Increasing Incidence and Pretransplantation Screening
of Hepatocellular Carcinoma
Gregory T. Everson
Key Points
1. The incidence of hepatocellular cancer (HCC) in the
United States and other traditionally “low-incidence”
countries is increasing.
2. The rise in incidence of HCC is related to chronic
hepatitis C.
3. Timely performance of liver transplantation is curative
in patients with early-stage HCC.
4. Cirrhotic patients, especially those with viral hepatitis,
should be screened for HCC.
5. The performance characteristics of current tests are
suboptimal, but serial ultrasonography and alphafetapro-
tein are recommended.
6. Estimated medical charges related to screening and
treatment suggest the $285,294 is required per “cured”
case. Assuming that this cure is associated with a 75% to
85% chance for high-quality 10-year survival, the charges
approximate $35,000 to $40,000/quality-adjusted life-
year (QALY). This cost-benefit analysis is nearly identical
to published rates for breast cancer screening ($30,000/
QALY). (Liver Transpl 2000;6:S2-S10.)
H epatocellular carcinoma (HCC) complicating
chronic viral hepatitis is emerging as an increas-
ingly important and difficult problem for liver trans-
plant programs. In the United States, there were
120,000 to 180,000 new cases of hepatitis C each year
in the 1970s and 1980s. Because it takes more than 10
years to develop cirrhosis and more than 20 years to
develop HCC, we are just now beginning to experience
the clinical and social impact of the previous incident
wave of cases. In the year 2000, there will be an esti-
mated 8,000 to 10,000 deaths in the United States from
liver disease caused by hepatitis C. This mortality rate is
expected to double or triple by the year 2015. One
cause of the projected excess mortality in these patients
is HCC.
Increasing numbers of patients are presenting for
transplantation with cirrhosis and HCC, and increasing
From the University of Colorado School of Medicine, Denver, CO.
Address correspondence to Gregory T. Everson, MD, FACP, Professor
of Medicine, Director of Hepatology, Medical Director of Liver Trans-
plantation, University of Colorado School of Medicine, 4200 East Ninth
Ave, B-154, Denver, CO 80262. Telephone: 303-372-8862; FAX:
303-372-8868; E-mail: greg.everson@uchsc.edu
Copyright © 2000 by the American Association for the Study of
Liver Diseases
1527-6465/00/0606-2014$3.00/0
doi:10.1053/jlts.2000.19182
S2 Liver Transplantation, Vol 6, No 6, Suppl 2 (November), 2000: pp S2-S10
numbers of patients are developing HCC while on the
waiting list for transplantation. The major risk factor
for HCC is cirrhosis caused by chronic viral hepatitis
from both hepatitis B virus (HBV) and hepatitis C virus
(HCV). In the United States, chronic hepatitis C is now
the most common diagnosis in patients listed for ortho-
topic liver transplantation (OLT). Time on the waiting
list before OLT is increasing for newly listed patients
because of the mismatch in donor liver supply and
recipient need. The risk for development of HCC in
patients with cirrhosis with chronic viral hepatitis
ranges from 0.8% to 5.8% per year. Currently listed
patients may wait years before undergoing OLT. For
example, at an incident rate of 5% per year, a person
would have a cumulative risk for developing HCC of
14.3% at 3 years and 22.8% at 5 years. Clearly, patients
with cirrhosis with chronic hepatitis C on waiting lists
represent an emerging and well-defined population at
great risk for HCC.
The purpose of this report is to present information
on the increasing incidence of HCC and to identify
subgroups of patients at high risk for HCC for consid-
eration of screening. A screening algorithm for the early
detection of HCC for patients on transplant waiting
lists is suggested.
Is the Incidence of HCC Increasing?
The United States is considered a low-incidence coun-
try for HCC. However, there is concern that HCC may
become a significant problem in the near future because
of the large number of cases of hepatitis C that occurred
in the 1970s and 1980s: approximately 120,000 to
180,000 per year. Current estimates suggest that it takes
20 to 30 years to develop HCC from chronic hepatitis
C, with nearly all cases occurring in the setting of cir-
rhosis. Given the slow progression of chronic hepatitis
C, liver disease programs in the United States are just
now beginning to see the emergence of HCC as a sig-
nificant clinical issue.
El-Serag and Mason1 studied the incidence of histo-
logically proven HCC in the United States between
1976 and 1995. The incidence of HCC was deter-
mined from 9 cancer registries that comprise the Sur-
veillance, Epidemiology, and End Results Program of
the National Cancer Institute, representing 14% of the

Increasing Incidence and Screening for HCC
Figure 1. The annual case rate of number of HCCs for the
state of Colorado (䊐) and the number evaluated and man-
aged at the UCHSC (‚). The incidence increased slowly
from 1988 to 1996 and dramatically from 1996 through
1998.
US population. Mortality statistics were determined
from the National Center for Health Statistics as part of
the US vital statistics database. Rates of hospitalization
for primary liver cancer were determined from the Pa-
tient Treatment File, a computerized database of the
Department of Veteran’s Affairs. The incidence of
HCC increased from 1.4 in 1976 to 1980 to 2.4 per
100,000 population in 1990 to 1995. During these
same periods, mortality from primary liver cancer in-
creased by 41%, and hospitalizations for liver cancer
increased by 46%. The incidence of HCC increased in
younger persons from 1991 to 1995 compared with
earlier years. The increase in HCC incidence and shift
to younger persons is consistent with the expected effect
of the epidemic of hepatitis C in the 1970s and 1980s.
Similar progressive increases in HCC incidence have
been noted in Japan,2 the United Kingdom,3 and
France.4 Thus, developed countries with a traditionally
low to intermediate incidence and prevalence of HCC
are now facing an increasing number of HCC cases.
This phenomenon has major implications for liver cen-
ters, transplant programs, and health care systems.
To begin to define the potential impact of HCC on
a single transplant center, we examined the annual case
rate of HCC in our state of Colorado, with a population
of approximately 4 million persons, during 1988 to
1998 (Fig. 1). We chose 1988 as the start date of our
analysis because that was the beginning of our current
liver transplant program. Data were collected from 2
sources, the Tumor Registry of the State of Colorado
and the Tumor Board of the University of Colorado
Health Sciences Center (UCHSC), our center’s tumor
registry.
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S3
The annual case rate for the state at the beginning of
this interval was 40 to 45 cases of HCC per year, and at
the end, 85 to 90 cases per year. The increase in number
of new cases was nonlinear and most dramatic for 1997
and 1998. During these same intervals, the number of
cases of HCC evaluated and treated in our center in-
creased approximately 4-fold, from 6 to 24 cases per
year. Certain characteristics of state and UCHSC pa-
tients were similar and reflective of US cases in general;
male-female ratios were 2.6:1 and 2.7:1; white patients,
68% and 67%; and patients with local tumor, 34% and
33%, respectively. However, UCHSC patients were
significantly younger, with 50% of the patients aged 40
to 60 years compared with the state, in which 50% of
the patients were aged older than 60 years. Approxi-
mately 75% of the UCHSC patients were HCV posi-
tive. Thus, the relatively greater increase in cases of
HCC at UCHSC was because of younger patients with
HCV referred for management and consideration of
transplantation. Thirty-eight percent of the transplan-
tations performed at UCHSC between 1995 and 1998
were in patients with HCV, and approximately half our
new listings were HCV-positive patients. Twenty-one
percent of HCV patients had associated HCC com-
pared with a prevalence of 5% in non-HCV patients.
Projecting these data into the near future, we anticipate
that by the year 2010, the number of patients poten-
tially suitable for transplantation with HCV-related,
locally confined HCC referred to our program and with
HCC developing on the waiting list will exceed the
cadaveric supply of donor livers. This emerging prob-
lem was a major stimulus for our center to move for-
ward with living donor liver transplantation (LDLT).
Who Is at Risk for HCC?
The 2 major and interrelated risk factors for HCC are
viral hepatitis, both hepatitis B and C, and cirrhosis.
Worldwide, the estimated incidence of HCC is
530,000 cases per year.5 HCC is responsible for approx-
imately 250,000 deaths worldwide each year, and its
global distribution correlates with geographic preva-
lence of HBV. There are 400 million carriers of HBV
worldwide, with the greatest prevalence in Southeast
Asia and Sub-Saharan Africa, where 10% to 25% of the
population is seropositive for HBV. Most cases are ac-
quired at birth through maternal-fetal transmission.
The United States is a low-prevalence country, with
only 0.5% seropositivity.6-8 Most US cases are acquired
in adult life through exposure to infected blood or body
fluids.
In Asia, HCC is strongly associated with hepatitis B
surface antigen (HBsAg) positivity; the risk for HCC is

S4 Gregory T. Everson
more than 200 times greater in HBsAg-positive patients
compared with HBsAg-negative patients.9,10 The risk
for HCC begins to increase after 20 to 30 years of
infection. The lifetime risk for developing HCC in
patients who acquired HCC by vertical transmission is
estimated at 50% for men and 20% for women. These
tumors have a particularly poor prognosis, with a 5-year
survival rate less than 5%.
HCC from HBV is a preventable disease. Wide-
spread use of HBV vaccination in Taiwan reduced the
rate of chronic HBV 10-fold and markedly reduced the
risk for HCC.11
Although the link of HBV to HCC was established
in the 1970s, the link of HCC to HCV was only appre-
ciated in recent years. HCV increases the risk for devel-
oping HCC approximately 100-fold. It is currently es-
timated that HCV is responsible for 70% of the cases of
HCC in Japan, 50% or more of the cases of HCC in the
United States, and more than 50% of the cases of HCC
in Europe. A recent series from Spain12 indicated that
77% of HCCs diagnosed in the setting of cirrhosis was
associated with HCV. Our own experience in Colorado
reflects this trend. Studies from Italy13 and Asia14 sug-
gest that patients with chronic viral hepatitis and cir-
rhosis may have an annual HCC incidence of 3% to
4%. Progression of liver disease and risk for developing
HCC may be accelerated by excessive alcohol intake.15
Cirrhosis is an independent risk factor for HCC.
Reviews of HCC indicate that approximately 90% of
the cases occur in the setting of cirrhosis. A recent
retrospective survey of 435 unselected patients with
HCC diagnosed between 1990 and 1992 from 16 Ital-
ian institutions indicated that 96% had cirrhosis.16 A
number of clinical, biochemical, histological, and im-
aging criteria correlate with poor survival: increasing
Child-Pugh score, poorly differentiated histological
characteristics, degree of elevation of alphafetaprotein
(AFP) level (⬎400 ng/mL), extrahepatic tumor spread,
poor functional status, and presence of portal vein
thrombosis. The first step in defining an effective
screening strategy is to focus on HCC in patients with
cirrhosis.
Other major causes of cirrhosis associated with a
high risk for HCC include hemochromatosis and alco-
holic liver disease, especially in HCV-positive persons.
Screening should be considered for these high-risk
groups. Less common associations include alpha1-anti-
trypsin deficiency, autoimmune hepatitis, primary bil-
iary cirrhosis, and glycogen storage disease. Screening is
not likely to be as effective in these lower-risk popula-
tions.
Other features that increase the risk for HCC in-
clude male sex and increasing age. In countries endemic
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for HBV, there is an age-related bimodal distribution of
cases, with 1 peak at the age of 45 years, presumably
because of the acquisition of viral hepatitis at an early
age, and another around the age of 65 years, presumably
caused by the combined effects of viral hepatitis, cirrho-
sis, and other cofactors, such as alcohol use.
What Is the Natural History of HCC?
Untreated HCC carries a grim prognosis. Length of
survival is directly related to tumor stage at the time of
diagnosis and degree of hepatic dysfunction caused by
cirrhosis. Patients with Child’s class C cirrhosis with
large tumor burden rarely survive beyond 6 months.
Patients with relatively preserved hepatic function and
small HCCs (⬍5 cm in diameter) have the best prog-
nosis. Even so, untreated HCC progresses; ultimately
all patients die of either tumor extension or liver failure.
Barbara et al17 examined patient survival (n ⫽ 39) and
growth rates of small HCCs (⬍5 cm in diameter; n ⫽
59) that developed in the setting of cirrhosis. Survival
rates by the Kaplan-Meier method were 81% at 1 year,
56% at 2 years, and only 21% at 3 years. The main
predictor of survival was severity of underlying liver
disease; the survival rate for patients with Child’s class A
disease was 82% at 2 years compared with only 36% for
those with Child’s classes B and C. No patient with
Child’s class B or C disease at the time of HCC diag-
nosis survived to 3 years. Previous studies suggested that
the 2-year survival rate of patients with cirrhosis with
HCCs less than 3 cm was only 56%,18 and that the
2-year survival rate of patients with Child’s class A
cirrhosis with HCC (not adjusted for tumor size) was
only 44%.19
Is Treatment for HCC Effective?
Transplantation and surgical resection are the only
treatments considered curative if applied to patients
with early-stage HCC and relatively preserved hepatic
function. However, resection is frequently followed by
high rates of recurrent HCC, even in these highly se-
lected cases.
One early series from Japan compared the outcome
of resection with transarterial chemoembolization
(TACE), transarterial chemotherapy without emboliza-
tion, and no treatment in 100 patients with cirrhosis
with solitary hepatomas less than 5 cm.20 Survival rates
at 3 years were 46%, 46%, 12%, and 0%, respectively.
Survival rates at 4 years were 28%, 45%, 0%, and 0%,
respectively. Although the numbers of patients in each
group were small, surgical resection or TACE was fa-

Increasing Incidence and Screening for HCC
vored over either intra-arterial chemotherapy or no
treatment.
Today, resection is reserved for patients without cir-
rhosis or patients with cirrhosis with a solitary or lim-
ited (segmental or lobar) hepatoma and preserved he-
patic function (Child’s class A). Bruix et al21 found that
resection restricted to patients with Child’s class A dis-
ease carries a greater than 50% likelihood of hepatic
decompensation within 3 months of resection. In a
review of the existing literature, Bruix et al22 found that
the 5-year survival rate of highly selected patients with
Child’s class A disease approximates 50%. However,
disease recurrence after 5 years is greater than 50%. One
series from Japan with follow-up beyond 10 years
showed that nearly all patients who underwent resec-
tion, including those with very small, “curable” tumors,
had recurrence.23 Recurrence was related to either me-
tastases from the initial primary tumor or new foci
developing in the cirrhotic liver.
OLT offers the promise for cure because both the
tumor and the focus for development of new tumor, the
cirrhotic liver, are removed. Initial series reporting the
results of OLT for HCC included a high percentage of
patients with advanced-stage tumors. Only 9% of the
patients survived disease free for more than 2 years
post-OLT.24 OLT is currently primarily used in pa-
tients with cirrhosis with a solitary tumor with a mean
diameter of 5 cm or less or up to 3 nodules, each with
diameter of 3 cm or less (total diameter ⱕ9 cm).25
Results in this group of patients are excellent, with a
greater than 80% long-term disease-free patient sur-
vival rate.
Although the choice of resection versus OLT re-
mains controversial, most clinicians, surgeons, and in-
vestigators in the field would agree that the optimum
chance for curing HCC in the setting of cirrhosis is the
application of OLT to early-stage lesions.25,26 Two
large series support the recommendation of OLT over
resection for cure in this setting.27,28 Proof for this rec-
ommendation was the finding of an 83% disease-free
survival rate after OLT for solitary tumors less than 5
cm or up to 3 tumors with additive diameters less than
9 cm.25 Although 1-year patient survival rates after re-
section may be similar to those after OLT in this group
of patients, recurrence rates are high (50% to 90% at 5
years) and likely related to understaging before surgery,
incomplete resections, intrahepatic metastases or satel-
lite lesions, or the development of new tumor foci in the
cirrhotic liver. One study observed a 3-year disease-free
survival rate of 83% for patients with cirrhosis with 1 or
2 HCCs less than 3 cm with OLT, but only 18% with
resection.28 The chance for cure with OLT diminishes
with increasing size of tumor (⬎5 cm in diameter),
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S5
increasing number of tumors, bilobar involvement, and
vascular invasion.29 Despite these guidelines, precise
predictability of outcome in a given patient is not pos-
sible because of the differing biological behaviors of
individual HCCs and the inability of current imaging
to accurately define stage and tumor burden.
Nonsurgical ablative treatments are typically used in
patients who are not candidates for either resection or
OLT. They are also used with increasing frequency in
patients awaiting OLT in an attempt to reduce tumor
burden and prevent progression of tumor stage.
Percutaneous ethanol injection has a high direct an-
titumoral effect and is simple and relatively inexpensive.
Although confirmation of tumor necrosis often requires
either computed tomography (CT), magnetic reso-
nance imaging (MRI), or angiography, 90% of the tu-
mors less than 3 cm undergo complete necrosis. How-
ever, tumor recurrence is frequent in follow-up.
Variations on this approach include the use of acetic
acid, heated saline, or radiofrequency thermal ablation.
In general, existing data suggest that these approaches
provide patient survival and rates of disease recurrence
similar to resection. Ablative treatments are used to
control primary tumor bulk and reduce overall tumor
burden. It is anticipated that effective treatment could
prolong survival by reducing the rate of intrahepatic
tumor spread and the development of metastatic dis-
ease. However, no randomized trial has been performed
in which treated and untreated patients were matched
for both stage of tumor and extent of underlying liver
disease; thus, the benefit of ablative therapy on patient
survival has not been shown.
TACE has been used primarily in unresectable
HCC, and results in reference to patient survival have
been mixed. One series of 90 patients with cirrhosis
from Japan suggested improved survival with TACE.30
TACE may be most beneficial in early-stage tumors in
the setting of relatively preserved hepatic function.
However, results from multiple prospective trials have
failed to show overall improvement in patient survival,
despite a suggestion that patients with extensive tumor
necrosis after TACE may experience improved sur-
vival.21,22
Systemic chemotherapy, hormonal manipulation,
and other strategies have failed to impact significantly
on HCC.
In short, OLT is the only treatment proven to cure
early-stage HCC (solitary tumor ⬍5 cm or up to 3
tumors with additive diameter ⬍9 cm). However, OLT
must be performed as soon as possible after the diagno-
sis of HCC is established.

S6
Table 1. Principles of Screening for Disease According to
the World Health Organization Criteria
1. The disease should be a significant health problem.
2. Accepted treatment for diagnosed patients should be
available.
3. Facilities for diagnosis and treatment should be
available.
4. The disease should be detectable at an early stage.
5. Suitable screening tests should be available.
6. Screening tests should be acceptable to the population
to be tested.
7. The natural history of the disease should be
understood.
8. Patient selection criteria for treatment should be
established.
9. Cost of diagnosis and treatment should be
economically balanced relative to the whole medical
expenditure.
10. The process of case finding must continue beyond the
period of screening.
Data from Wilson and Junguer.31
How Effective Are Current Screening
Strategies?
The World Health Organization has established criteria
for effective screening strategies (Table 1).31 The goal of
screening is to detect early-stage HCC that can be cured
by definitive therapy. Enthusiasm for screening is some-
what dampened by the characteristics of our current
screening tests, primarily AFP level and ultrasonogra-
phy, which have suboptimal sensitivity, specificity, and
predictive value. Other tests, such as helical CT, MRI,
and angiography, may have improved ability to detect
early-stage lesions, but they are costly and impractical as
screening tests.
Despite these concerns, there is direct evidence of
improved patient outcome from screening. Yuen et al32
examined treatment options and outcomes in 306 Chi-
nese patients with HCC primarily related to HBV. One
hundred forty-two HCCs were discovered by routine
screening and 164 HCCs only after the appearance of
symptoms. HCC discovered by screening was charac-
terized by smaller size, unilobar involvement, tendency
to be solitary, less vascular invasion, and less risk for
metastases. These patients were also more likely to be
candidates for surgical therapy (resection mainly) or
TACE and had better survival. Improved survival was
believed to be related to both earlier stage disease and
beneficial effects of treatment
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Gregory T. Everson
Frequency of Testing
Frequency of screening is dependent on the rate of
growth of HCC, the resolving capacity of ultrasonog-
raphy, and the correlation of increase in AFP level with
tumor growth.33 Although growth rates are highly vari-
able, the average doubling time of HCC is approxi-
mately 6 months.34 Limits of detection of current ul-
trasonographic equipment range from 0.5 to 1.5 cm.
Additional studies have shown correlation of AFP level
with tumor doubling in approximately 50% of the tu-
mors. In addition, small (ⱕ1cm), potentially curable
tumors that escape detection by initial screening would
not likely increase in size beyond a curable stage over 6
months. In series examining growth rates of small tu-
mors, the most rapidly dividing tumor took 5 months
to increase from 1 to 3 cm. For this reason, the most
common interval for screening tests has been 6 months.
AFP Level
AFP level is elevated (ⱖ20 ng/mL) in approximately
70% to 80% of the patients with HCC. However,
persistent marked elevations in AFP level that are more
likely to be diagnostic, i.e., 200 ng/mL or greater for
HCV and 400 ng/mL or greater for HBV, occur in only
20% to 25% of the patients. In addition, AFP level may
be elevated in the absence of HCC (false-positive test
result), usually because of flares of underlying viral hep-
atitis. In 1 study of Alaskan Eskimos with chronic
HBV, only 15 of 56 persons (27% positive predictive
value) with elevated AFP levels (ⱖ25 ng/mL) had
HCC. Examination of a large number of surveillance
studies showed the following ranges for test perfor-
mance: sensitivity, 39% to 64%; specificity, 76% to
91%; and positive predictive value, 9% to 32%.33 The
variation is primarily caused by variation in the preva-
lence of HCC in the populations studied. The predic-
tive value is greatest when AFP level is applied to groups
of patients with a greater prevalence of HCC (patients
with cirrhosis).
Des-Carboxy Prothrombin
This marker has shown some promise in the early de-
tection of HCC. It is less sensitive and specific than AFP
level, but its level may be elevated in some patients with
HCC who have negative AFP levels. Its main role may
be in combination with AFP and ultrasonography.
Ultrasonography
Because AFP level is relatively insensitive as a screening
test, supplemental or complementary testing with ultra-
sonography is required. The sensitivity of ultrasonogra-
phy to detect small lesions of 1 cm or less is 60% to

Increasing Incidence and Screening for HCC
80%. In contrast, ultrasonography detects 85% to 95%
of the lesions 3 to 5 cm in diameter. In surveillance
studies of patients without cirrhosis, sensitivity was
71%, specificity was 93%, and positive predictive value
was only 14%. In surveillance studies of patients with
cirrhosis, sensitivity was 78%, specificity was 93%, and
positive predictive value was 73%. CT is similarly sen-
sitive over these size ranges for the primary liver tumor;
but CT is much more expensive than ultrasonography
and less applicable as a screening tool. Examination of
the positive predictive values of AFP levels and ultra-
sonography suggests they would be most effective in
screening patients with cirrhosis.
It is difficult to distinguish HCC from benign he-
patic tumors in patients without cirrhosis and from
macroregenerative nodules (MRNs) in patients with
cirrhosis. Studies from Japan suggest that MRNs are
common in cirrhosis and may be a risk factor for the
development of HCC. A recent study from the Univer-
sity of California at San Francisco examined 110 cir-
rhotic explants for the presence of MRNs.35 Nineteen
cirrhotic livers had 40 MRNs; 28 were benign and 12
were HCCs (3 HCCs arose in 1 MRN), and 75% of the
HCCs occurred in the absence of MRNs. Thus, many
nodules suspicious for HCC by imaging are benign
MRNs accounting for false-positive test results, an issue
rarely discussed in the HCC screening literature. For
example, if the given sensitivity and specificity for a
screening procedure are both 80%, and the prevalence
of disease to be detected is 10% (approximate cumula-
tive risk for HCC over 3 years in patients with cirrhosis
with viral hepatitis), then the predictive value of a pos-
itive test result of HCC is only 31%. Two thirds of
detected lesions will not be HCC. Costs of diagnostic
tests and procedures used to define non-HCC lesions
detected by screening are rarely described in the HCC
screening literature.
Another recent study evaluated the sensitivity of ul-
trasonography in the detection of HCC in patients with
cirrhosis before OLT.36 Although ultrasonography de-
tected HCC in 80% of the cases, multicentricity was
only detected in 17%. These sensitivities were inferior
to those for CT (87% and 58%, respectively) and an-
giography (90% and 58%, respectively). Gores37 esti-
mated that as many as 50% of HCCs, particularly larger
HCCs greater than 5 cm in diameter, are understaged
by imaging methods. Some have suggested that small
lesions (⬍2 cm) and multicentricity are better detected
by MRI.38
A recent study from Pittsburgh suggested that most
tumors missed by screening tend to be small, focal, and
without vascular invasion.39 They examined the records
of 39 patients who underwent OLT for cirrhosis and
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S7
had an incidental hepatoma on explant histological ex-
amination. All patients had undergone screening with
AFP testing every 6 to 12 months and annual CT of the
liver while on the waiting list. All had AFP levels less
than 20 ng/mL and negative CT results before OLT.
Retrospective analysis of CT after knowledge of explant
diagnosis showed that only 15% could have been de-
tected before OLT; 85% were less than 2 cm, 74% were
solitary, 78% were stage I or II, and 70% lacked vascu-
lar invasion. However, 23% of the patients had tumor
characteristics with poor prognostic features. There
were 7 deaths, only 1 related to metastatic HCC. The
32 remaining patients have been followed up for a mean
of 30 months and lack detectable recurrence. Thus,
tumors that escape detection by initial AFP testing and
ultrasonography tend to be relatively early-stage lesions,
and if patients undergo OLT, they have an excellent
post-OLT prognosis.
How Costly Is Screening?
Before the awareness and ability to diagnose HCV,
much of the focus on screening was related to cirrhosis
from HBV.40 A National Institutes of Health consensus
conference recommended that AFP levels be measured
every 3 to 4 months and that ultrasonography be per-
formed every 4 to 6 months for patients with cirrhosis
with chronic HBV.41 Costs of this screening procedure
were estimated by assuming an annual incidence of
HCC of 0.5%, cost of AFP testing of $20/test, and cost
of ultrasonography of $240/test. Using these assump-
tions, the screening costs were $216,000 for each de-
tected curable hepatoma. Costs of screening for each
curable hepatoma would diminish with an increase in
the prevalence of HCC in the study population. How-
ever, costs related to providing curative therapy would
necessarily increase.
One study screened 2,000 chronic hepatitis B and C
carriers over 3 years.32 One hundred forty-two cases of
HCC were detected, and 102 cases were believed to be
detected at a stage in which therapy (resection or
TACE) could be administered and exert a positive ben-
efit. Analysis suggested that 14 cases would need to be
screened to detect 1 HCC; 20 would have to be
screened to detect 1 treatable HCC. They estimated
cost of screening using $25 for each AFP test and $100
for each ultrasonographic study. Each patient was
screened twice yearly; the cost of detecting 1 HCC was
$1,167 ([14 ⫻ ($125 ⫻ 2)]/3), and the cost of detect-
ing 1 treatable HCC was $1,667 ([20 ⫻ ($125 ⫻
2)]/3).

S8 Gregory T. Everson
Cost of Treating HCC Detected by Screening
In the study of Yuen et al,32 85% of the patients had
underlying cirrhosis, 61% of the tumors detected by
screening were less than 5 cm in diameter, 85% of the
tumors were unilobar, and only 3% of the patients had
evidence of metastasis. Thus, at least 60% of the tumors
detected by screening with AFP testing and ultrasonog-
raphy would be amenable to OLT.
The only treatment modality with a proven cure rate
for early-stage HCC is OLT. Current charges related to
standard OLT are estimated at $150,000 to $250,000
annually. LDLT further increases these charges by an-
other $35,000 to $45,000. With expansion of waiting
lists and increasing waiting times, timely performance
of OLT is becoming increasingly rare. Delays in the
performance of OLT caused by the large waiting list
and prolonged waiting time will further compromise
outcome because tumor stage will increase and out-
come will worsen. Strategies to prevent stage progres-
sion on the waiting list, such as TACE, ethanol injec-
tion, and radiofrequency thermal ablation, are under
investigation, but in themselves are costly and often
require repeated performance. The greater cost related
to LDLT compared with OLT will likely be eliminated
by the need to use these procedures. In addition, all the
procedures noted carry the added risk for inadvertently
inducing metastatic disease. Thus, LDLT appears to be
the most potentially effective treatment in this setting.
However, LDLT has additional limitations. In our
experience, only 15% of the potential recipients of liv-
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Figure 2. An algorithm show-
ing the expected treatment
options available to 100 pa-
tients diagnosed with early-
stage HCC by screening with
serial AFP tests and ultra-
sonography. (PEI, percutane-
ous ethanol injection; RFTA,
radiofrequency thermal abla-
tion.)
ing donor liver transplants were considered to be can-
didates and could identify a suitable donor. Even if our
selection criteria were relaxed, it is unlikely that more
than 30% of the patients with cirrhosis with early-stage
HCC would be candidates for LDLT. An algorithm
showing the distribution of treatments that would oc-
cur in response to the detection of early-stage HCC is
shown in Figure 2.
If the cure rate is 85% with either LDLT or OLT for
early-stage HCC, then 51% ([25% ⫹ 35%] ⫻ .85) of
all detected early-stage, potentially curable HCCs
would be cured (Fig. 2). Patients who do not undergo
OLT will also likely be treated; at least 5% will undergo
resection and 35% will undergo nonsurgical treat-
ments. The estimated charge of resection is $35,000 to
$50,000. Other patients will undergo postoperative ad-
juvant medical therapies (charges, $5,000 to $20,000/
yr). Because most nonsurgical treatments require inter-
ventional radiology and angiographic guidance or
verification of efficacy, we estimate the charge of each
treatment to be $10,000 and the average number of
sessions per patient to be 3. Using the treatment
schemes shown in Figure 2, we arrive at the charges
listed in Table 2 related to treatments given to early-
stage HCC.
The potential burden to the US healthcare system is
illustrative. Start with screening of all patients with
cirrhosis with HCV. We will assume that approxi-
mately 20% of the current 2.7 million persons in the
United States with active HCV have cirrhosis (n ⫽

Increasing Incidence and Screening for HCC
Table 2. Estimates of Charges Related to Treatment of “Curable” Hepatoma
No. of Patients
LDLT 25
OLT 35
Resection 5 50,000
Nonsurgical treatment 35
Total
Charges/patient
Charges/cure
540,000). However, we will assume that only 50% of
these cases have been identified. The potential size of
the population to be screened is therefore 270,000 per-
sons. If the cost of annual screening is $1,200 (2 AFP
tests and 2 ultrasonographic examinations), then
$324,000,000 would be spent each year just on screen-
ing. If the rate of development of HCC is 2.5% per
year, sensitivity of detection of HCC by tests is 80%,
and 60% of detected HCCs are early stage, then 1.2%
of 270,000 patients (N ⫽ 3,240) would be candidates
for the treatments shown in Figure 2. The charges for
administering treatment would be $471,420,000. The
projected total annual cost for screening patients with
cirrhosis with HCV and treating the detected HCC
would be $795,420,000. The charges for each quality-
adjusted life year gained would range from $35,000 to
$45,000. It seems like a lot of money, but this amount
is actually much less than the amount spent each year
for laparoscopic cholecystectomy for gallstone disease.
For comparison, the cost of screening women for
breast cancer is $30,000 to $100,000 per year of life
saved, and screening for cervical cancer costs $15,000 to
$30,000 per year of life saved.42
Will There Be Enough Donor Organs to Meet
Recipient Need?
The answer to this question is already in: no! The in-
creasing number of patients with chronic hepatitis C
has already expanded waiting lists beyond their capacity
to provide adequate numbers of donor organs in a
timely fashion. Within this subgroup of patients, an-
other phenomenon is occurring: an increasing number
of patients developing HCC either before listing or
after they have been listed. Once HCC develops in
these patients with cirrhosis, the clock is ticking. The
limited cadaveric donor supply cannot meet this need.
A recent review suggested that the only current way
to feasibly expand the cadaveric donor supply would be
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S9
No. of
$/Treatment Treatments Total Charge ($)
250,000 1 6,250,000
200,000 1 7,000,000
1 250,000
10,000 3 1,050,000
14,550,000
145,500
285,294
the widespread use of split-liver transplantation.43
However, this type of approach has multiple barriers:
technical skills required for optimum splitting of the
liver are considerable, long-distance transportation of
split livers has not been evaluated, graft survival is less,
and retransplantation rates are greater. Besides, patients
with failed split livers would be elevated to status 1, and
retransplantations related to failed split livers would
further compromise the cadaveric pool. Overall out-
come from transplantation in terms of patient and graft
survival would diminish.
In conclusion, standard cadaveric transplantation,
even with the widespread use of split-liver transplanta-
tion, is not likely to adequately address the burgeoning
number of cases of HCC in patients with cirrhosis
referred for transplantation. It is my opinion that in the
future, the single most common indication for adult
LDLT will be HCC occurring in patients with cirrhosis
with chronic HCV.
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