J Hepatobiliary Pancreat Sci (2010) 17:892–897
DOI 10.1007/s00534-010-0290-4
ORIGINAL ARTICLE
Perioperative change in white blood cell count predicts outcome
of hepatic resection for hepatocellular carcinoma
Yuki Fujiwara • Hiroaki Shiba • Kenei Furukawa • Tomonori Iida •
Taro Sakamoto • Takeshi Gocho • Shigeki Wakiyama • Shoichi Hirohara
Yuichi Ishida • Takeyuki Misawa • Toya Ohashi • Katsuhiko Yanaga
Received: 5 January 2010 / Accepted: 30 March 2010 / Published online: 7 May 2010
Ó Japanese Society of Hepato-Biliary-Pancreatic Surgery and Springer 2010
Abstract
Background In spite of improvements in surgical man-
agement, hepatocellular carcinoma (HCC) still recurs after
operation in 60–70% of patients. Therefore, we investi-
gated the relation between perioperative change in white
blood cell count (WBC) and tumor recurrence as well as
survival in patients with HCC after hepatic resection.
Methods Subjects were 53 patients who underwent elec-
tive hepatic resection for HCC. We retrospectively exam-
ined the relation between perioperative change in WBC
and recurrence of HCC as well as overall survival.
Results Advanced tumor stage and increasing of WBC on
postoperative day (POD) 1 were positively associated with
worse disease-free survival rate on both univariate and
multivariate analysis (P \ 0.05). Advanced tumor stage,
increasing of WBC on POD 1, and blood transfusion were
positively associated with worse overall survival rate on
univariate analysis (P \ 0.05), while change in WBC was
the only independent factor on multivariate analysis
(P \ 0.05).
Conclusions Perioperative change in WBC after elective
hepatic resection for HCC is positively associated with
recurrence and worse survival.
Y. Fujiwara (&)
H. Shiba
K. Furukawa
T. Iida

T. Sakamoto
T. Gocho
S. Wakiyama
S. Hirohara

Y. Ishida
T. Misawa
K. Yanaga
Department of Surgery, Jikei University School of Medicine,
3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan
e-mail: sheetan@jikei.ac.jp
Y. Fujiwara
K. Furukawa
T. Ohashi
Department of Gene Therapy, Institute of DNA Medicine,
Jikei University School of Medicine, Tokyo, Japan
123
•
Keywords Hepatocellular carcinoma
Hepatectomy

White blood cell count
Introduction
Hepatocellular carcinoma (HCC) is one of the commonest
malignant cancers in the world [1]. Hepatic resection is one
of the most effective treatments for patient with HCC [2].
In spite of improvements in surgical technique, instru-
ments, and perioperative management, HCC recurs after
hepatic resection in 60–70% of patients [2–8]. The 5-year
overall survival rate after hepatic resection is reported as
about 54% [9] and 62% [10]. Most investigators agree that
vascular invasion, intrahepatic metastasis, and tumor size
are independent risk factors for tumor recurrence after
curative hepatic resection [11–15].
Recent studies of immunosuppression in patients with
cirrhosis suggest contribution to HCC development [19,
20]. Several studies have indicated that elevated preoper-
ative neutrophil-to-lymphocyte ratio (NLR) or increased
preoperative monocyte count in peripheral blood is related
to poor prognosis in patients with HCC [16–18]. Moreover,
liver cirrhosis frequently results in pancytopenia, especially
severe leukocytopenia, due to hypersplenism [21]. It is the
hepatitis and cirrhotic patients are in a unique immune
status.
Therefore, we hypothesized that perioperative changes
in immune response might be one of the predictors of
tumor recurrence and survival in HCC patients after
elective hepatic resection. In this study, we retrospec-
tively investigated the relation between perioperative
change in white blood cell count (WBC) and disease-free
survival as well as overall survival after hepatic resection
for HCC.
J Hepatobiliary Pancreat Sci (2010) 17:892–897
Patients and methods
Between January 2002 and December 2006, 70 patients
underwent hepatic resection for HCC in the Department of
Surgery, Jikei University Hospital, Tokyo, Japan. Of these,
17 patients were excluded, including 2 patients for con-
comitant microwave coagulation or radiofrequency abla-
tion therapy, 5 patients for additional procedures for other
malignancies, 2 patients for secondary hepatic resection, 5
patients for lack of data, and 3 patients who were lost to
follow-up, leaving the remaining 53 patients for this study.
Generally, extent of hepatic resection was determined
based on retention rate of indocyanine green at 15 min
(ICGR15) before surgery and hepatic reserve, as described
by Miyagawa et al. [22].
Hemogram and chemistry profile were routinely mea-
sured for each patient preoperatively and on postoperative
day (POD) 1. Absolute WBC, lymphocyte, and each subset
were routinely determined in peripheral venous blood
samples. Serum biochemistry data and hemogram included
serum total bilirubin, serum albumin, prothrombin time,
C-reactive protein (CRP), and ICGR15. Use of blood prod-
ucts and dose were determined by the preference of
attending surgeons based on guidelines for administration
of blood products by the Japanese Ministry of Health and
Welfare settled in 1999 [23], as well as intraoperative blood
loss, postoperative data of hemoglobin, platelets, serum
albumin, and prothrombin time. Tumor factor (T factor)
staging was based on the general rules for clinical and
pathological study of primary liver cancer by the Liver
Cancer Study Group of Japan [24]. The type of resection was
classified into two groups: anatomical resection (extended
lobectomy, lobectomy, segmentectomy, or subsegmentec-
tomy) and nonanatomical limited partial resection.
For assessment of perioperative change in WBC, sub-
jects were classified into two groups: increasing of WBC
more than threefold on POD 1 in comparison with that
before operation, and increasing of WBC less than three-
fold on POD 1 in comparison with that before operation.
Then, we analyzed patient characteristics in relation to
perioperative change in WBC, using the following ten
factors: age, hepatitis virus status, preoperative ICGR15,
Child classification, presence or absence of liver cirrhosis,
T factor based on tumor pathology, type of resection,
duration of operation, intraoperative blood loss, and peri-
operative blood transfusion.
Next, we investigated the relation between clinical
variables and disease-free or overall survival after hepatic
resection by univariate and multivariate analysis. The
factors included the following 14 factors: age, hepatitis
virus status, preoperative ICGR15, Child classification,
presence or absence of liver cirrhosis, T factor based on
tumor pathology, type of resection, duration of operation,
893
intraoperative blood loss, perioperative blood transfusion,
and change in WBC, lymphocyte, CRP, and hemoglobin.
Recurrence of HCC was defined as newly detected
hypervascular hepatic or extrahepatic tumors by ultraso-
nography, computed tomography, magnetic resonance
image or angiography with or without increase in serum
a-fetoprotein, or protein induced by vitamin K absence or
antagonist-II. For recurrent HCC in the liver, repeated
hepatic resection, local ablation therapy, or transarterial
chemoembolization was given based on hepatic functional
reserve judged mainly by ICGR15. Extrahepatic recurrence
was mainly treated conservatively.
Statistical analysis
Data are expressed as mean ± standard deviation (SD).
Univariate analysis was performed using nonpaired Stu-
dent’s t test and chi-square test. Analysis of disease-free
and overall survival was performed using log-rank test.
Factors found to significantly influence disease-free or
overall survival were then used in the Cox proportional
regression model for multivariate analysis. All P values
were considered statistically significant when the associ-
ated probability was less than 0.05.
Results
Association between clinical variables and change
in white blood cell counts
Table 1 lists the relationship between clinical variables and
perioperative change in WBC. On univariate analysis, T
factor of tumor pathology was positively correlated with
perioperative change in WBC (P = 0.0157). Child classi-
fication showed a trend towards correlation with periop-
erative change in WBC but without significant difference
(P = 0.0527).
Univariate and multivariate analysis of disease-free
and overall survival after hepatic resection and clinical
variables
Table 2 lists the relationship between the clinical variables
and disease-free as well as overall survival after hepatic
resection. On univariate analysis, worse disease-free sur-
vival was positively correlated with advanced T factor of
tumor pathology (P = 0.0064) and increasing of WBC
more than threefold on POD 1 compared with before
operation (P = 0.0287, Fig. 1a). Worse overall survival
was positively correlated with T factor of tumor pathology
(P = 0.0025), increasing of WBC more than threefold on
123
894
Table 1 Univariate analysis of patient characteristics in relation to perioperative change in white blood cell count
Factor
Age (years)
Hepatitis virus (HBV:HCV:no)
ICGR15 (%)
Child classification (A:B:C)
Liver cirrhosis (present:absent)
T factor (T1:T2:T3:T4)
Type of resection (anatomical:nonanatomical)
Duration of operation (min)
Blood loss (g)
Blood transfusion (yes:no)
WBC white blood cell count, HBV hepatitis B virus, HCV hepatitis C virus, T factor tumor factor
a
Mean ± SD
POD 1 compared with before operation (P = 0.0002,
Fig. 1b), and perioperative blood transfusion
(P = 0.0142). On multivariate analysis, T factor of tumor
pathology (P = 0.0133) and increasing of WBC more than
threefold on POD 1 compared with before operation
(P = 0.0498) were significant predictors of disease-free
survival (Table 3), but only increasing of WBC more than
threefold on POD 1 compared with before operation
(P = 0.0483) was a significant predictor of overall survival
(Table 4).
Discussion
Recently, several investigators have reported the relation
between perioperative immunological and inflammatory
findings, and tumor recurrence and prognosis in patients
with various malignant tumors [18, 25–27]. Bruckner
et al. [25] reported that pretreatment WBC \10,000/mm3,
absolute granulocyte count \6,000/mm3, lymphocyte
count [1,500/mm3, and monocyte count 300–900/mm3
were independent good prognostic factors of patients with
metastatic gastric carcinoma. Gomez et al. [17] reported
that preoperative NLR was associated with prognosis of
patients with HCC after curative resection, because
patients with elevated NLR had relative lymphocytopenia
and weakened lymphocytic infiltration. Several investi-
gators reported that the number of forkhead box P3
(FOXP3?), CD4?, and/or CD25? regulatory T (Treg)
cells in peripheral blood and/or tumors are increased, and
that elevated Treg count after surgery was a poor prog-
nostic factor of patients with malignant tumors of the
ovary [28], head and neck [29], liver [30–33], gastroin-
testinal tract [34, 35], pancreas [36, 37], breast [36], lung
123
J Hepatobiliary Pancreat Sci (2010) 17:892–897
Change in WBC P value
C3 times (n = 13) \3 times (n = 40)
62.8 ± 14.8 60.0 ± 8.5a 0.4988
2:9:2 18:15:7 0.1060
14.5 ± 10.8 13.1 ± 9.0 0.6406
10:3:0 38:2:0 0.0527
7:6 15:25 0.4202
2:6:2:3 11:21:8:0 0.0157
3:10 12:38 0.6362
314.2 ± 124.6 296.5 ± 115.5 0.6391
1,234.5 ± 1,590.3 750.0 ± 734.7 0.1368
5:8 7:33 0.1167
[38, 39], and prostate [40], because Treg inhibited tumor-
infiltrating lymphocyte that plays an important role in
immune response to tumor. Moreover, FOXP3?, CD4?,
and/or CD25? Treg are inhibited by interleukin-6 (IL-6),
which play important roles as a proinflammatory cytokine
and in CRP production in hepatocytes [41]. Lan et al.
[42] reported raised serum IL-6 and CRP responses after
hepatic resection in patients with liver disease. Several
investigators reported that pre- and postoperative CRP
were prognostic factors in patients with HCC [43, 44] and
colorectal liver metastases [45]. Besides, immunosup-
pression may easily occur in HCC patients with liver
cirrhosis due to hepatitis virus infection [19, 20, 46].
Kawarabayashi et al. [46] reported that the total number
of CD56? T cells in liver tissue, which might play an
important role in both hepatocyte injury in chronic viral
hepatitis and antitumor immunity in the liver, were
decreased in patients with liver cirrhosis more than in
those without hepatitis C virus infection. This immuno-
suppression in patients with severe lymphopenia due
to liver cirrhosis might be associated with progression
of HCC. Therefore, perioperative immunological and
inflammatory changes of HCC patients are more impor-
tant than those of other malignancy patients for tumor
recurrence and patient prognosis. In the present study,
perioperative WBC more than threefold higher on POD 1
compared with before operation in peripheral blood was
shown to be an independent prognostic factor of both
disease-free and overall survival in patients with HCC
after elective hepatic resection. Because pretherapeutic
inflammatory or immunological findings such as periph-
eral WBC, monocyte counts, or Glasgow prognostic score
predict outcome of treatment for malignancies [25, 30,
47], perioperative alterations of WBC also may reflect
J Hepatobiliary Pancreat Sci (2010) 17:892–897 895

Table 2 Univariate analysis of disease-free and overall survival after

hepatic resection
Factor N Disease-free survival Overall survival
Median P value Median P value
(years) (years)

Age (years)
\60 26 2.95 0.1156 3.44 0.5347
C60 27 2.24 3.78
Hepatitis virus
HBV 20 2.91 0.3203 3.44 0.9666
HCV 24 2.19 3.78
No 9 2.89 3.93
ICGR15 (%)
\15 37 2.85 0.0754 3.91 0.5928
C15 16 1.88 3.61
Child classification
A 48 2.78 0.1735 3.64 0.5295
B or C 5 2.30 3.71
Liver cirrhosis
Absent 31 3.12 0.0558 3.78 0.0791
Present 22 2.47 3.38
T factor
T1 or T2 40 2.95 0.0064 3.71 0.0025
T3 or T4 13 1.53 3.42
Type of resection
Anatomical 15 2.75 0.1638 3.93 0.4975
Fig. 1 White blood cell count increasing more than threefold on
Nonanatomical 38 2.75 3.64 POD 1 compared with before operation was positively correlated with
Duration of operation (min) both worse disease-free survival (a P = 0.0287) and worse overall
\300 27 2.47 0.2739 3.93 0.8309 survival (b P = 0.0002)
C300 26 2.78 3.34
Blood loss (g)
\1,000 39 2.73 0.3955 3.51 0.9227
C1,000 14 3.00 4.58 Table 3 Multivariate analysis of disease-free survival after hepatic
Blood transfusion resection
Yes 12 2.47 0.5373 3.81 0.0142 Factor Odds ratio (95% CI) P value
No 41 2.89 3.71
Change in WBC T factor (T3 or T4) 2.835 (1.243–6.467) 0.0133
\3 times 40 2.85 0.0287 3.64 0.0002 Change in WBC (C3 times) 2.283 (1.001–5.208) 0.0498
C3 times 13 1.44 3.71 T factor tumor factor, WBC white blood cell count, CI confidence
Change in lymphocyte (/ll) interval
\-500 30 2.80 0.8481 3.71 0.1557
C-500 23 2.60 3.64
Table 4 Multivariate analysis of overall survival after hepatic
Change in CRP (mg/dl) resection
\8.0 38 2.30 0.7521 3.373 0.4762
Factor Odds ratio (95% CI) P value
C8.0 15 3.14 3.905
Change in Hb (g/dl) T factor (T3 or T4) 7.285 (0.743–71.468) 0.0883
\-3 32 2.75 0.1782 4.23 0.8239 Change in WBC (C3 times) 10.610 (1.017–110.655) 0.0483
C-3 21 3.18 4.02 Blood transfusion (yes) 1.886 (0.278–12.784) 0.5159

HBV hepatitis B virus, HCV hepatitis C virus, T factor tumor factor, T factor tumor factor, WBC white blood cell count, CI confidence
WBC white blood cell count, CRP C-reactive protein, Hb hemoglobin interval

123
896
inflammatory and immunological status of patients, and
may correlate with prognosis after hepatic resection for
HCC.
Patients with HCC are frequently characterized by
peripheral blood cytopenia, neutropenia, leukocytopenia,
and thrombocytopenia. Savill et al. [48] reported the rela-
tion between neutrophil lifespan and apoptosis. Kusaba
et al. [49] reported that neutrophil lifespan in cirrhotic
patients was shortened by accelerated apoptosis in vitro. In
this study, preoperative peripheral WBC levels in only 36
of 53 patients were within normal limits, whereas those in
13 of 53 patients were below normal limits, probably due
to these mechanisms. Several investigators have reported it
was detectable to high concentration of tumor necrosis
factor-alpha (TNF-a), granulocyte-macrophage colony-
stimulating factor (GM-CSF), and interferon-gamma (IFN-
c) in the serum, which play important roles in proliferation,
antiapoptosis [50, 51], and neutrophil apoptosis [52, 53]. It
is suggested that such a unique internal environment makes
the perioperative immunological and inflammatory reac-
tion of the patient with HCC, and assessment of more
cases, necessary to analyze and prevent tumor recurrence
after hepatic resection.
Conclusion
Perioperative change in WBC in peripheral blood is an
independent risk factor for disease-free and overall
survival, and may be a predictor of tumor recurrence
and survival in HCC patients after elective hepatic
resection.
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