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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1209_Библиотеки_им_академика_М_И_Перельмана.pdf
95
screening modality varied, different inclusion criteria were used for the studies
included in this review. For the performance of serum AFP, studies were excluded
if they specifi cally addressed diagnosis of hepatocellular carcinoma after a lesion
has been detected in the liver rather than screening, or if noncirrhotic patients were
the only study subjects. For the performance of ultrasound as a screening test, only
prospective studies of cirrhotic cohorts were included. For cross-sectional imaging,
studies reviewed refl ect the latest progress in the technology of computed tomography ( CT ) and magnetic resonance imaging (MRI). For CT, only studies assessing
the performance of 16-slice or more multidectector CT (MDCT) with triple or
quadruple phase imaging and explant pathology used as the reference standard
were included. For MRI, studies using dynamic MRI with both hepatobiliary phase
and diffusion weighted imaging MRI were included. The data was classifi ed using
the GRADE system.
Results
Clinical Relevance and Risk Factors of Hepatocellular Carcinoma
Screening is the administration of diagnostic tests to subjects who have a defi ned
risk for developing HCC, but in whom there is no suspicion for HCC to be present
prior to the screening . Surveillance is the repeated administration of screening tests.
An intervention is considered effective if it provides an increase in longevity of
about 100 days or 3 months [ 17 ], and interventions that can be achieved at a cost of
<$50,000/year of life gained is considered to be cost-effective in 1992 [ 18 ], although
this cost is likely higher in today’s market rates.
Major advances in medicine have increased the ability to cure HCC when
diagnosed early, although medical and locoregional interventions may still extend
Table 9.1 PICO table for screening for hepatocellular carcinoma in cirrhotic patients
P (Patients) I (Intervention) C (Comparator group) O (Outcomes measured)
Patients with
cirrhosis
Serum AFP assay No screening Diagnosis of hepatocellular
carcinoma within Milan criteria,
mortality
Patients with
cirrhosis
Ultrasound
examination
No screening or
screening via another
modality
Diagnosis of hepatocellular
carcinoma, mortality
Patients with
cirrhosis
CT examination No screening or
screening via another
modality
Diagnosis of hepatocellular
carcinoma, mortality
Patients with
cirrhosis
MRI examination No screening or
screening via another
modality
Diagnosis of hepatocellular
carcinoma, mortality
9 What Is the Best Way to Screen Cirrhotic Patients for Hepatocellular Carcinoma…
96
survival in later stages. Despite the absence of high quality data from RCT of HCC
surveillance versus no HCC surveillance, the ability to change patient outcomes
with appropriate interventions at acceptable costs is compelling reason to prompt
the AASLD to recommend HCC surveillance in high-risk population. Cirrhosis is a
well-established risk factor for HCC, wherein surveillance for an HCC incidence of
1.5 %/year is expected to increase survival by about 3 months [ 10 ]. Hepatitis B car-
riers who are Asian males aged over 40 years and Asian females aged over 50 years
have an HCC incidence of 0.4–0.6 %/year, and those with a family history of HCC
are known to have a higher HCC incidence than those without. African and North
American Blacks with hepatitis B also are known to develop HCC at a younger age.
Cirrhotic hepatitis B carriers have an HCC incidence of 3–8 %/year, while patients
with hepatitis C cirrhosis and stage 4 primary biliary cirrhosis have an HCC incidence
of 3–5 %/year. The HCC incidence in cirrhotics with genetic hemochromatosis,
alpha 1- antitrypsin defi ciency and other causes are not established but may approach
>1.5 %/year for most cases [ 7 ]. Another growing group at risk for HCC is
the population affl icted with non-alcoholic steatohepatitis, where the incidence is
2.6 %/year in one study [ 19 , 20 ].
Screening Strategies
Serum Alpha-Feto Protein (AFP)
Serum AFP is the most widely tested biomarker in the diagnosis of HCC, but its
performance as a surveillance tool has been suboptimal. The only RCT evaluating
serum AFP alone as a screening tool for HCC was conducted in hepatitis B infected
patients who were mostly non-cirrhotic; the fi ndings included an earlier diagnosis
of HCC [ 21 ]. Data in cirrhotic patients have been limited to case control studies,
which have consistently shown a low sensitivity of a serum AFP cut-off of 20 ng/ml
at about 60 % for detection of HCC (Table 9.2 ) [ 22 – 27 ]. Trevisani et al. reported the
positive predictive value of a serum AFP cut-off value of >20 ng/ml to be dismal at
25.1 % in a population with an HCC prevalence of 5 % [ 25 ]. Currently, serum AFP
is not part of the recommended screening process for HCC by both the AASLD [ 28 ]
and the EASL guidelines [ 16 , 28 ].
The potential value of measuring serial serum AFPs to survey for HCC has also
been investigated in another case-control study involving hepatitis C-infected
patients with advanced fi brosis or cirrhosis . Lee et al. found that both the standard
deviation and the rate of increase of serum AFP were independently associated with
HCC. Incorporation of these metrics along with patient-specifi c risk factors resulted
in improved accuracy for HCC prediction to an area under the receiver-operating
characteristic curve of 0.81 when compared with 0.76 when only the most recent
serum AFP value was used [
29 ]. However, these fi ndings need to be validated
further to determine its true value in HCC screening .
A.P. Desai and H.S. Te
97
Ultrasonography (US) with or Without Serum AFP
While US technology has been used for diagnostic purposes since the 1940s, its use
for screening for liver masses was fi rst reported in the early 1980s [ 30 ]. Since then,
many studies evaluating the performance of US with or without serum AFP in surveillance programs aimed to detect early stages of HCC have been done [ 8 , 31 – 33 ].
Despite a variety of study methodologies involved, a recent meta-analysis calculated
the pooled odds of early detection as 2.08 (95 % CI 1.80–2.37). More importantly,
screening increased the odds of receipt of curative therapy (OR 2.24, 95 % CI 1.99–
2.52) and the odds of 3-year survival (OR 1.90, 95 % CI 1.90–2.17) [ 33 ]. It is
important to note that this data has limited accuracy and applicability, as most of
the studies included in the meta-analysis were observational studies susceptible to
lead-time and selection bias, and these also included a wide variety of patient populations, utilized different screening programs and had largely different screening
uptakes as well. Three randomized trials have been done in Europe and Asia to
study the effi cacy of screening with ultrasound with or without serum AFP [ 34 – 36 ],
but cirrhotic patients were not included or defi ned [ 36 ] so these studies are not
included in this discussion.
More recent data on HCC screening in patients with cirrhosis published after
2000 included prospective studies that assessed the performance of US with or
without serum AFP in the real world. Overall, the sensitivity of US for detecting
HCC has a wide range of 43–90 % and a specifi city of 83–97 % (Table 9.3 ) [ 26 , 34 ,
37 – 41 ]. While current guidelines do not recommend use of serum AFP, most stud-
ies included serum AFP testing in their surveillance program. In fact, one study
attempted to assess the role of serum AFP by creating randomization arms that
consisted of imaging surveillance without serum AFP, but discovered high usage
rates of serum AFP assays in the imaging alone group, necessitating the fi nal analysis
to include imaging in combination with serum AFP [ 34 ]. The optimal interval
Table 9.2 Sensitivity and specifi city of serum AFP in detecting early stage HCCs
Study
AFP cut-off
(ng/ml)
Sensitivity
(%)
Specifi city
(%)
Study type ( quality
of evidence)
Gamberin-Gelwan
et al. [ 22 ]
20 58 91 Case-control (low)
Trevisani et al. [
25 ] a >20 60 91 Case-control (low)
Nguyen et al. [
24 , 64 ] >20 63 80 Case-control (low)
Snowberger et al. [
27 ] b 8.9 62 80 Case-control (low)
50 31 96
Marrero et al. [
24 ] >20 59 90 Case-control (low)
Lok et al. [
23 ] >20 61 81 Case-control (low)
Singal et al. [
26 ] >20 66 90 Prospective cohort
(moderate)
a
In a population with 50 % HCC prevalence
b
Used explants as gold standard
9 What Is the Best Way to Screen Cirrhotic Patients for Hepatocellular Carcinoma…
98
Table 9.3 Summary of prospective studies of hepatocellular carcinoma (HCC) screening in cirrhotics using ultrasonography (US) with or without serum alpha
feto protein (AFP)
Study
Screening
method Cohort Sensitivity Specifi city Clinical effectiveness
Study type ( quality
of evidence)
Henrion et al.
[
37 ]
US and serum
AFP assay every
6 months
Belgian cirrhotics 83 % Insuffi cient data Compliance to surveillance
program overall was 66 % and was
signifi cantly higher in those with
cirrhosis due to non-alcoholic
causes
Prospective cohort
(low)
Bolondi et al.
[
35 ]
US and serum
AFP assay every
6 months
Italian Child- Pugh
A or B cirrhotics
82 % Insuffi cient data Higher rate of unifocal and smaller
HCC for screened vs control group
(80 % vs. 53 %, p < 0.001)
Prospective cohort
(low)
Longer 3-year survival for
screened vs control group (45 %
vs 31.7 %, p = 0.02)
Similar rate of treatment for HCC
in screened vs control group (58.6
% vs 68.8 %, p = NS)
Cost per year of life
saved = $112,996
Sangiovanni
et al. [
39 ]
Annual US and
serum AFP
assay
a
Italian Child A
and B cirrhotics,
aged 36–72
Insuffi cient data Insuffi cient data Smaller nodules detected in latest
study period with mean diameter
of 2.2 cm (1997–2001) vs. 3.0 cm
(1992–1996) vs. 3.7 cm
(1987–1991)
Prospective cohort
(low)
Improved survival in those
screened in the latest study period,
linked to earlier diagnosis and
improved linkage to treatment
A.P. Desai and H.S. Te
99
(continued)
Study
Screening
method Cohort Sensitivity Specifi city Clinical effectiveness
Study type ( quality
of evidence)
Trinchet et al.
[
32 ]
US every 3 or 6
months
French or Belgian
Child-Pugh A or B
cirrhotics
86.6 % Insuffi cient data No difference in diagnosis of early
HCC or overall survival
Randomized control
trial (high)
Increased incidence of non-
malignant focal lesions (especially
those ≤10 mm) when US was
completed every 3 months. If
lesions were followed per EASL
recommendations, the time of
HCC diagnosis and treatment
would not have changed
Singal et al. [
26 ] US and serum
AFP assay every
6–12 months
b
American
Child-Pugh A or B
cirrhotics
US: 43.9 % US: 91.5 % 38.7 % of study population
received inconsistent or no
surveillance
Prospective cohort
(moderate)
US + AFP: 90.2 % US + AFP: 83.3 % US sensitivity was lower in
non-Caucasian race and lower
MELD score
Majority of participants only had
one positive surveillance study
(AFP or US) prior to HCC
diagnosis
Di Martino et al.
[
36 ]
Doppler US
followed by
cross-sectional
imaging
Italian OLT
candidates over 3
year period who
underwent all
three imaging tests
in 1 month
e
71 % 62 % US sensitivity decreased with
decreasing nodule size, with only
22 % sensitivity for nodules under
10 mm
Prospective cohort
(moderate)
Lower specifi city due to
signifi cant numbers of false
positive examinations when state
of the art US technology was used
9 What Is the Best Way to Screen Cirrhotic Patients for Hepatocellular Carcinoma…
100
Table 9.3 (continued)
Study
Screening
method Cohort Sensitivity Specifi city Clinical effectiveness
Study type ( quality
of evidence)
Pocha et al. [
38 ] US every 6
months vs.
annual CT
c,d
American Child A
cirrhotics
f
US: 71.4 % US: 97.5 % Signifi cant number of participants
went off-protocol
Randomized control
trial (moderate)
CT: 66.7 % CT: 94.4 % Ultrasound comparable to CT in
detecting early stage HCC
AFP added little value to overall
HCC detection
Cost of one HCC detected was
signifi cantly higher with CT
($35,383) vs US ($17,041)
a
If AFP >20 ng/dL, US and serum AFP assay frequency were increased to every 6 months
b
Screening was obtained at the discretion of the treating hepatologist, no reminders were sent to patient or medical care providers
c
computed tomography
d
±AFP every 6 months in both arms
e
Excluded three cholangiocarcinoma nodules (in two patients) and three hepatocholangiocarcinoma nodules (in one patient)
f
Participants had to be potential candidates for treatment of HCC; advanced medical condition and those who were unable to receive IV contrast due to renal
insuffi ciency or allergy were excluded
A.P. Desai and H.S. Te
101
between screenings is not clear with most studies using 6 month or 12 month
intervals. Shorter intervals appears to only increase detection of non-malignant
focal lesions in the 3-month group, particularly those <10 mm in diameter, which
did not impact clinical care or outcomes in most cases [ 34 ]. Although one study in
a Veterans Administration hospital setting found no incremental benefi t of the addition
of serum AFP to imaging studies [ 40 ], one prospective cohort study involving 446
patients in real world practice reported substantial advantage of using serum AFP in
conjunction with US than with US alone, with increased sensitivity to 90.2 % and
specifi city to 83.3 % [ 26 ].
Cross Sectional Imaging
The clinical effectiveness of US in screening for HCC is largely limited by low
adherence rates, variability in operator experience, diffi culty in visualization of the
liver in patients with morbid obesity or very nodular livers, and poor sensitivity
when identifying early HCC’s (i.e., those <20 mm). These limitations have fueled
the search for improved modalities in screening those at high risk for HCC. Both
computed tomography ( CT ) and magnetic resonance imaging (MRI) of the abdomen have been used to further evaluate and diagnose liver lesions found during
ultrasound examination. Therefore, both offer attractive alternatives for screening
of those at risk for HCC.
Computed Tomography
Beginning in the 1990s, use of arterial-phase imaging during intravenous contrast
medium-enhanced CT studies improved the sensitivity of small nodule detection
[ 42 ]. In the 2000s, multidetector-row helical CT (MDCT) technology allowed for
faster acquisition, thinner slices (0.5 mm for 64-slice MDCT vs. 5–10 mm for helical CT) in a single breath-hold and repetitive imaging during multiple perfusion
phases after contrast material injection [ 42 , 43 ]. In combination with four-phase CT
protocols, which provide images during the pre-contrast, arterial, portal venous and
delayed phases, 16-, 64- and even 128-slice MDCT has allowed for the detection of
a signifi cantly higher number of cases of HCC [ 42 , 44 ]. Current UNOS policy out-
lines minimum criteria for the use of CT to accurately diagnose HCC radiographically [ 45 ]. Many of the studies assessing the sensitivity and specifi city of triple
phase 16- or 64-slice MDCT have been performed in individuals awaiting liver
transplantation . Most are retrospective; however, many have used the explant pathology as the gold standard, thus increasing their validity with sensitivities of 77–89 %
and specifi cities of 44–93 % (Table 9.4 ) [ 44 , 46 – 48 ]. Due to the lack of prospective
data, the screening interval for CT has yet to be established. Overall, even studies of
the most advanced CT technology only show marginal superiority over US as a
screening tool, largely due to better sensitivity for lesions <20 mm in size.
9 What Is the Best Way to Screen Cirrhotic Patients for Hepatocellular Carcinoma…
102
Table 9.4 Summary of studies using triple or four-phase protocols with 16- or greater slice multidetector-row helical computed tomography (MDCT) for the
diagnosis of hepatocellular carcinoma (HCC) with explant pathology as gold standard
Study Imaging method Cohort Sensitivity Specifi city Clinical performance
Study type ( quality
of evidence)
Ronzoni
et al. [
48 ]
Triple-phase MDCT
original reports vs.
images reviewed
retrospectively
a
OLT recipients
with CT within
6 months of
OLT
Original report:
64 % by lesion,
77 % by patient
Original report:
75 % by patient
f
32 % of false negative
lesions were due to prior
locoregional therapy and
70 % were <10 mm in size
Retrospective (low)
Retrospective
review:
Retrospective
review: 77.5 % by
patient
c
14 % of the study
population would have
been denied or referred to
OLT due to false-negative
or false-positive results,
respectively
73.3 % by lesion,
83.4 % by patient
Denecke
et al. [
47 ]
Triple-phase MDCT
images reviewed
retrospectively by two
radiologists
OLT recipients
with HCC with
CT within 100
days of OLT
c
Observer 1: 78 % Observer 1: 45 % Sensitivity for both
observers decreased with
decreasing size of the
nodule (43 % and 53 %
observers 1 and 2 for
nodules <10 mm,
respectively, vs. 94 % for
both observers for
11–20 mm nodules vs. 89
% and 95 %, respectively,
for nodules >20 mm)
Retrospective (low)
Observer 2: 83 % Observer 2: 44 %
Poor specifi city with high
false positive rate for both
observers noted
A.P. Desai and H.S. Te
103
Study Imaging method Cohort Sensitivity Specifi city Clinical performance
Study type ( quality
of evidence)
Luca
et al. [
44 ]
Triple-phase MDCT
images retrospectively
reviewed by three
blinded radiologists
b
OLT recipients
imaged with
CT
pre-transplant
Hypervascular lesion
with washout on
portal venous and/or
delayed phase
images: 43 %
Hypervascular lesion
with washout: 93 %
Pattern of hypervascular
nodule with washout has
poor sensitivity but
excellent specifi city for the
diagnosis of HCC
Retrospective (low)
Overall: 89 %
e
Limitation to hypervascular
lesions with delayed phase
washout only improved
diagnostic accuracy
Pattern of hypervascular
nodule with washout
established an accurate
staging of disease in 46 % of
cases, underestimated in 52 %
and overestimated in only 2 %
Hypervascular lesions
>10 mm without washout
and hypovascular lesions
>20 mm have signifi cant risk
of HCC
Addley
et al. [
46 ]
Triple-phase MDCT
reviewed by three
radiologist
OLT recipients
with CT within
5 months of
OLT
d
Observer 1:78 % Observer 1:47 % Sensitivity for each
radiologist was signifi cantly
lower if lesion <20 mm
Retrospective (low)
Observer 2: 72 % Observer 2: 69 % Observer expertise and
years of experience
improved accuracy of HCC
detection but decreased
sensitivity
Observer 3: 65 % Observer 3: 88 %
a
Diagnosis reached by consensus between two unblinded radiologists
b
Diagnosis reached by consensus amongst three blinded radiologists
c
Patients with incomplete histopathologic report and those who had intermittent tumor treatment were excluded
d
Patients who had previously undergone treatment of HCC, those with malignancy other than HCC and those with multifocal HCC were excluded
e
MDCT fi ndings of hypervascular nodule with washout, hypervascular nodule without washout, and hypovascular nodules were included
f
Specifi city by lesion not reported
9 What Is the Best Way to Screen Cirrhotic Patients for Hepatocellular Carcinoma…
104
Magnetic Resonance Imaging
As with CT , MRI is evolving with new techniques allowing for improved diagnostic
accuracy. With MR, however, there are a variety of techniques for imaging acquisition,
image sequences and optimization, as well as image processing that can impact the
ultimate performance of MR in liver lesion detection and accurate characterization.
Current UNOS policy outlines specifi c minimum technical requirements for MRI in
diagnosing HCC radiographically [ 49 ]. Of the recent advances in MR technology,
dynamic imaging, hepatobiliary phase (HBP) imaging with hepatocyte- specifi c
contrast agents, and use of diffusion weight image (DWI) characteristics have
allowed MRI to evaluate tumor vascularity, increased tissue cellularity and absence
of normal hepatocytes with greater detail and accuracy [ 50 – 54 ].
The reported sensitivity of dynamic contrast enhanced MR imaging (with an
extracellular fl uid contrast agent) is noted to be from 70 to 100 % in various studies
with a pooled sensitivity of 81 % [ 31 ]. Even with dynamic, contrast-enhanced MRI,
the detection of early HCC remains a challenge, particularly with the background of
a cirrhotic liver where arterial enhancement of small <1 cm lesions is less diagnostically accurate for HCC. For these lesions, MRI offers several advantages over CT
despite some inherent limitations [ 55 – 57 ].
Hepatobiliary phase (HPB) imaging may improve the ability to detect and diagnose early HCC. Use of gadoxetic acid (Eovist ® ) or gadobenate dimeglumine
(MultiHance ® ) allows for both dynamic imaging during the extracellular phase and
delayed imaging in the HBP phase, when the contrast is taken up by the hepatocytes
[ 52 , 53 ]. These agents can help differentiate arterial-enhancing pseudolesions.
One study documented 95.5 % of HCC’s displayed hypointensity during the HBP
while 94.3 % of pseudolesions were isointense during the HBP. In this study, the
sensitivity of MRI for diagnosing HCC was 93.9 % [ 58 ]. Another study showed
lesions without arterial phase hyperenhancement, but with both venous phase
hypoenhancement and HBP hypointensity, carry a higher probability of being welldifferentiated HCC in cirrhotic livers [ 55 ]. A meta-analysis of gadoxetic acid-based
MRI reported a pooled sensitivity of 91 % and specifi city of 95 %. For studies
focused on lesions <2 cm, performance continued to be excellent with a reported
sensitivity range of 87–99 % and specifi city range of 92–96 % [ 52 ].
Diffusion weighted imaging (DWI) in MRI is a functional MRI technique that
offers its own advantages in the detection and diagnosis of HCC in those with cirrhosis . DWI capitalizes on the changes that accompany the development of HCC,
such as changes in cellularity and extracellular space structure, to detect HCC
lesions. A reported 70–80 % of HCC’s, including those <1–2 cm in size, appear
hyperintense on DWI [ 51 ]. The sensitivity and specifi city of DWI were better at
91.2 % and 82.9 %, respectively, when compared to dynamic, gadolinium-based
MRI at 67.6 % and 61 %, respectively [ 59 ]. A study also highlighted the utility of
MRI enhanced with DWI as a screening tool for HCC for those in whom intravenous iodine contrast administration is contraindicated [ 54 ]. In another study, use of
A.P. Desai and H.S. Te