Original article

Hepatocellular carcinoma tumour burden score to stratify

prognosis after resection

D. I. Tsilimigras1 , D. Moris1 , J. M. Hyer1 , F. Bagante1,4 , K. Sahara1 , A. Moro1 , A. Z. Paredes1 ,

R. Mehta1 , F. Ratti5 , H. P. Marques6 , S. Silva6 , O. Soubrane7 , V. Lam8 , G. A. Poultsides3 , I. Popescu10 ,
S. Alexandrescu10 , G. Martel11 , A. Workneh11 , A. Guglielmi4 , T. Hugh9 , L. Aldrighetti5 ,
I. Endo12 , K. Sasaki2 , A. Rodarte2 , F. N. Aucejo2 and T. M. Pawlik1

Departments of Surgery, 1 Ohio State University Wexner Medical Center, Columbus, and 2 Digestive Disease Institute, Cleveland Clinic, Cleveland,
Ohio, and 3 Stanford University, Stanford, California, USA, Departments of Surgery, 4 University of Verona, Verona, and 5 Ospedale San Raffaele, Milan,
Italy, 6 Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal, 7 Department of Hepatobiliopancreatic Surgery, Assistance Publique – Hôpitaux
de Paris, Beaujon Hospital, Clichy, France, Departments of Surgery, 8 Westmead Hospital, and 9 University of Sydney, School of Medicine, Sydney, New
South Wales, Australia, 10 Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania, 11 Department of Surgery, University of Ottawa,
Ottawa, Ontario, Canada, and 12 Yokohama City University School of Medicine, Yokohama, Japan
Correspondence to: Professor T. M. Pawlik, Department of Surgery, Ohio State University, Wexner Medical Center, 395 W 12th Avenue, Suite 670,
Columbus, Ohio 43210-1240, USA (e-mail: tim.pawlik@osumc.edu)

Background: Although the Barcelona Clinic Liver Cancer (BCLC) staging system has been largely
adopted in clinical practice, recent studies have emphasized the need for further refinement and
subclassification of this system.
Methods: Patients who underwent hepatectomy with curative intent for BCLC-0, -A or -B hepatocellular
carcinoma (HCC) between 2000 and 2017 were identified using a multi-institutional database. The
tumour burden score (TBS) was calculated, and overall survival (OS) was examined in relation to TBS
and BCLC stage.
Results: Among 1053 patients, 63 (6⋅0 per cent) had BCLC-0, 826 (78⋅4 per cent) BCLC-A and 164
(15⋅6 per cent) had BCLC-B HCC. OS worsened incrementally with higher TBS (5-year OS 77⋅9, 61
and 39 per cent for low, medium and high TBS respectively; P < 0⋅001). No differences in OS were
noted among patients with similar TBS, irrespective of BCLC stage (61⋅6 versus 58⋅9 per cent for
BCLC-A/medium TBS versus BCLC-B/medium TBS, P = 0⋅930; 45 versus 13 per cent for BCLC-A/high
TBS versus BCLC-B/high TBS, P = 0⋅175). Patients with BCLC-B HCC and a medium TBS had better
OS than those with BCLC-A disease and a high TBS (58⋅9 versus 45 per cent; P = 0⋅005). On multivariable
analysis, TBS remained associated with OS among patients with BCLC-A (medium TBS: hazard ratio
(HR) 2⋅07, 95 per cent c.i. 1⋅42 to 3⋅02, P < 0⋅001; high TBS: HR 4⋅05, 2⋅40 to 6⋅82, P < 0⋅001) and
BCLC-B (high TBS: HR 3⋅85, 2⋅03 to 7⋅30; P < 0⋅001) HCC. TBS could also stratify prognosis among
patients in an external validation cohort (5-year OS 79, 51⋅2 and 28 per cent for low, medium and high
TBS respectively; P = 0⋅010).
Conclusion: The prognosis of patients with HCC varied according to the BCLC stage but was largely
dependent on the TBS.

Paper accepted 15 November 2019

Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.11464

Introduction of cancer-related death, with model-based simulations

Hepatocellular carcinoma (HCC) is the most common
primary liver malignancy, with over 750 000 new cases
and a nearly equal number of cancer-related deaths each
year1,2 . In the USA, HCC is the fastest growing cause
forecasting a continued increase in the incidence of HCC
until at least 20303,4 . Cancer staging is necessary as it
helps define prognosis, as well as informs treatment
recommendations5,6 . Among the staging systems available,
the Barcelona Clinic Liver Cancer (BCLC) system has

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 D. I. Tsilimigras, D. Moris, J. M. Hyer, F. Bagante, K. Sahara, A. Moro et al.
been used widely in the West and has been endorsed by
the European Association for the Study of the Liver7 – 9 .
According to the BCLC system, resection should be
offered only to patients with BCLC-0 and BCLC-A HCC,
whereas those with more advanced disease (BCLC-B and
BCLC-C) are recommended to undergo other types of
treatment, including transarterial chemoembolization
(TACE) and sorafenib8,9 .
The original BCLC system was refined in 2011, with
single large HCCs (at least 5 cm) designated as BCLC-A
rather than BCLC-B10 . As such, single tumours of at least
2 cm as well as two or three tumours smaller than 3 cm
are currently considered as BCLC-A HCC8 . Neverthe-
less, these criteria have been considered too vague, with
studies11,12 showing heterogeneous outcomes after resec-
tion of HCC within the same stage. In addition, several
investigators13 – 16 have recently advocated extending the
criteria for resection, acknowledging that certain patients
with BCLC-B HCC may benefit more from surgery than
other locoregional therapies (TACE). The prognostic dis-
crimination as well as the treatment allocation of the
revised BCLC classification have been questioned, empha-
sizing the need for refinement and further subclassification
of this system17 .
First proposed by Sasaki and colleagues18 , the tumour
burden score (TBS) incorporates both tumour number
and tumour size as continuous variables, and has been
demonstrated to differentiate prognosis among patients
undergoing resection for colorectal liver metastases. To
date, no study has assessed the ability of TBS to predict
outcomes among patients undergoing resection of HCC
of various BCLC stages. The objective of the present
study was to evaluate the impact of TBS in relation to
the prognosis of patients undergoing resection for HCC.
In addition, this study sought to examine whether TBS
could be used as a tool to stratify prognosis and identify
patients who may benefit the most from resection beyond
(BCLC-B) the current BCLC resection criteria.
Methods
Patients who underwent resection of HCC with curative
intent between 2000 and 2017 were identified from an
international multi-institutional database. Patients were
treated at one of 11 participating institutions: Ohio State
University Wexner Medical Center, Columbus, Ohio,
USA; Yokohama City University School of Medicine,
Yokohama, Japan; University of Verona, Verona, Italy;
Ospedale San Raffaele, Milan, Italy; Curry Cabral Hos-
pital, Lisbon, Portugal; Assistance Publique – Hôpitaux
de Paris, Beaujon Hospital, Clichy, France; Westmead
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Hospital, Sydney, New South Wales, Australia; Stanford
University, Stanford, California, USA; Fundeni Clinical
Institute, Bucharest, Romania; University of Ottawa,
Ottawa, Ontario, Canada; and University of Sydney,
School of Medicine, Sydney, New South Wales, Australia.
Follow-up data for patients who underwent HCC resec-
tion were recorded in an international, multi-institutional
database. Patients with BCLC stages 0, A and B HCC8
were included in the final cohort. Patients who did not
undergo resection with curative intent (intent of resection
defined before operation), those with BCLC-C tumours
and patients with inadequate follow-up data were excluded
from the analysis. Patients who died within 90 days of
operation (31, 2⋅9 per cent) were not excluded from the
analysis. The study was approved by the institutional
review boards of all participating institutions.
Outcomes and variables of interest
The primary outcome was overall survival (OS), defined
as the interval between the date of hepatectomy and the
date of death or last follow-up. The secondary outcome was
disease-free survival (DFS), defined as the interval between
the date of hepatectomy and the date of recurrence or
last follow-up. The primary independent variables were
BCLC stage8 and TBS. Demographic and clinical data
included: age, sex, ASA fitness grade, history of cirrhosis,
hepatitis B virus (HBV) and hepatitis C virus (HCV) infec-
tion, α-fetoprotein (AFP) level, Child–Pugh grade, mini-
mally invasive surgery, extent of surgical resection (minor
or major), tumour size and grade, pathological lymphovas-
cular invasion, liver capsule involvement, margin status (R0
or R1) and TBS.
Definitions
Single tumours smaller than 2 cm were designated as
BCLC-0; a single tumour of at least 2 cm, or two to three
nodules all smaller than 3 cm, as BCLC-A; and two to
three nodules of at least 3 cm, or four or more nodules, as
BCLC-B8,19 . Tumour size was defined by the size of the
largest lesion if there were multiple nodules. Major hepate-
ctomy was defined as resection of three or more Couinaud
segments20 . TBS was defined as the distance from the ori-
gin of a Cartesian plane and comprised two variables18 :
maximum tumour size (x-axis) and number of tumours
(y-axis) so that TBS2 = (maximum tumour diameter)2 +
(number of tumours)2 . For each patient, the maximum
tumour diameter and number of tumours were obtained
from the final pathological report. Cut-off values of TBS
were determined by X-tile, a bioinformatics tool produced
by Camp and colleagues21 .
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Tumour burden score for hepatocellular carcinoma

Table 1 Clinicopathological characteristics of the entire cohort

Total BCLC-0 BCLC-A BCLC-B

(n = 1053) (n = 63) (n = 826) (n = 164) P†

Age (years)* 67 (59–73) 64 (58–71) 67 (59–74) 68 (62–74) 0⋅012‡

≤ 65 444 (43⋅6) 30 (52) 362 (45⋅0) 52 (33⋅3)
> 65 575 (56⋅4) 28 (48) 443 (55⋅0) 104 (66⋅7)
Sex 0⋅184
M 789 (75⋅1) 44 (71) 613 (74⋅3) 132 (80⋅5)
F 262 (24⋅9) 18 (29) 212 (25⋅7) 32 (19⋅5)
ASA fitness grade 0⋅113
≤ II 578 (62⋅5) 40 (66) 435 (60⋅8) 103 (69⋅6)
> II 347 (37⋅5) 21 (34) 281 (39⋅2) 45 (30⋅4)
Cirrhosis 0⋅035
No 646 (61⋅5) 30 (48) 520 (63⋅2) 96 (58⋅5)
Yes 404 (38⋅5) 33 (52) 303 (36⋅8) 68 (41⋅5)
HBV infection 0⋅082
No 769 (73⋅9) 39 (63) 614 (75⋅2) 116 (71⋅6)
Yes 272 (26⋅1) 23 (37) 203 (24⋅8) 46 (28⋅4)
HCV infection 0⋅346
No 723 (69⋅4) 39 (62) 574 (70⋅3) 110 (67⋅9)
Yes 319 (30⋅6) 24 (38) 243 (29⋅7) 52 (32⋅1)
AFP (ng/ml) 0⋅018
≤ 400 725 (80⋅7) 52 (88) 564 (81⋅7) 109 (73⋅2)
> 400 173 (19⋅3) 7 (12) 126 (18⋅3) 40 (26⋅8)
Child–Pugh grade 0⋅620
A 704 (95⋅3) 47 (94) 534 (95⋅7) 123 (93⋅9)
B 35 (4⋅7) 3 (6) 24 (4⋅3) 8 (6⋅1)
Minimally invasive surgery < 0⋅001
No 792 (75⋅5) 29 (46) 621 (75⋅5) 142 (87⋅1)
Yes 257 (24⋅5) 34 (54) 202 (24⋅5) 21 (12⋅9)
Type of resection < 0⋅001
Minor 668 (65⋅4) 53 (87) 526 (65⋅7) 89 (55⋅6)
Major 354 (34⋅6) 8 (13) 275 (34⋅3) 71 (44⋅4)
Tumour size (cm)* 5⋅0 (3⋅0–8⋅5) 1⋅5 (1⋅2–1⋅7) 5⋅0 (3⋅2–8⋅5) 6⋅0 (4⋅3–9⋅0) < 0⋅001‡
Differentiation grade 0⋅243
Well/moderate 806 (80⋅2) 45 (78) 639 (81⋅3) 122 (75⋅8)
Poor/undifferentiated 199 (19⋅8) 13 (22) 147 (18⋅7) 39 (24⋅2)
Lymphovascular invasion < 0⋅001
No 560 (62⋅0) 50 (85) 439 (63⋅6) 71 (46⋅1)
Yes 343 (38⋅0) 9 (15) 251 (36⋅4) 83 (53⋅9)
Liver capsule involvement < 0⋅001
No 513 (67⋅8) 40 (87) 405 (69⋅0) 68 (54⋅8)
Yes 244 (32⋅2) 6 (13) 182 (31⋅0) 56 (45⋅2)
Margin status 0⋅024
R0 907 (88⋅6) 54 (93) 720 (89⋅4) 133 (82⋅6)
R1 117 (11⋅4) 4 (7) 85 (10⋅6) 28 (17⋅4)
Tumour burden score < 0⋅001
Low 269 (25⋅5) 63 (100) 206 (24⋅9) –
Medium 675 (64⋅1) – 535 (64⋅8) 140 (85⋅4)
High 109 (10⋅4) – 85 (10⋅3) 24 (14⋅6)

Values in parentheses are percentages unless indicated otherwise; *values are median (i.q.r.). Data were incomplete for some variables. BCLC, Barcelona
Clinic Liver Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, α-fetoprotein. †χ2 or Fisher’s exact test, except ‡Kruskal–Wallis one-way
ANOVA.

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 D. I. Tsilimigras, D. Moris, J. M. Hyer, F. Bagante, K. Sahara, A. Moro et al.

Fig. 1 Kaplan–Meier survival curves for entire cohort by Barcelona Clinic Liver Cancer stage and tumour burden score

a Overall survival by BCLC stage b Overall survival by TBS

1·0 1·0

0·8 0·8
Overall survival

Overall survival
0·6 0·6

0·4 0·4
BCLC-0 Low TBS
BCLC-A Medium TBS
0·2 0·2
BCLC-B High TBS

0 12 24 36 48 60 0 12 24 36 48 60
Time after surgery (months) Time after surgery (months)
No. at risk No. at risk
BCLC-0 63 51 38 30 20 15 Low TBS 269 215 156 120 86 62
BCLC-A 826 628 464 337 232 171 Medium TBS 675 523 385 276 190 171
BCLC-B 164 122 77 57 39 24 High TBS 109 63 38 28 20 14

c Disease-free survival by TBS

1·0

0·8
Disease-free survival

0·6

0·4

Low TBS
0·2
Medium TBS
High TBS

0 12 24 36 48 60
Time after surgery (months)
No. at risk
Low TBS 269 182 112 79 47 32
Medium TBS 675 410 252 173 115 82
High TBS 109 43 21 17 12 10

a Overall survival by Barcelona Clinic Liver Cancer (BCLC) stage; b overall and c disease-free survival by tumour burden score (TBS). a P = 0⋅010,
b P < 0⋅001, c P < 0⋅001 (log rank test).

External validation cohort Statistical analysis

The ability of TBS to predict prognosis was subsequently
validated externally. Data from patients who underwent
hepatectomy with curative intent for HCC between 2007
and 2019 at Cleveland Clinic, Cleveland, Ohio, USA,
were analysed. The external validation cohort included
patients who met the same inclusion criteria as those in the
multi-institutional cohort. The institutional review board
approved the study.
Descriptive statistics for continuous and categorical
variables are presented as median (i.q.r.) and number
(percentage) respectively. Bivariable analyses comprised
Kruskal–Wallis one-way ANOVA for continuous variables
and χ2 or Fisher’s exact test for categorical variables, as
appropriate. Bivariable survival analyses were performed
using Kaplan–Meier curves and the log rank test. Vari-
ables that were significant in bivariable Cox regression

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Tumour burden score for hepatocellular carcinoma

Fig. 2 Kaplan–Meier survival curves by tumour burden score for Barcelona Clinic Liver Cancer stages A and B separately

a Overall survival, BCLC-A b Overall survival, BCLC-B

1·0 1·0

0·8 0·8
Overall survival

Overall survival
0·6 0·6

0·4 0·4
Low TBS
Medium TBS
0·2 High TBS 0·2

0 12 24 36 48 60 0 12 24 36 48 60
Time after surgery (months) Time after surgery (months)
No. at risk No. at risk
Low TBS 206 164 118 90 66 47 Medium TBS 140 106 71 53 37 23
Medium TBS 535 417 314 223 153 111 High TBS 24 16 6 4 2 1
High TBS 85 47 32 24 18 13

c Disease-free survival, BCLC-A d Disease-free survival, BCLC-B

1·0 1·0

0·8 0·8
Disease-free survival

Disease-free survival

0·6 0·6

0·4 0·4

0·2 0·2

0 12 24 36 0 12 24 36
Time after surgery (months) Time after surgery (months)
No. at risk No. at risk
Low TBS 206 139 83 58 Medium TBS 140 76 42 26
Medium TBS 535 334 210 147 High TBS 24 8 2 1
High TBS 85 35 19 16

Overall survival for patients with a Barcelona Clinic Liver Cancer (BCLC) A and b BCLC-B tumours; and disease-free survival for patients with c BCLC-A
and d BCLC-B tumours by tumour burden score (TBS). a P < 0⋅001, b P < 0⋅001, c P = 0⋅008, d P = 0⋅043 (log rank test).

analysis (P < 0⋅050) were entered into a multivariable
model, and backward step selection was used to eliminate
non-significant variables using P < 0⋅100. The level of
statistical significance for all tests was set at α = 0⋅05. All
statistical analyses were undertaken in SPSS version 25
(IBM, Armonk, New York, USA) and SAS® version 9.4
(SAS Institute, Cary, North Carolina, USA).
Results
A total of 1053 patients who underwent resection of HCC
with curative intent met the inclusion criteria and were
included in the final cohort. Overall, 63 patients (6⋅0 per
cent) had BCLC-0, 826 (78⋅4 per cent) had BCLC-A
and 164 (15⋅6 per cent) had BCLC-B HCC (Table 1).
Median age was 67 (i.q.r. 59–73) years and most patients
were men (789, 75⋅1 per cent). The ASA fitness grade
was II or less in 578 patients (62⋅5 per cent). There was
a history of cirrhosis, HBV and HCV infection in 404
(38⋅5 per cent), 272 (26⋅1 per cent) and 319 (30⋅6 per
cent) patients respectively. One-quarter of the patients
(257, 24⋅5 per cent) underwent a minimally invasive pro-
cedure and one-third (354, 34⋅6 per cent) had a major

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 D. I. Tsilimigras, D. Moris, J. M. Hyer, F. Bagante, K. Sahara, A. Moro et al.

Fig. 3 Kaplan–Meier overall survival curves according to com-

patients with BCLC-0 HCC had a low TBS. Patients with
bined tumour burden score and Barcelona Clinic Liver Cancer BCLC-A tumours had a low (206, 24⋅9 per cent), medium
stage subgroups (535, 64⋅8 per cent) or high (85, 10⋅3 per cent) TBS,
whereas those with BCLC-B HCC had a medium (140,
BCLC-A/low TBS
85⋅4 per cent) or high (24, 14⋅6 per cent) TBS (P < 0⋅001).
BCLC-A/medium TBS
BCLC-A/high TBS
BCLC-B/medium TBS
BCLC-B/high TBS Tumour burden score predicts survival across
1·0 BCLC stages

0·8 After a median follow-up of 27⋅4 (i.q.r. 12⋅6–52⋅4) months,

5-year OS following liver resection with curative intent
Overall survival

0·6 was 62⋅9 per cent for the entire cohort. Five-year OS
varied based on BCLC stage (78, 63⋅8 and 52⋅8 per cent
0·4
respectively for BCLC-0, BCLC-A and BCLC-B respec-
0·2 tively; P = 0⋅010) (Fig. 1a). TBS was also able to stratify
prognosis as OS worsened incrementally with higher TBS
0 12 24 36 48 60 (5-year OS: 77⋅9, 61 and 39 per cent for low, medium and
Time after surgery (months) high TBS respectively; P < 0⋅001) (Fig. 1b). Of note, TBS
No. at risk was also associated with DFS (5-year DFS: 40⋅7, 35⋅4 and
BCLC-A/low
206 164 118 90 66 47
28⋅5 per cent for low, medium and high TBS respectively;
TBS
BCLC-A/medium
P < 0⋅001) (Fig. 1c).
535 417 314 223 153 111
TBS To investigate whether TBS could predict outcomes
BCLC-A/high
TBS
85 47 32 24 18 13 across BCLC stages, subgroup analyses were performed
BCLC-B/medium among patients with BCLC-A and BCLC-B HCC. In
140 106 71 53 37 23
TBS the BCLC-A group, OS worsened incrementally with
BCLC-B/high
TBS
24 16 6 4 2 1 higher TBS (5-year OS: 78, 61⋅6 and 45 per cent for low,
medium and high TBS respectively; P < 0⋅001) (Fig. 2a).
BCLC, Barcelona Clinic Liver Cancer; TBS, tumour burden score. Similarly, among patients with BCLC-B HCC, those
P < 0⋅001 (overall), P < 0⋅001 (BCLC-A/low TBS versus BCLC-B/high with a high TBS had worse 5-year OS than those with
TBS), P = 0⋅007 (BCLC-A/low TBS versus BCLC-B/medium TBS), a medium TBS (13 versus 58⋅9 per cent respectively;
P = 0⋅005 (BCLC-A/high TBS versus BCLC-B/medium TBS) (log rank
test).
P < 0⋅001) (Fig. 2b). DFS also worsened incrementally
with higher TBS among both patients with BCLC-A
HCC (3-year DFS: 57⋅4, 49⋅4 and 38 per cent for
resection. Among 668 patients (65⋅4 per cent) who had a low, medium and high TBS respectively; P = 0⋅008)
minor resection, 459 (68⋅7 per cent) underwent anatom- (Fig. 2c) and those with BCLC-B tumours (medium
ical and 209 (31⋅3 per cent) non-anatomical resection. versus high 31⋅4 and 15 per cent respectively; P = 0⋅043)
Median tumour size was 5⋅0 (3⋅0–8⋅5) cm and the major- (Fig. 2d).
ity of patients (806, 80⋅2 per cent) had a well or moder-
ate tumour differentiation grade. On final pathology, 343
Tumour burden score as a tool to select patients
patients (38⋅0 per cent) had lymphovascular invasion and
for resection beyond BCLC criteria
244 (32⋅2 per cent) had liver capsule involvement. Surgical
margin status was R0 in the majority of patients (907, To identify subgroups of patients with BCLC-B tumours
88⋅6 per cent). who had favourable outcomes after resection, combina-
tions of BCLC stage and TBS were analysed. Patients
with a similar TBS had comparable outcomes, irrespec-
Distribution of tumour burden score
tive of BCLC stage (5-year OS: 61⋅6 versus 58⋅9 per
Patients were divided into three groups according to the cent for BCLC-A/medium TBS versus BCLC-B/medium
TBS: high TBS (over 13⋅74; 109, 10⋅4 per cent), medium TBS, P = 0⋅930; 45 versus 13 per cent for BCLC-A/high
TBS (3⋅36–13⋅74; 675, 64⋅1 per cent) and low TBS (less TBS versus BCLC-B/high TBS; P = 0⋅175) (Fig. 3). Per-
than 3⋅36; 269, 25⋅5 per cent) (Fig. S1, supporting informa- haps of more interest, patients with BCLC-B HCC and a
tion). The distribution of TBS values across BCLC stages medium TBS had even better 5-year OS than those with
is shown in Fig. S2 (supporting information). Of note, all 63 BCLC-A tumours and a high TBS (58⋅9 versus 45 per cent;

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Tumour burden score for hepatocellular carcinoma

Table 2 Multivariable Cox regression analysis of survival

BCLC-A BCLC-B

Hazard ratio P Hazard ratio P

Age (years)
≤ 65 1⋅00 (reference)
> 65 1⋅48 (1⋅13, 1⋅93) 0⋅004
ASA fitness grade
≤2 1⋅00 (reference)
>2 2⋅05 (1⋅17, 3⋅60) 0⋅012
Cirrhosis
No 1⋅00 (reference)
Yes 2⋅07 (1⋅56, 2⋅75) < 0⋅001
HBV infection
No 1⋅00 (reference)
Yes 0⋅74 (0⋅53, 1⋅04) 0⋅087
AFP (ng/ml)
≤ 400 1⋅00 (reference)
> 400 1⋅65 (1⋅23, 2⋅22) 0⋅001
Differentiation grade
Well/moderate 1⋅00 (reference) 1⋅00 (reference)
Poor/undifferentiated 1⋅33 (0⋅98, 1⋅80) 0⋅059 2⋅80 (1⋅57, 5⋅02) 0⋅001
Lymphovascular involvement
No 1⋅00 (reference)
Yes 1⋅86 (1⋅41, 2⋅46) < 0⋅001
Margin status
R0 1⋅00 (reference)
R1 1⋅61 (1⋅07, 2⋅42) 0⋅020
Tumour burden score
Low 1⋅00 (reference)
Medium 2⋅07 (1⋅42, 3⋅02) < 0⋅001 1⋅00 (reference)
High 4⋅05 (2⋅40, 6⋅82) < 0⋅001 3⋅85 (2⋅03, 7⋅30) < 0⋅001

Values in parentheses are 95 per cent confidence intervals. The final step of the backward stepwise model is presented for both Barcelona Clinic Liver
Cancer (BCLC) A and B stages. HBV, hepatitis B virus; AFP, α-fetoprotein.

P = 0⋅005). In contrast, patients with BCLC-A HCC and a
low TBS had better 5-year OS than those with BCLC-B
tumours and a medium (78 versus 58⋅9 per cent; P = 0⋅007)
or high (78 versus 13 per cent; P < 0⋅001) TBS.
Factors associated with overall survival after
resection for BCLC-A and BCLC-B hepatocellular
carcinoma
A number of clinicopathological factors were associ-
ated with prognosis after resection for BCLC-A and
BCLC-B HCC (Table S1, supporting information). In
univariable analysis, minimally invasive surgery was not
associated with long-term survival among patients with
BCLC-A (hazard ratio (HR) 0⋅76, 95 per cent c.i. 0⋅54
to 1⋅08; P = 0⋅127) or BCLC-B (HR 0⋅62, 0⋅24 to 1⋅55;
P = 0⋅305) disease. In multivariable analysis, after adjusting
for competing factors, age over 65 years (HR 1⋅48, 1⋅13
to 1⋅93; P = 0⋅004), cirrhosis (HR 2⋅07, 1⋅56 to 2⋅75;
P < 0⋅001), AFP level exceeding 400 ng/ml (HR 1⋅65, 1⋅23
to 2⋅22; P = 0⋅001), lymphovascular involvement (HR
1⋅86, 1⋅41 to 2⋅46; P < 0⋅001), R1 resection (HR 1⋅61,
1⋅07 to 2⋅42; P = 0⋅020) and higher TBS (versus low TBS;
medium TBS: HR 2⋅07, 1⋅42 to 3⋅02, P < 0⋅001; high TBS:
HR 4⋅05, 2⋅40 to 6⋅82, P < 0⋅001) remained independent
predictors of OS among patients with BCLC-A HCC
(Table 2). Only ASA grade above II (HR 2⋅05, 1⋅17 to 3⋅60;
P = 0⋅012), poor/undifferentiated tumour grade (HR 2⋅80,
1⋅57 to 5⋅02; P = 0⋅001) and high TBS (versus medium TBS:
HR 3⋅85, 2⋅03 to 7⋅30; P < 0⋅001) independently predicted
worse outcomes among patients with BCLC-B HCC.
External validation of tumour burden score
The ability of TBS to stratify prognosis among patients
undergoing resection with curative intent for HCC was

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 D. I. Tsilimigras, D. Moris, J. M. Hyer, F. Bagante, K. Sahara, A. Moro et al.

Fig. 4 Kaplan–Meier survival curves by tumour burden score for external validation cohort

a Overall survival, entire cohort b Overall survival, BCLC-A

1·0 1·0

0·8 0·8
Overall survival

Overall survival
0·6 0·6

0·4 0·4

Low TBS
0·2 Medium TBS 0·2
High TBS

0 12 24 36 48 60 0 12 24 36 48 60
Time after surgery (months) Time after surgery (months)

No. at risk No. at risk

Low TBS 42 33 24 17 13 10 Low TBS 32 26 17 12 10 8
Medium TBS 100 66 43 32 19 15 Medium TBS 75 48 34 25 15 13
High TBS 16 11 8 3 3 2 High TBS 12 8 5 2 2 1

c Disease-free survival, entire cohort d Disease-free survival, BCLC-A

1·0 1·0

0·8 0·8
Disease-free survival

Disease-free survival

0·6 0·6

0·4 0·4

0·2 0·2

0 12 24 0 12 24
Time after surgery (months) Time after surgery (months)

No. at risk No. at risk

Low TBS 42 26 20 Low TBS 32 20 8
Medium TBS 100 43 27 Medium TBS 74 31 20
High TBS 16 3 2 High TBS 12 2 1

Overall survival for a entire cohort and b Barcelona Clinic Liver Cancer (BCLC) A subgroup; and disease-free survival for c entire cohort and d BCLC-A
subgroup by tumour burden score (TBS). a P = 0⋅010, b P = 0⋅006, c P < 0⋅001, d P < 0⋅001 (log rank test).

validated using an external cohort of 158 patients from
Cleveland Clinic. A total of 41 patients (25⋅9 per cent)
underwent minimally invasive surgery in the external val-
idation cohort, similar to the multi-institutional data set.
Ten patients (6⋅3 per cent) had BCLC-0, 119 (75⋅3 per
cent) had BCLC-A and 29 (18⋅4 per cent) had BCLC-B
HCC. The distribution of TBS in the entire cohort was
low (42, 26⋅6 per cent), medium (100, 63⋅3 per cent) and
high (16, 10⋅1 per cent).
Survival analysis based on the TBS revealed excellent
prognostic discrimination across the entire cohort. Patients
with a low, medium and high TBS had a 5-year OS of
79, 51⋅2 and 28 per cent respectively (P = 0⋅010) (Fig. 4a).
Similarly, patients with BCLC-A tumours had an incre-
mentally worse 5-year OS with higher TBS (72, 55 and
21 per cent respectively for low, medium and high TBS;
P = 0⋅006) (Fig. 4b). Among patients with a medium TBS,
there was no difference in OS between those with BCLC-A

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Tumour burden score for hepatocellular carcinoma
versus BCLC-B HCC (5-year OS: 55 versus 42 per cent:
P = 0⋅214). Similarly, DFS worsened with higher TBS
among patients in the entire cohort (3-year DFS: 71, 53⋅8
and 17 per cent for low, medium and high TBS respectively;
P < 0⋅001) (Fig. 4c), as well as among those with BCLC-A
HCC (3-year DFS: 74, 54 and 12 per cent respectively;
P = 0⋅001) (Fig. 4d).
Discussion
In the USA, the incidence of HCC has increased steadily
over the past three decades, with a concomitant increase
in HCC mortality1,3 . Cancer staging is necessary to accu-
rately predict the prognosis of patients with HCC as well
as to define the appropriate treatment strategy5,6 . Among
the traditional staging systems, the BCLC classification
is unique in that it assesses patient prognosis, but also
recommends a specific treatment strategy based on the
respective prognostic stages defined by the classification
itself7,8 . Nevertheless, there has recently been debate as
to whether this system performs well in terms of prog-
nostic stratification. Previous studies11,12 have shown het-
erogeneous outcomes after HCC resection of the same
stage, especially among patients with BCLC-A HCC.
Indeed, a strong relationship between tumour size and inci-
dence of microvascular invasion has been demonstrated,
suggesting an increased possibility of recurrence among
patients with large BCLC-A HCC22,23 . Previous studies
have attempted to subclassify patients within BCLC stages,
yet none of these suggestions have been adopted by the
most recent BCLC classification8 . In addition, these sub-
classifications have largely used arbitrary cut-off values of
tumour number and size that assume an independent rather
than related effect of these variables on outcomes after
resection.
The present study used TBS, a recently developed mea-
sure that incorporates both tumour number and size in a
continuous fashion, to determine prognosis after resection
of HCC across different BCLC stages. Of note, patients
had a range of TBS values among the different BCLC
stages, yet those with a similar TBS had comparable out-
comes, irrespective of BCLC stage. In fact, patients with
BCLC-B HCC and a medium TBS had better outcomes
than those with BCLC-A tumours who had a high TBS.
Furthermore, TBS remained an independent predictor of
OS among both BCLC-A and BCLC-B stages even after
controlling for competing factors. Importantly, the TBS
could discriminate prognosis accurately when applied to an
external validation cohort.
Several investigators24,25 have suggested subclassifica-
tions within BCLC stages. Bolondi and colleagues24
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Published by John Wiley & Sons Ltd
subclassified patients with BCLC-B HCC into four dif-
ferent groups according to the beyond Milan and up-to-7
criteria, suggesting distinct prognosis and treatment
approaches for each subgroup. Wang and co-workers26
proposed a modified BCLC system, with HCC exceeding
7 cm considered BCLC-B instead of BCLC-A. The ITA
.LI.CA study group25 proposed a new staging system and
suggested subclasses within BCLC stages, considering
different cut-off values for tumour number and size. No
previous study has used the TBS to stratify prognosis after
resection of HCC across BCLC stages.
By using the Pythagorean theorem (α2 = β2 + γ2 ), TBS
takes into account the collective impact of tumour number
and tumour size, which are known predictors of overall dis-
ease burden18 . Of note, the TBS calculates disease burden
in a continuous, rather than dichotomous, fashion, which
allows a more granular prognostication of outcomes than
the established Milan or up-to-7 criteria18,27 . The ITA.LI
.CA group27 recently demonstrated better discriminative
ability of the TBS compared with the Milan criteria and
other tumour-specific scores, with a 6 per cent increased
risk of death for each point increase in TBS. By using the
X-tile bioinformatics tool21 , the optimal cut-off values of
TBS in relation to OS were determined in the present
study. Interestingly, although patients with BCLC-0 dis-
ease had only low TBS values, patients with BCLC-A
tumours had scores ranging from low to high (Fig. S2,
supporting information). In turn, outcomes after resection
for BCLC-A HCC were largely dependent on TBS; the
5-year OS rate was as high as 78 per cent for patients with
a low TBS, but only 45 per cent among those with a high
TBS. Similarly, TBS was able to stratify prognosis among
patients with BCLC-B HCC. Patients with BCLC-B dis-
ease and a medium TBS had a 5-year OS rate that was
even better than that of patients with BCLC-A HCC and a
high TBS (58⋅9 versus 45 per cent; P = 0⋅005). Importantly,
TBS remained an independent predictor of OS among
both BCLC-A and BCLC-B groups. TBS could also pre-
dict DFS across the entire cohort, as well as within the
different BCLC stages. The value of TBS and its predic-
tive performance in terms of OS and DFS was validated
in an independent external cohort. Data from the present
study strongly suggest that TBS could be used as an adjunc-
tive tool to stratify prognosis among patients undergoing
resection for HCC, and to identify subgroups of patients
within each BCLC stage who may benefit most from
surgery.
Although the current BCLC guidelines recommend
surgery only for BCLC-A HCC, hepatobiliary sur-
geons have questioned whether resection of HCC
should be undertaken in selected patients with BCLC-B
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 D. I. Tsilimigras, D. Moris, J. M. Hyer, F. Bagante, K. Sahara, A. Moro et al.
tumours16,28,29 . Indeed, an increasing number of
studies16,30 – 35 have reported acceptable outcomes after
resection for BCLC-B HCC, suggesting that liver resec-
tion may be justified beyond the BCLC resection criteria
in selected patients. For example, Wada and colleagues13
reported a 5-year OS rate of 63⋅4 per cent after liver
resection for multinodular BCLC-B HCC. Kim and
co-workers30 reported superior outcomes with resection
versus non-surgical treatment for BCLC-B HCC in a
propensity score-matched analysis (5-year OS: 63 versus
22 per cent). In another study33 , resection of multinodular
HCC was associated with an acceptable 5-year OS rate
of 57 per cent among patients with BCLC-B disease.
A propensity-score matched study34 from Asia similarly
noted a survival benefit with liver resection versus TACE
for patients with BCLC-B/C HCC. Of note, a recent
meta-analysis16 revealed a survival benefit of surgery com-
pared with TACE for BCLC-B disease, raising questions
about the treatment algorithm proposed by the current
BCLC classification.
In the present analysis of a large multi-institutional
database, an acceptable 5-year OS rate of 52⋅8 per cent was
noted among patients with BCLC-B HCC. Furthermore,
applying the TBS, it was found that patients with BCLC-B
and a medium TBS had outcomes comparable to those with
BCLC-A HCC and a medium TBS, and even better out-
comes than those with BCLC-A HCC and a high TBS.
Collectively, these data suggest that surgery could indeed
be beneficial in selected patients with BCLC-B HCC and
so resection should not be denied a priori to such patients.
Rather, the TBS may be helpful in identifying patients with
BCLC-B HCC beyond the current BCLC criteria who
may derive a survival benefit and therefore be candidates
for resection.
The present study has certain limitations that should be
taken into consideration when interpreting the results. As
with all retrospective studies, it may be subject to selec-
tion bias regarding which patients were offered surgery
(patients with BCLC-B HCC likely had a more favourable
tumour profile and were fit for surgery). In addition,
most patients included in the analysis had Child–Pugh
grade A liver function; the conclusions may not per-
tain to those with more severe underlying liver disease.
Furthermore, owing to smaller numbers in the external
validation cohort, it was not possible to undertake fur-
ther survival analyses to examine whether patients with
BCLC-B HCC and a medium TBS had better outcomes
than those with BCLC-A tumours and a high TBS, as
shown in the multi-institutional cohort. There was also a
slight difference in study periods for the multi-institutional
and external validation cohorts, but this is unlikely to have
© 2020 BJS Society Ltd
Published by John Wiley & Sons Ltd
influenced the results of the study. Finally, the lack of a
comparison group did not allow assessment of whether
the TBS would also be able to stratify prognosis among
patients with BCLC-B HCC who underwent locoregional
therapies (TACE). The present data emphasize the need
for further subclassification within the current BCLC
guidelines, and highlight the need for refinement of the
proposed treatment algorithm using an assessment of total
tumour burden.
Disclosure
The authors declare no conflict of interest.
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Supporting information
Additional supporting information can be found online in the Supporting Information section at the end of the
article.

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