Prognostic Significance of Computed Tomography Scan-derived Splenic Volume in Hepatocellular Carcinoma Treated With Radiofrequency Ablation.

Abstract

GOALS:: To evaluate the clinical implication of splenic volume measured by computed tomography (CT) scan in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). BACKGROUND:: Splenomegaly is an important sign of portal hypertension and poor liver function in patients with advanced liver disease. But whether it could predict the prognosis of patients with HCC is still obscure. STUDY:: We enrolled 161 treatment-naive HCC patients. Splenomegaly was defined as splenic volume >300 mL by CT scan and its impact on prognosis was analyzed. Moreover, noninvasive serum markers were validated to predict splenomegaly. RESULTS:: A total of 78 patients were with splenomegaly, while the remaining 83 patients had normal splenic volume at the time of receiving RFA. After a median follow-up of 38.1±20.8 months, 41 patients died. The cumulative 5-year survival rates were 54.8% and 77.8% in patients with splenomegaly and in those with normal splenic volume, respectively (P=0.003). By multivariate analysis, age 65 years and older, serum albumin levels ≤3.5 g/dL, and splenic volume >300 mL were independent risk factors associated with poor overall survival after RFA. For predicting splenomegaly by noninvasive serum markers, platelet count yielded the highest area under the curve from corresponding receiver operating curves with a level of 0.868 at a cut-off value of 11,7000/mm. CONCLUSIONS:: HCC patients with splenomegaly measured by CT scan have relatively poorer liver functional reserve than those with normal splenic volume. Splenomegaly is an independent risk factor predicting overall survival for patients with small HCC undergoing RFA.

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Prognostic Significance of Computed Tomography
Scan-derived Splenic Volume in Hepatocellular
Carcinoma Treated With Radiofrequency Ablation
Wen-Chieh Wu, MD,* Yi-You Chiou, MD,wz Hung-Hsu Hung, MD,*zz Wei-Yu Kao, MD,*zy
Yi-Hong Chou, MD,z8 Chien-Wei Su, MD,*zz Jaw-Ching Wu, MD, PhD,z# Teh-Ia Huo, MD,***
Yi-Hsiang Huang, MD, PhD,*z Kuei-Chuan Lee, MD,*zz Han-Chieh Lin, MD,*z
and Shou-Dong Lee, MDzwwzz
Goals: To evaluate the clinical implication of splenic volume
measured by computed tomography (CT) scan in hepatocellular
carcinoma(HCC)patientsundergoing
frequency ablation (RFA).
percutaneousradio-
Background: Splenomegaly is an important sign of portal hyper-
tension and poor liver function in patients with advanced liver
disease. But whether it could predict the prognosis of patients with
HCC is still obscure.
Study: We enrolled 161 treatment-naive HCC patients. Splenome-
galy was defined as splenic volume >300mL by CT scan and its
impact on prognosis was analyzed. Moreover, noninvasive serum
markers were validated to predict splenomegaly.
Results: A total of 78 patients were with splenomegaly, while the
remaining 83 patients had normal splenic volume at the time of
receiving RFA. After a median follow-up of 38.1±20.8 months,
41 patients died. The cumulative 5-year survival rates were 54.8%
and 77.8% in patients with splenomegaly and in those with normal
splenic volume, respectively (P=0.003). By multivariate analysis,
age 65 years and older, serum albumin levels r3.5g/dL, and splenic
volume >300mL were independent risk factors associated with poor
overall survival after RFA. For predicting splenomegaly by non-
invasive serum markers, platelet count yielded the highest area under
the curve from corresponding receiver operating curves with a level of
0.868 at a cut-off value of 11,7000/mm3.
Conclusions: HCC patients with splenomegaly measured by CT
scan have relatively poorer liver functional reserve than those with
normal splenic volume. Splenomegaly is an independent risk factor
predicting overall survival for patients with small HCC undergoing
RFA.
Key Words: hepatocellular carcinoma, liver fibrosis, prognosis,
radiofrequency ablation, splenic volume
(J Clin Gastroenterol 2012;46:789–795)
T
is now the third most common cause of cancer mortality
in the world.1,2Substantial advances in the surveillance of
high-risk groups and in diagnosis and treatment have im-
proved the long-term prognosis of HCC patients in recent
years such that more and more patients are diagnosed ear-
lier and have the opportunity to receive curative therapies.3
However, although surgical resection and liver trans-
plantation can provide better prognosis, these are often not
feasible because of the shortage of liver transplantation
donors or the relatively poor liver functional reserve of the
patients themselves, which preclude resection.4Local abla-
tion therapies have been introduced as management of small
HCC in patients not eligible for liver transplantation or
resection therapy.5,6Among the local ablation therapies,
percutaneous radiofrequency ablation (RFA) is superior
because of fewer therapy sessions, better local tumor con-
trol, lower incidence of recurrence, and higher survival
rates.7–9Consequently, RFA has been considered poten-
tially curative for early-stage HCCs.10–13
Several factors like tumor size, number of tumors,
presence of venous invasion, performance status, age and
degree of hepatic fibrosis, and liver functional reserve have
been shown to determine the prognosis of HCC pa-
tients.14–16In patients with early tumor stage, tumor factors
(multinodularity, large tumor size, or venous invasion) have
less impact.17In contrast, field factors such as background
fibrosis, portal hypertension, and liver functional reserve
may play more important roles in determining the overall
survival of small HCC patients after RFA.5,17–19
Splenomegaly is an important sign of portal hyper-
tension and poor liver functional reserve in patients with
chronic hepatitis. Previous studies demonstrate that meas-
uring splenic volume by computed tomography (CT) scan is
a reliable surrogate marker for assessing the stage of hepatic
fibrosis and cirrhosis.20,21However, whether splenic volume
can predict the prognosis of patients with early-stage HCC
after RFA is still unclear. We deduce that HCC patients
with splenomegaly measured by CT scan have more ad-
vanced liver fibrosis on the nontumor part and poorer liver
functional reserve, which may lead to dismal outcomes
after RFA. To validate this hypothesis, we conducted this
he prevalence and related mortality of hepatocellular
carcinoma (HCC) are increasing worldwide, and HCC
Received for publication December 9, 2011; accepted April 30, 2012.
From the Departments of *Medicine, Division of Gastroenterology;
wRadiology, Division of Gastrointestinal Radiology; 8Radiology,
Division of Ultrasonography; yMedicine, Division of Gastro-
enterology, Taoyuan Branch; #Medical Research and Education,
Taipei Veterans General Hospital; zFaculty of Medicine; zInstitute
of Clinical Medicine; **Institute of Pharmacology, School of
Medicine, National Yang-Ming University; wwDepartment of
Medicine, National Defense Medical Center, School of Medicine;
and zzCheng Hsin General Hospital, Taipei, Taiwan.
Supported by grants from the National Science Council, Taiwan
(98-2314-B-075-030-MY2, 100-2314-B-075-073), Taipei Veterans
General Hospital (V98C1-120, V100A-034, V100C-034), and the
Center of Excellence for Cancer Research at TVGH (DOH100-TD-
C-111-007), Taipei, Taiwan.
The authors declare that they have nothing to disclose.
Reprints: Chien-Wei Su, MD, Department of Medicine, Division of
Gastroenterology, Taipei Veterans General Hospital; No. 201,
Sec.2, Shih-Pai Road, 11217 Taipei, Taiwan (e-mail: cwsu2@vghtpe.
gov.tw).
Copyrightr2012 by Lippincott Williams & Wilkins
ORIGINAL ARTICLE
J Clin Gastroenterol?Volume 46, Number 9, October 2012 www.jcge.com|789

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retrospective study to evaluate the impact of splenomegaly
on the clinical manifestations and prognosis of HCC pa-
tients undergoing RFA.
MATERIALS AND METHODS
Patients and Follow-up
This cohort study retrospectively enrolled 161 HCC
patients who underwent percutaneous RFA in Taipei Vet-
erans General Hospital from December 2002 to December
2007. The inclusion criteria were fulfillment of the diagnostic
criteria of HCC by the American Association for the Study
of Liver Disease (consensus, 2010)22; tumor size <5cm
without extrahepatic metastasis; r3 tumors; grade A or B
Child-Pugh classification of liver function; no other major
diseases that might complicate RFA; and available CT scan
image file in the imaging archive of our hospital. This study
complied with the standards of the Declaration of Helsinki.
The device and procedure of RFA were as previously
described.5,13Briefly, it was performed with real-time ultra-
sonography guidance and the radiofrequency electrode of
the Cool-Tip Radiofrequency System (Radionics, Burling-
ton, MA) was advanced into the tumor. Treatment was
performed with a single (2- or 3-cm active tip) needle elec-
trode. Each tumor had 1 to 4 ablations per session depending
on the tumor size. After RFA, all patients underwent im-
mediate follow-up ultrasonography to evaluate the possi-
bility of bleeding or fluid accumulation.
Dynamic CT scan was performed 1 month after all of
the tumors were ablated by RFA. For residual tumors
confirmed by CT scan, subsequent courses of RFA were
performed.
If no viable tumor was detected, the patient was fol-
lowed up with testing for serum liver biochemistries, a-fe-
toprotein (AFP) levels, and ultrasonography every 3 months;
and CT scan or magnetic resonance imaging (MRI) every 6
months until December 31, 2010. The starting date of follow-
up for tumor recurrence was the day when all of the tumors
ablated by RFA were confirmed by CT scan or MRI.
Tumor recurrence was suspected if there was elevated
serum AFP level (>20ng/mL) or a new lesion detected by
surveillance ultrasonography. These were confirmed and
diagnosed by dynamic CT or MRI.
Biochemical and Serologic Markers
Serum liver function and biochemical tests, including
albumin, bilirubin, blood urea nitrogen, creatinine, alanine
aminotransferase (ALT), aspartate aminotransferase (AST),
alkaline phosphatase, g-glutamyltransferase, and glucose
levels, were tested by Roche/Hitachi Modular Analytics
Systems (Roche Diagnostics GmbH, Mannheim, Germany).
Serum hepatitis B surface antigen and AFP level were de-
termined by radioimmunoassay (Abbott Laboratories,
North Chicago, IL and Serono Diagnostic SA, Coinsin/VD,
Switzerland, respectively), whereas antibody to hepatitis C
virus (HCV) was investigated by second-generation enzyme
immunoassay (Abbott Laboratories).
Splenic Volume Calculation
Splenic volume was calculated for all patients accord-
ing to the following procedures and software (Virtual Place
workstation, AZE, Tokay, Japan). The whole spleen was
scanned (while holding the breath) with 5mm slice thickness
and interval settings. The area of each image was de-
termined on the monitor by tracking the splenic margin with
a built-in cursor controlled by 1 single experienced radiol-
ogist (Y.Y.C., with 14y of experience in diagnostic radio
logy). The area was then calculated. A 3-D reconstruction of
the spleen was rendered using CT data and the total splenic
volume was calculated. In this study, the patients were
divided into 2 groups, with 300mL as cut-off level of splenic
volume and splenomegaly was defined as splenic volume
>300mL.23,24
Statistical Analysis
Baseline characteristics for evaluation with outcomes
were selected using the 2001 European Association for the
Study of the Liver guidelines.25Pearson w2analysis or
TABLE 1. Comparison of Demographic Data of Between Patients With and Those Without Splenic Volume >300mL
ParametersTotal (n=161)
r300 mL (n=83) >300 mL (n=78)P
Patient demographics
Age (y) (mean±SD)
Sex (male/female) (%)
Serum biochemistry tests and liver function tests (median; 25 and 75 percentiles)
Albumin (g/dL)
Cholesterol (mg/dL)
Total bilirubin (mg/dL)
ALT (U/L)
AST (U/L)
Creatinine (mg/dL)
Alk-P (U/L)
Platelet count ( /mm3)
Viral factors
HBsAg (positive/negative) (%)
Anti-HCV (positive/negative) (%)
Tumor factors
Tumor size (cm) (median; 25 and 75 percentiles)
Single/multinodularity (%)
AFP (ng/mL) (median; 25 and 75 percentiles)
Splenic volume (median; 25 and 75 percentiles)
67.5±11.4
104/57 (64.6%/35.4%)
65.2±11.0
54/29 (65.1%/34.9%)
69.6±11.4
50/28 (64.1%/35.9%)
0.013
1.000
3.9; 3.5-4.2
162.0; 138.0-186.0
0.8; 0.6-1.3
52.0; 32.0-103.5
55.0; 36.0-98.5
1.0; 0.8-1.2
104.0; 74.0-143.3
113000; 84500-152000
4.0; 3.8-4.4
165.5; 148.5-197.8
0.7; 0.5-1.1
49.0; 29.0-93.0
46.0; 29.0-92.0
1.0; 0.8-1.3
86.0; 67.0-133.0
147000; 119000-186000
3.7; 3.2-4.0
153.0; 125.0-174.0
1.0; 0.7-1.6
57.0; 36.0-111.3
61.5; 39.8-101.5
1.0; 0.8-1.1
110.0; 80.0-149.5
88000; 61750-109000
<0.001
0.004
<0.001
0.270
0.498
0.988
0.036
<0.001
74/84 (46.8%/53.2%)
71/87 (44.9%/55.1%)
41/40 (50.6%/49.4%)
30/51 (37.0%/63.0%)
33/40 (42.9%/57.1%)
41/36 (53.2%/46.8%)
0.414
0.059
2.2; 1.8-2.92.2; 1.6-2.7
70/13 (84.3%/15.7%)
15.1; 5.2-49.7
174.0; 118.6-252.1
2.3; 1.8-2.9
58/20 (74.4%/25.6%)
23.7; 9.9-48.1
494.8; 380.3-798.3
0.293
0.170
0.319
128/33 (79.5%/20.5%)
18.0; 7.2-49.2
292.0; 171.2-485.1<0.001
AFP indicates a-fetoprotein; ALT, alanine aminotransferase; Alk-P, alkaline phosphatase; AST, aspartate aminotransferase; HBsAg, hepatitis B surface
antigen; HCV, hepatitis C virus; SD, standard deviation.
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Fisher exact test were used to compare categorical varia-
bles, whereas the Mann-Whitney U test was used to com-
pare continuous variables. Cumulative recurrence rates or
overall survival rates were estimated by the Kaplan-Meier
method and compared using the Cox proportional hazards
model.
The accuracy of serum markers for splenomegaly was
determined by testing sensitivity, specificity, positive pre-
dictive value, and negative predictive value, and by calcu-
lating the area under the curve for the corresponding receiver
operating curves (AUROC). The AUROC was expressed as
plots of the test sensitivity versus 1?specificity. The AUROC
cut-off value was determined by MedCalc (version 4.20,
MedCalc Software, Mariakerke, Belgium).
Variables with statistical significance (P<0.05) or
proximate to it (P<0.1) by univariate analysis underwent
multivariate analysis by Cox forward stepwise logistic re-
gression model. A 2-tailed P<0.05 was considered stat-
istically significant. All statistical analyses were performed
using the Statistical Package for Social Sciences (SPSS 17.0
for Windows, SPSS Inc., Chicago, IL).
RESULTS
Demographics Data of RFA Patients Stratified by
Splenic Volume
The demographic characteristics of all patients are
shown in Table 1. Of the 161 patients, 137 were successfully
treated with 1 RFA session, whereas 18 had 2 sessions. The
remaining 6 patients who had treatment failure after 2 RFA
sessions either underwent further RFA (3 patients) or
transarterial chemoembolization (3 patients) as rescue
therapies. In the study cohort, 22 patients received antiviral
therapy after RFA, including 7 with lamivudine, 4 with
entecavir, and 11 patients with pegylated interferon therapy.
A total of 78 patients had splenomegaly measured by
CT scan, while the remaining 83 patients had normal
splenic volume at the time of receiving RFA. Patients with
splenomegaly were older, had lower serum albumin, cho-
lesterol levels, platelet counts, and higher serum bilirubin
and alkaline phosphatase levels than their counterpart.
They also had a trend of higher rates of HCV infection
(P=0.059). Tumor factors, the tumor size, tumor number,
and serum AFP levels were comparable between patients
with and those without splenomegaly.
Factors Associated With Overall Survival and
Recurrence
After a median follow-up of 38.1±20.8 months, 41
patients died and 120 were still alive on their last visit. The
overall cumulative survival rates at 1, 2, 3, and 5 years were
96.0%, 85.5%, 76.2%, and 67.5%, respectively. Stratified
by splenic volume, the overall cumulative survival rates at
1, 2, 3, and 5 years were 97.5%, 88.5%, 87.0%, and 77.8%,
respectively, in patients with normal splenic volume, and
94.5%, 82.1%, 63.5%, and 54.8%, respectively, in patients
with splenomegaly (P=0.003) (Fig. 1A).
Multivariate analysis revealed that age 65 years and
older [hazard ratio (HR), 2.543; 95% confidence interval
(CI), 1.242-5.204; P=0.011], serum albumin r3.5g/dL
(HR, 4.854; 95% CI, 2.558-9.174; P<0.001), and splenic
volume >300mL (HR, 2.152; 95% CI, 1.086-4.263; P=
0.028) were the independent risk factors associated with
poor overall survival (Table 2). If splenic volume was not
enrolled in the multivariate analysis, age 65 years and above
(HR, 2.367; 95% CI, 1.170-4.788; P=0.017), serum albu-
min levels r3.5g/dL (HR, 4.132; 95% CI, 2.079-8.197;
P<0.001), and platelet count r105/mm3(HR, 2.119; 95%
CI, 1.053-4.274; P=0.035) were the independent risk fac-
tors associated with poor overall survival.
After RFA therapy, 113 patients had tumor re-
currence. The cumulative rate of recurrence at 1, 2, 3, and 5
years were 38.7%, 55.5%, 69.8%, and 82.4%, respectively.
Stratified by splenic volume, the cumulative recurrence
rates were comparable between patients with and without
splenomegaly (P=0.786) (Fig. 1B).
Validation of Noninvasive Serum Markers for
Predicting Splenomegaly in HCC Patients
On the basis of several noninvasive serum markers
previously validated for predicting the stage of liver fibrosis
in patients with chronic hepatitis, including AST to ALT
ratio, AST to platelet ratio index (APRI), cirrhosis discrim-
inant score (CDS), age-platelet index (API), Lok model, and
FIB-4 (Table 3),18,26–32the current study assessed 8 non-
invasive serum markers for predicting splenomegaly in our
cohort. HCC patients with splenomegaly had significantly
higher APRI, API, CDS, FIB-4, and Lok model, but lower
platelet count and lower serum albumin levels than those
FIGURE 1. Comparison of cumulative overall survival and re-
currence in hepatocellular carcinoma patients after radio-
frequency ablation stratified by splenic volume. A, Patients with
splenomegaly had poorer overall survival rate than those with
normal splenic volume (P=0.003). B, The recurrence rates were
comparable between the 2 groups.
J Clin Gastroenterol?Volume 46, Number 9, October 2012Splenic Volume Predicts RFA Prognosis
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with normal splenic volume. However, the AST to ALT ratio
levels were comparable between the 2 groups (Fig. 2).
The receiver operating curves of these markers for
predicting splenomegaly are shown in Figure 3. APRI, API,
CDS, FIB-4, Lok model, platelet count, and serum albumin
all showed reliable abilities to predict splenomegaly in HCC
patients. Platelet count, APRI, and API had excellent sensi-
tivity and negative predictive value, whereas platelet count,
serum albumin level, and CD4 had relatively good specif-
icity and positive predictive value (Table 4). Platelet count
yielded the highest AUROC with a level of 0.868 at a cut-
off value of 11,7000/mm3.
DISCUSSION
The present study demonstrates that HCC patients
with splenomegaly measured by CT scan have relatively
poorer liver functional reserve, represented by lower platelet
counts and serum albumin levels and higher serum bilirubin
levels, than those with normal splenic volume. Splenome-
galy is an independent risk factor predicting overall survival
for patients with small HCC undergoing RFA, which sug-
gests that splenomegaly is an objective, reliable, and feasible
marker for assessing liver functional reserve and predicting
outcomes for patients with early-stage HCC.
Although RFA can provide an acceptable overall
survival for HCC patients who cannot undergo resection
surgery or liver transplantation, the recurrence rate after
therapy remains high.4,5,17Moreover, reliable markers to
predict long-term prognosis after RFA are still scarce. To
improve the outcomes of HCC patients after RFA, it is
necessary to elucidate the mechanism of hepatocarcino-
genesis and search for the clinically critical risk factors as-
sociated with long-term prognosis, which may be the
potential therapeutic target for adjuvant therapy. In this
study, older age, lower serum albumin level, and spleno-
megaly are independent risk factors associated with poor
overall survival for patients with HCC undergoing RFA,
suggesting that liver functional reserve and splenomegaly
may have more profound impact than tumor factors on
determining prognosis in patients with early-stage HCC.
Splenomegaly is an important clinical indicator of por-
tal hypertension and cirrhosis. Possible mechanisms include
the pooling of blood in the red pulp of the spleen, hyper-
plasia of histiocytes, increased reticuloendothelial fibers and
of subcapsular myofibroblasts, and a progressive enlarge-
ment and hyperplasia of arterial terminals with the pro-
gression of liver fibrosis.33In the present study, patients
with splenic volume >300mL have significantly higher
serum bilirubin levels and lower levels of albumin, choles-
terol, and platelet counts. This is reasonable because sple-
nomegaly found in patients with liver disease is thought as
TABLE 2. Univariate and Multivariate Analysis of Factors Associated With Poor Overall Survival After RFA for HCC
Univariate AnalysisMultivariate Analysis
Variables
Age >65/r65y
Sex F/M
HBsAg positive/negative
Anti-HCV positive/negative
Albumin r3.5/>3.5g/dL
Bilirubin >1.6/r1.6mg/dL
ALT >40/r40U/L
AST >45/r45U/L
Platelet r105/>105/mm3
AFP >20/r20ng/mL
Multiple tumor (yes/no)
Tumor size >2cm/r2cm
Splenic volume >300mL/r300mL*
Case No. HR (95% CI)PHR (95% CI)P
94/67
57/104
74/84
71/87
43/108
20/140
100/61
93/68
58/103
77/84
33/128
96/65
78/83
1.985 (0.994-3.961)
2.134 (1.156-3.939)
0.848 (0.455-0.582)
1.493 (0.802-2.778)
5.495 (2.941-10.309)
4.242 (2.068-8.702)
2.043 (1.001-4.168)
2.871 (1.406-5.860)
3.610 (1.927-6.757)
2.294 (1.203-4.376)
1.784 (0.893-3.565)
1.314 (0.701-2.463)
2.559 (1.340-4.887)
0.052
0.015
0.605
0.206
2.543 (1.242-5.204)0.011
<0.001
<0.001
0.050
0.004
<0.001
0.012
0.097
0.394
0.003
4.854 (2.558-9.174)<0.001
2.152 (1.086-4.263)0.028
*If splenic volume was not enrolled in the multivariate analysis, age 65 years and older (HR, 2.367; 95% CI, 1.170-4.788; P=0.017), serum albumin levels
r3.5g/dL (HR, 4.132; 95% CI, 2.079-8.197; P<0.001), and platelet count r105/mm3(HR, 2.119; 95% CI, 1.053-4.274; P=0.035) were the independent risk
factors associated with poor overall survival.
AFP indicates a-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HBsAg, hepatitis B surface antigen;
HCV, hepatitis C virus; HCC, hepatocellular carcinoma; HR, hazard ratio; RFA, radiofrequency ablation.
TABLE 3. Noninvasive Serum Markers for Predicting the Stage of
Liver Fibrosis
MarkersCalculations
AAR
APRI
AST/ALT
([AST/upper limit of normal value: 45 IU/L] /
platelet counts (109/L)) ? 100
(1) Platelets (?1000/mm3): >340=0;
280-339=1, 220-279=2; 160-219=3;
100-159=4; 40-99=5; and <40=6.
(2) ALT/AST ratio: >1.7=0; 1.2-1.7=1;
0.6-1.19=2; and <0.6=3.
(3) PT INR: <1.1 =0; 1.1-1.4=1; and
>1.4=2.
CDS is the sum of the above 3 parameters
(possible value, 0-11)
(1) Age (y): <30=0; 30-39=1; 40-49=2;
50-59=3; 60-69=4; r70=5
(2) Platelet count (?109/L): Z225=0;
200-224=1; 175-199=2; 150-174=3;
125-149=4; <125=5
API is the sum of the above 2 parameters
(possible value, 0-10)
Log odds= ?5.56-0.0089?platelet
(109/L)+1.26?AST/ALT ratio+5.27?INR
Age (y)?AST [U/L]/(platelets [109/L]?
(ALT [U/L])1/2
CDS
API
Lok model
FIB-4
AAR indicates AST to ALT ratio; ALT, alanine aminotransferase; API,
age-platelet index; APRI, AST to platelet ratio index; AST, aspartate ami-
notransferase; CDS, cirrhosis discriminant score; INR, international nor-
malized ratio; PT, prothrombin time.
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the result of portal hypertension and a sequelae of ad-
vanced liver fibrosis.5Serum bilirubin and albumin levels
are the components of Child-Pugh score for evaluating liver
function and lower serum albumin or elevated total bilir-
ubin levels indicate poor liver functional reserve. Choles-
terol is synthesized by the liver, and lower serum cholesterol
level is also related to poor liver function in patients with
chronic hepatitis. The increased size of pool for platelet
sequestration can also explain the lower platelet count of
patients with larger splenic volumes. Consequently, larger
splenic volume in HCC patients may be interpreted as poor
liver function because of more advanced stages of portal
hypertension and liver fibrosis, which in turn leads to poor
prognosis after RFA.5
In early-stage HCCs, the impact of tumor factors de-
creases and background field factors play more important
roles in determining prognosis after curative therapies.14,18
Our previous study has demonstrated that the degree of
liver fibrosis on the nontumor part is associated with
prognosis for solitary small HCC after resection surgery.18
Consequently, assessing portal hypertension and the degree
of liver fibrosis at the time of diagnosis may help physicians
predict the outcomes of HCC patients in the early tumor
stage. As CT scan is essential for the diagnosis of HCC by
current consensus, abdominal organ volume can easily be
measured without additional image survey or radiation and
contrast medium exposure.22The current study demon-
strates that splenic volume measured by CT scan is a readily
available and reliable marker to evaluate the degree of liver
functional reserve and predict prognosis after RFA. It may
be recommended for clinical practice.
Although splenomegaly is a well-known important sign
of portal hypertension in patients with chronic hepatitis,
how to measure splenic volume and define splenomegaly by
imaging study is still controversial. Ultrasonography is
widely applied for evaluating splenomegaly in daily clinical
practice. However, it is relatively dependent on the exam-
iners and may be confounded by the variable, irregular
contour of the spleen and overlapping of splenic outline by
bone, kidney, or bowel gas.34Estimating spleen or liver
volume by CT scan has been introduced for assessing the
FIGURE 2. Box and whisker graphs of the relationship between splenic volume and (A) platelet count, (B) FIB-4, (C) Lok model, (D) AST
to ALT ratio (AAR), and (E) albumin. The middle horizontal line inside each box depicts the median, and the width of each box
represents the 25th and 75th percentiles. Vertical lines represent the 10th and 90th percentiles. ALT indicates alanine aminotransferase;
AST, aspartate aminotransferase.
FIGURE 3. Receiver operating curves of noninvasive serum
markers in predicting splenomegaly. AAR indicates AST to ALT
ratio; ALT, alanine aminotransferase; API, age-platelet index;
APRI, AST to platelet ratio index; AST, aspartate aminotransferase;
CDS, cirrhosis discriminant score.
J Clin Gastroenterol?Volume 46, Number 9, October 2012 Splenic Volume Predicts RFA Prognosis
r2012 Lippincott Williams & Wilkinswww.jcge.com|793

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degree of liver fibrosis and cirrhosis.20,21There is a trend
towards a decrease in liver volume and an increase in splenic
volume with higher stages of hepatic fibrosis. Splenic vol-
ume has a better discriminative ability for predicting the
stage of liver fibrosis and cirrhosis compared with liver
volume.20
Furthermore, splenic volume is not influenced by age,
body height, weight, body mass index, and the transverse
diameter of the first lumber vertebra.23In contrast, liver
volume is related to body height, weight, and body surface
area.35,36As such, the estimation of splenic volume by CT
scan is clinically applicable and does not need to be ad-
justed by demographic characteristics. Regarding HCC
patients, the presence of tumor may confound the meas-
urement of liver volume. Taken together, splenic volume
measured by CT scan seems to be a reliable and feasible
marker for assessing the stage of liver fibrosis for HCC
patients. Previous studies suggest an upper limit volume of
314.5mL measured by CT scan for the normal spleen.23,24
The present study further demonstrates that splenic vol-
ume, with a cut-off level of 300mL, can reflect liver func-
tion and predict outcomes for patients with early-stage
HCC undergoing RFA.
Liver biopsy is regarded as the gold standard for as-
sessing the degree of liver fibrosis and for establishing the
diagnosis of cirrhosis in patients with concomitant chronic
hepatitis.37However, it is costly and is an invasive proce-
dure, with 1.1% risk of serious adverse advents, including
bleeding, pneumothorax, punctured gall bladder, and syn-
cope.38Sampling errors, intraobserver bias, and interob-
server variation also decrease the reliability of liver biopsy.18
Several noninvasive serum markers have been introduced as
surrogates for evaluating the degree of liver fibrosis and for
predicting outcomes in patients with chronic hepatitis.37,39,40
The present study also validates these markers for predicting
the presence of splenomegaly by showing that platelet count,
serum albumin levels, APRI, API, CDS, FIB-4, and Lok
model exhibit reliable discriminative ability to predict the
presence of splenomegaly. This suggests a close relationship
between splenomegaly and the stage of liver fibrosis.
Among these markers, platelet count has the highest
AUROC with a level of 0.868. It echoes the role of higher
sequestration of platelets in the enlarged spleen of patients
with advanced hepatic fibrosis and cirrhosis. However, even
though platelet count and splenomegaly both predicted
poor overall survival by univariate analysis, only spleno-
megaly remained as an independent risk factor by multi-
variate analysis. This implies that splenomegaly may have
more pathologic significance in reflecting the degree of
liver functional reserve or portal hypertension than platelet
counts. Splenomegaly may be more suitable than throm-
bocytopenia as the prognostic marker for patients with
early-stage HCC after RFA. Nevertheless, if splenic volume
measurement is not available, our data demonstrate that
thrombocytopenia could be served as a reliable surrogate to
predict not only splenomegaly but also long-term prognosis
of HCC patients who undergo RFA.
The major etiologies of HCC in our cohort are chronic
hepatitis B virus (46.8%) and HCV (44.9%) infections.
HCC caused by different viruses may have diverse degrees
of liver fibrosis and portal hypertension in the nontumor
part.16However, because of the relatively small number of
patients in each group, the limitation of our study is that we
could not evaluate the predictive value of portal hyper-
tension and splenic volume for the post-RFA outcomes
stratified by each etiology of HCC. Further prospective
studies are warranted to assess this issue.
In conclusion, HCC patients with splenomegaly
measured by CT scan have relatively poorer liver functional
reserve than those with normal splenic volume. Splenome-
galy (>300mL) is an independent risk factor predicting
overall survival for patients with small HCC after RFA.
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TABLE 4. Diagnostic Accuracies of Noninvasive Serum Markers for Predicting Splenomegaly
Parameters Cut-Off
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(%)
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PPV
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