocellular 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 identied in Western countries.
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

A large, retrospective cohort study conrmed an almost 2-fold increase in the incidence of hepatocellular cancer from 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 According 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 hepatocellular cancer in Europe and the United States is approximately 60 years.7 This is in contrast with patients in Asia and Africa, where it is between 20 and 50 years.

CAUSE
The major clinical risk factor for the development of hepatocellular cancer is cirrhosis of the liver. Chronic infections with hepatitis B virus (HBV) and HCV and chronic heavy alcohol use are the most important risk factors for the

0002-9343/$ -see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.11.020

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development of cirrhosis. HBV accounts for the majority of weight loss. However, more and more hepatocellular canhepatocellular cancer in China and Africa, where most of cers are now detected at an asymptomatic stage because of the infection is acquired early in life either from mother to the growing awareness of these tumors in patients with the offspring or by horizontal transmission.8,9 In contrast, chronic liver disease and cirrhosis.19 Other clinical presenHCV accounts for most of the cases in the Western hemitations, such as spontaneous rupture of the tumor into sphere. Chronic alcohol use of the peritoneal cavity, obstructive greater than 80 g per day for more jaundice, and bony pain from methan 10 years increases the risk tastasis, are extremely uncommon. CLINICAL SIGNIFICANCE of hepatocellular cancer 5-fold.10 Various paraneoplastic syndromes Furthermore, chronic alcohol use have been associated with hepato In the US, the incidence of hepatocelluin HBV or HCV infection doubles cellular cancer. These include erythlar cancer doubled between 1975 and the risk of hepatocellular cancer rocytosis (erythropoietin), hypogly1998 and is expected to continue to inover either infection alone.11 cemia (insulin-like growth factor), crease for the next 2 decades. The magnitude of risk and hypercalcemia (parathyroid-reof hepatocellular cancer from cirlated protein). Physical ndings in The American Association for the Study rhosis due to other causes is not patients with hepatocellular cancer of Liver Diseases recommends an ultrawell known. There have been regenerally reect the severity of the sound of the liver every 6 months in ports in patients with hereditary underlying chronic liver disease and high-risk patients to screen for hepatohemochromatosis,12 alpha-1 anticirrhosis. The liver may be enlarged cellular cancer. and a vascular bruit is sometimes trypsin deciency,13 and autoim Liver transplantation remains the only deheard, consistent with hypervascumune hepatitis. An increased incilarity of the tumor. dence has been associated with nitive treatment of hepatocellular cansmoking14 and exposure to aacer, although surgical resection and pertoxin, a mycotoxin that contamicutaneous therapies are more commonly DIAGNOSIS nates peanuts and soybeans, and applied in routine clinical practice. A consensus statement from the causes mutations in the p53 tumor European Association for the 15,16 suppressor gene. ApproxiStudy of Liver Diseases (EASL) mately one quarter of all cases dihas been formulated to help clinicians standardize diagagnosed in the United States do not have any of these risk nostic approaches20 (Table 2). factors. There is growing interest in the role of insulin resistance syndrome as a risk factor for these cryptogenic Lesions Greater Than 2 Centimeters cases. Insulin resistance syndrome is present in virtually all in Diameter cases of nonalcoholic fatty liver disease; this condition is In nodules greater than 2 cm diameter in size, a diagnosis of thought to predispose to nonalcoholic steatohepatitis and hepatocellular cancer can be made if any 2 imaging studies cirrhosis in 10% to 20% of cases.17 Diabetes and obesity, 2 (including ultrasonography, computed tomography, magmajor manifestations of insulin resistance syndrome, have netic resonance imaging, or hepatic arteriography) show been shown to double the risk of hepatocellular cancer18 increased vascularity. Alternatively, only 1 imaging study (Table 1). with an alpha-fetoprotein level greater than 400 ng/mL is diagnostic. Our ability to diagnose these tumors noninCLINICAL FEATURES vasively rests on the premise that they are seen on a The typical clinical manifestations of hepatocellular cancer background of cirrhosis and enhance with contrast on are right upper quadrant abdominal pain, early satiety, and rapid-sequence imaging secondary to their neovascularity. These radiologic criteria for diagnosis have excellent diagnostic accuracy with reported sensitivity of 100% and specicity of 98.8%.21-24 In cases of indeterminate Table 1 Major Causes of Hepatocellular Cancer radiologic ndings, ne-needle aspiration biopsy is Infections: recommended.25,26
Chronic hepatitis C Chronic hepatitis B Chronic hepatitis D Toxins: Alcohol Aatoxin Metabolism: Diabetes mellitus, nonalcoholic fatty liver disease Hereditary hemochromatosis Primary biliary cirrhosis, autoimmune hepatitis

Lesions Less Than 2 Centimeters in Diameter

Imaging techniques for lesions less than 2 cm do not have sufcient accuracy in distinguishing hepatocellular cancer from other conditions. Alpha-fetoprotein levels may be normal or only slightly elevated and thus provide no diagnostic utility. Hepatic lesions less than 1 cm in size have a less than 50% chance of being malignant,27 and serial ultrasound

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Table 2 Diagnostic Criteria for Hepatocellular Cancer

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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 identies 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 200 ng/mL an arteriogram conrming a tumor a biopsy conrming hepatocellular cancer, prior chemoembolization of lesion, radiofrequency, cryoablation, or chemical ablation of the lesion
AFP alpha-fetoprotein; US ultrasound; CT computed tomography; MRI magnetic resonance imaging.

(every 3 months) is recommended. On the other hand, ne-needle aspiration biopsy should be performed in lesions between 1 and 2 cm in size.

Role of Liver Biopsy

The role of liver biopsy has been the subject of great controversy. For almost all other types of cancer, histopathologic conrmation is necessary to make a diagnosis. However, as elucidated in Table 2, both the EASL and United Network for Organ Sharing criteria28 do not require a biopsy for the diagnosis of hepatocellular cancer 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 denite 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 However, 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 falsenegative rate from biopsy of lesions less than 2 cm is approximately 30% to 40%.29 Thus, a negative biopsy does not conclusively rule out the diagnosis of hepatocellular cancer.

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 ( 10%) is specic for small hepatocellular cancer. Protein induced by vitamin K antagonist-II is also more specic than total alpha-fetoprotein in detecting hepatocellular cancer. However, these are not available in most nonresearch laboratories in the United States at this time.

SCREENING
Although there is no denite evidence that screening in hepatocellular cancer improves survival, many physicians screen patients in high-risk groups with either serum alphafetoprotein or ultrasound of the liver or both. Two recent randomized controlled trials completed in China demonstrated a signicant reduction in hepatocellular cancer-related mortality in patients who underwent screening.37,38 Ultrasound of the liver is the preferred screening test because it has a sensitivity of 84% and specicity 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 falsepositive rates.40,41 The United States Preventive Services Task Force, National Comprehensive Cancer Network, and American Cancer Society do not have any specic guidelines for screening patients for hepatocellular cancer. The National Cancer Institute recommends against routine screening for lack of a survival benet. The American Association for the Study of Liver Diseases and EASL recommend ultrasound of the

Role of Serum Markers

The 3 most commonly used serum markers are alpha-fetoprotein, Lens culinaris agglutinin-reactive alpha-fetoprotein (alpha-fetoprotein-L3), and protein induced by vitamin K antagonist-II.33 The sensitivity and specicity of these markers to diagnose hepatocellular cancer vary according to the threshold level used. Total alpha-fetoprotein has a sensitivity of 60% and specicity of 90% at cutoff values between 10 and 20 ng/mL. A systematic review conrmed

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Table 3 Cancer

Hepatocellular Cancer

197 malignant nodular lesions to cancerous lesions in the cirrhotic liver.43 Progression takes an average of approximately 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 absence 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 monotherapy in patients with cirrhosis decreases the risk of hepatocellular cancer, and it is expected that combination therapy with pegylated interferon and ribavirin may reduce this risk even further.45,46 Predicting survival in hepatocellular cancer is complicated by the fact that 2 disease processes, namely, the tumor and underlying cirrhosis, are present simultaneously. Numerous studies have shown that prognosis is directly proportional 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

High-Risk Groups for Screening of Hepatocellular

Cirrhosis: Hepatitis B Hepatitis C Alcoholic cirrhosis Hereditary hemochromatosis Primary biliary cirrhosis Nonalcoholic steatohepatitis Patients waiting on the liver transplant list
No cirrhosis: Chronic hepatitis B carriers: males aged 40 y and females aged 50 y, family history of hepatocellular cancer in a patient with chronic hepatitis B. Screening for patients with cirrhosis secondary to alpha-1 antitrypsin deciency, autoimmune hepatitis, and Wilsons disease is considered low-moderate risk, and there are no recommendations for screening at this time.

liver every 6 months for high-risk patients42 (Table 3 and Figure 1).

NATURAL HISTORY AND PROGNOSIS

Prospective studies have shown that most hepatocellular cancers develop through a progressive pathway from pre-

Figure 1 Surveillance of hepatocellular cancer in patients with cirrhosis of the liver. HCC alpha-fetoprotein.

hepatocellular cancer; AFP

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Table 4 Stage A B C D Barcelona Clinic Liver Cancer Staging Classication47 Performance Status Test* 0 0 1-2 3-4 Tumor Stage

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Okuda Stage I-II I-II I-II III

Liver Function Status Child Child Child Child Pugh Pugh Pugh Pugh A-B A-B A-B C

Single Large multinodular Vascular invasion, extrahepatic spread Any

For Stages A and B: All criteria should be fullled. For Stages C and D: At least 1 criterion must be fullled. *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 50% of the day, 3: symptomatic and in bed 50% 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 Classication, see Table 5.

(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 classication, has severe limitations because it does not include the severity of underlying cirrhosis. Therefore, other staging systems such as the Barcelona Clinic Liver Cancer staging classication48 (Table 4) and Cancer of Liver Italian Score have been developed.

MANAGEMENT
The denitive treatment of hepatocellular cancer is liver transplantation; this cures both the cancer and the underlying cancer-prone cirrhotic liver (Figure 2).

Surgical Therapy
Resection. Resection of the tumor is the treatment of choice for hepatocellular cancer.49,50 Before using resection, it is necessary to demonstrate sufcient liver reserve by calculating the Child-Pugh Score (Table 5). Generally, patients with Child-Pugh class A can safely undergo resection. However, not all patients with class A have homogenous liver function, and therefore, presence of portal hypertension is assessed to determine feasibility of resection. With these criteria, a 5-year survival of approximately 60% to 70% can be achieved. However, tumor recurrence complicates approximately 70% of patients at 5 years.51 Adjuvant chemotherapy and chemoembolization have not been shown to be of any added benet.52,53 Various other adjuvant treatment approaches, including internal radiation with I-131labeled lipiodol,54 adoptive immunotherapy with activated lymphocytes,55 and interferon,56,57 have shown promising results but need further validation. Liver Transplantation. The indications for liver transplantation as the primary method of treatment continue to evolve. In the 1980s, poor patient selection led to dismal

outcomes with 5-year survival of less than 40%.58 A landmark clinical trial in 1996 established the so-called Milan Criteria for selecting ideal candidates for liver transplantation. The investigators included patients with a single lesion less than 5 cm in size or 3 lesions each less than 3 cm in size. Their 5-year survival exceeded 70%, and the recurrence 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 transplantation 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 for End-Stage Liver Disease score and thus, get a priority for transplant over those with similar degrees of liver dysfunction, 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 appearance of contraindications, with survival decreasing to less than 50% using an intention-to-treat principle.61 Given the difculties in obtaining a cadaveric liver in a timely fashion, bridging therapies such as surgical resection, neoadjuvant local ablation, and chemoembolization have been tried with promising results.62,63 Living-donor liver transplantation is being increasingly performed in the United States with results comparable to those undergoing cadaveric transplantation.64

Nonsurgical Therapy
The majority of hepatocellular cancers identied 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 chemical (ethanol, acetic acid) and thermal (radiofrequency, cryoablation) techniques. Ablation is commonly used with curative intent in patients with unresectable tumors, with survival similar to resection. Percutaneous ethanol injection

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Figure 2 A simplied approach to the management of newly diagnosed hepatocellular cancer. aResectable lesions evaluate for liver transplantation: Surgical resection and liver transplantation compete as rst-line therapy for patients with small single tumors and preserved liver function. bUNOS criteria: See Table 6. cBridging therapy constitutes surgical resection, RFA, or TACE before liver transplantation. PEI percutaneous ethanol injection; RFA radiofrequency ablation; TACE transcatheter arterial chemoembolization; UNOS United Network for Organ Sharing.

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 limitation of local ablation is its inability to achieve meaningful response rates in inltrative lesions and in tumors larger than 4 to 5 cm in size. Transarterial Therapy. Transarterial interventions are available 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 techniques 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 cirrhosis and good functional status, arterial embolization improved 2-year survivals.69 Postembolization syndrome, associated with abdominal pain and fever, can sometimes occur and precipitate ascites and hepatic encephalopathy.

200 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 transcatheter 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 established in a larger number of patients. Systemic Treatment. Numerous systemic therapies, including doxorubicin, tamoxifen, megestrol, interferon alpha, and anti-androgens, have been tried and compared in randomized trials. The use of most of these agents is associated with signicant toxicity without any discernible benet with regard to survival or complete response.71,72

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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 5 cm in diameter or 2 to 3 tumors each 3 cm No macrovascular involvement No extrahepatic spread of tumor to surrounding lymph nodes, lungs, abdominal organs, or bone

FUTURE TRENDS
Proteomics has led to the discovery of new molecular markers, such as des-gamma carboxyprothrombin and human hepatocyte growth factor, for screening hepatocellular cancer, and these are being validated for clinical use. Antiangiogenesis agents such as vascular endothelial growth factor antibodies and thalidomide, nonspecic inhibitors of carcinogenesis such as Sandostatin and arsenic, and better means of delivering radiation such as yttrium microspheres are all being actively investigated for the treatment of hepatocellular cancer. Expanding the criteria for selecting patients for liver transplantation, such as the University of California San Francisco criteria, which include a single tumor less than 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

factors for the development of hepatocellular cancer, diabetes 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 in the battle against hepatocellular cancer will be the application of effective preventive strategies aimed at decreasing the risk of transmission of HBV and HCV, and the development of safe and effective medications for the treatment of chronic HBV and HCV.

ACKNOWLEDGMENTS
We are indebted to Drs Richard Goodgame, Hashem ElSerag, and Prashant Kapoor for their critical review of this article.

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CONCLUSION
The 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

Table 5

Child-Pugh Score Points for Increasing Abnormality

Chemical and Biochemical Parameters Encephalopathy (grade) Ascites Albumin (g/dL) Prothrombin time prolonged (sec) Bilirubin (mg/dL)

1 None None 3.5 1-4 1-2

2 1-2 Slight 2.8-3.5 4-6 2-3

3 3-4 Moderate 3.5 6 3

Class A: 5-6 points (good operative risk); Class B: 7-9 points (moderate operative risk); Class C: 10-15 points (poor operative risk).

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