Download Hepatocellular Cancer: A Guide for the Internist

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 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 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 confirm 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 identified 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: [email protected]
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2006.11.020
A large, retrospective cohort study confirmed 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
Parikh and Hyman
Hepatocellular Cancer
195
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 findings 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 reflect 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 deficiency,13 and autoim● Liver transplantation remains the only deheard, consistent with hypervascumune hepatitis. An increased incilarity of the tumor.
dence has been associated with
finitive treatment of hepatocellular cansmoking14 and exposure to aflacer, 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
20
nostic
approaches
(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 specificity of 98.8%.21-24 In cases of indeterminate
Table 1 Major Causes of Hepatocellular Cancer
radiologic findings, fine-needle aspiration biopsy is
Infections:
recommended.25,26
Chronic hepatitis C
Chronic hepatitis B
Chronic hepatitis D
Toxins:
Alcohol
Aflatoxin
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
sufficient 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
196
The American Journal of Medicine, Vol 120, No 3, March 2007
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 ⬍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
AFP ⫽ alpha-fetoprotein; US ⫽ ultrasound; CT ⫽ computed tomography; MRI ⫽ magnetic resonance imaging.
(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 Biopsy
The role of liver biopsy has been the subject of great
controversy. For almost all other types of cancer, histopathologic confirmation 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 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 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.
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 specificity of these
markers to diagnose hepatocellular cancer vary according to
the threshold level used. Total alpha-fetoprotein has a sensitivity of 60% and specificity of 90% at cutoff values
between 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 (⬎10%) is specific for small hepatocellular cancer. Protein induced by vitamin K antagonist-II is also more specific 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 definite 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 significant 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 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 falsepositive rates.40,41
The United States Preventive Services Task Force, National Comprehensive Cancer Network, and American Cancer Society do not have any specific guidelines for screening
patients for hepatocellular cancer. The National Cancer Institute 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
Parikh and Hyman
Table 3
Cancer
Hepatocellular Cancer
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 deficiency, autoimmune hepatitis, and Wilson’s 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-
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
Figure 1 Surveillance of hepatocellular cancer in patients with cirrhosis of the liver. HCC ⫽ hepatocellular cancer; AFP ⫽
alpha-fetoprotein.
198
Table 4
The American Journal of Medicine, Vol 120, No 3, March 2007
Barcelona Clinic Liver Cancer Staging Classification47
Stage
Performance Status Test*
Tumor Stage
Okuda Stage†
Liver Function Status
A
B
C
D
0
0
1-2
3-4
Single
Large multinodular
Vascular invasion, extrahepatic spread
Any
I-II
I-II
I-II
III
Child
Child
Child
Child
Pugh‡
Pugh‡
Pugh‡
Pugh‡
A-B
A-B
A-B
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 ⬍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 Classification, 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 classification, 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 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 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 sufficient 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 benefit.52,53 Various other adjuvant treatment
approaches, including internal radiation with I-131–labeled
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 difficulties 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 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 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
Parikh and Hyman
Hepatocellular Cancer
199
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.
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 infiltrative 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
The American Journal of Medicine, Vol 120, No 3, March 2007
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 significant toxicity without any discernible benefit with regard to survival or complete response.71,72
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, nonspecific 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
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
2
3
None
None
⬎3.5
1-4
1-2
Slight
2.8-3.5
4-6
3-4
Moderate
⬍3.5
⬎6
1-2
2-3
⬎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).
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
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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