Ann Surg Oncol

https://doi.org/10.1245/s10434-023-13863-z

ORIGINAL ARTICLE – HEPATOBILIARY TUMORS

Impact of Tumor Size on the Difficulty of Laparoscopic Major

Hepatectomies: An International Multicenter Study
Yutaro Kato, MD, PhD1, Atsushi Sugioka, MD, PhD1, Masayuki Kojima, MD, PhD1,
Nicholas L. Syn, MBBS2,3, Wang Zhongkai, MBBS, MMed, FRCS4,
Rong Liu, MD, PhD5, Federica Cipriani, MD, PhD6, Thomas Armstrong, MD, PhD7,
Davit L. Aghayan, MD, PhD8, Tiing‑Foong Siow, MD9, Chetana Lim, MD, PhD10,
Olivier Scatton, MD, PhD10, Paulo Herman, MD, PhD11, Fabricio Ferreira Coelho, MD, PhD11,
Marco V. Marino, MD, PhD, FACS, FEBS12,13, Vincenzo Mazzaferro, MD, PhD14,
Adrian K. H. Chiow, MBBS, MMed, FRCS15, Iswanto Sucandy, MD, FACS16, Arpad Ivanecz, MD, PhD17,
Sung Hoon Choi, MD18, Jae Hoon Lee, MD, PhD19, Mikel Gastaca, MD, PhD20, Marco Vivarelli, MD21,
Felice Giuliante, MD22, Bernardo Dalla Valle, MD23, Andrea Ruzzenente, MD23, Chee‑Chien Yong, MD24,
Constantino Fondevila, MD25,26, Mikhail Efanov, MD, PhD27, Fabrizio Di Benedetto, MD, PhD, FACS28,
Andrea Belli, MD, PhD29, James O. Park, MD30, Fernando Rotellar, MD, PhD31,32,
Gi‑Hong Choi, MD33, Ricardo Robles‑Campos, MD34, Xiaoying Wang, MD, PhD35,
Robert P. Sutcliffe, MD, FRCS36, Moritz Schmelzle, MD37, Johann Pratschke, MD37,
Eric C. H. Lai, MBChB, FRACS38, Charing C. N. Chong, MBChB, MSc, FRCS39,
Mathieu D’Hondt, MD, PhD40, Kazuteru Monden, MD, FACS41, Santiago Lopez‑Ben, MD42,
T. Peter Kingham, MD43, Fabio Forchino, MD44, Alessandro Ferrero, MD44,
Giuseppe Maria Ettorre, MD45, Giovanni Battista Levi Sandri, MD, PhD45, Franco Pascual, MD46,
Daniel Cherqui, MD46, Olivier Soubrane, MD, PhD47, Go Wakabayashi, MD, PhD48,
Roberto I. Troisi, MSc, MD, PhD, FEBS48, Tan‑To Cheung, MS, MD, FRCS49, Zewei Chen, MD50,
Mengqiu Yin, MD50, Mizelle D’Silva, MD51, Ho‑Seong Han, MD, PhD51, Phan Phuoc Nghia, MD52,
Tran Cong duy Long, MD, PhD52, Bjørn Edwin, MD, PhD8, David Fuks, MD, PhD47,
Kuo‑Hsin Chen, MD9, Mohammad Abu Hilal, MD, PhD7,53, Luca Aldrighetti, MD, PhD6,
Brian K. P. Goh, MBBS, MMed, MSc, FRCSEd4,54 , and International Robotic and Laparoscopic Liver
Resection Study Group Investigators

1
Department of Surgery, Fujita Health University School of Medicine, Toyoake, Aichi, Japan; 2Yong Loo Lin School
of Medicine, National University of Singapore, Singapore, Singapore; 3Ministry of Health Holdings, Singapore, Singapore;
4
Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre
Singapore, Singapore, Singapore; 5Faculty of Hepatopancreatobiliary Surgery, The First Medical Center of Chinese
People’s Liberation Army (PLA) General Hospital, Beijing, China; 6Hepatobiliary Surgery Division, IRCCS San Raffaele
Hospital, Milan, Italy; 7Department of Surgery, University Hospital Southampton, Southampton, UK; 8The Intervention
Centre and Department of HPB Surgery, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Oslo,
Norway; 9Division of General Surgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan;
10
Department of Digestive, HBP and Liver Transplantation, Hopital Pitie‑Salpetriere, Sorbonne Universite, Paris, France;
11
Liver Surgery Unit, Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil;
12
General Surgery Department, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy; 13Oncologic

© Society of Surgical Oncology 2023

First Received: 17 November 2022
Accepted: 19 June 2023

B. K. P. Goh, MBBS, MMed, MSc, FRCSEd

e-mail: bsgkp@hotmail.com

Vol.:(0123456789)
 Y. Kato et al.

Surgery Department, P. Giaccone University Hospital, Palermo, Italy; 14HPB Surgery and Liver Transplantation,
Fondazione IRCCS Istituto Nazionale Tumori di Milano and University of Milan, Milan, Italy; 15Hepatopancreatobiliary
Unit, Department of Surgery, Changi General Hospital, Singapore, Singapore; 16Digestive Health Institute, AdventHealth
Tampa, Tampa, FL; 17Department of Abdominal and General Surgery, University Medical Center Maribor, Maribor,
Slovenia; 18Department of General Surgery, CHA Bundang Medical Center, CHA University School of Medicine,
Seongnam, Korea; 19Division of Hepato‑Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center,
University of Ulsan College of Medicine, Seoul, Korea; 20Hepatobiliary Surgery and Liver Transplantation Unit,
Biocruces Bizkaia Health Research Institute, Cruces University Hospital, University of the Basque Country, Bilbao,
Spain; 21HPB Surgery and Transplantation Unit, United Hospital of Ancona, Department of Experimental and Clinical
Medicine Polytechnic, University of Marche, Ancona, Italy; 22Hepatobiliary Surgery Unit, Fondazione Policlinico
Universitario A. Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy; 23General and Hepatobiliary
Surgery, Department of Surgery, GB Rossi Hospital, Dentistry, Gynecology and Pediatrics University of Verona, Verona,
Italy; 24Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 25General and Digestive Surgery,
Hospital Universitario La Paz, IdiPAZ, Madrid, Spain; 26General and Digestive Surgery, Hospital Clinic, IDIBAPS,
CIBERehd, University of Barcelona, Barcelona, Spain; 27Department of Hepato‑Pancreato‑Biliary Surgery, Moscow
Clinical Scientific Center, Moscow, Russia; 28HPB Surgery and Liver Transplant Unit, University of Modena and Reggio
Emilia, Modena, Italy; 29Division of Hepatopancreatobiliary Surgical Oncology, Department of Abdominal Oncology,
National Cancer Center – IRCCS-G. Pascale, Naples, Italy; 30Department of Surgery, University of Washington Medical
Center, Seattle; 31HPB and Liver Transplant Unit, Department of General Surgery, Clinica Universidad de Navarra,
Universidad de Navarra, Pamplona, Spain; 32Institute of Health Research of Navarra (IdisNA), Pamplona, Spain;
33
Division of Hepatopancreatobiliary Surgery, Department of Surgery, Severance Hospital, Yonsei University College
of Medicine, Seoul, Korea; 34Department of General, Visceral and Transplantation Surgery, Clinic and University Hospital
Virgen de la Arrixaca, IMIB-ARRIXACA​, El Palmar, Murcia, Spain; 35Department of Liver Surgery and Transplantation,
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; 36Department of Hepatopancreatobiliary
and Liver Transplant Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 37Department
of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin, Corporate Member
of Freie Universität Berlin and Berlin Institute of Health, Berlin, Germany; 38Department of Surgery, Pamela Youde
Nethersole Eastern Hospital, Chai Wan, Hong Kong, SAR, China; 39Department of Surgery, Prince of Wales Hospital, The
Chinese University of Hong Kong, Ma Liu Shui, New Territories, Hong Kong, SAR, China; 40Department of Digestive
and Hepatobiliary/Pancreatic Surgery, Groeninge Hospital, Kortrijk, Belgium; 41Department of Surgery, Fukuyama
City Hospital, Hiroshima, Japan; 42Hepatobiliary and Pancreatic Surgery Unit, Department of Surgery, Dr. Josep Trueta
Hospital, IdIBGi, Girona, Spain; 43Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY;
44
Department of General and Oncological Surgery, Mauriziano Hospital, Turin, Italy; 45Division of General Surgery
and Liver Transplantation, San Camillo Forlanini Hospital, Rome, Italy; 46Department of Hepatobiliary Surgery,
Assistance Publique Hopitaux de Paris, Centre Hepato-Biliaire, Paul-Brousse Hospital, Villejuif, France; 47Department
of Digestive, Oncologic and Metabolic Surgery, Institute Mutualiste Montsouris, Universite Paris Descartes, Paris, France;
48
Division of HPB, Minimally Invasive and Robotic Surgery, Department of Clinical Medicine and Surgery, Federico
II University Hospital Naples, Naples, Italy; 49Department of Surgery, The School of Clinical Medicine, Queen Mary
Hospital and HKU Shenzhen Hospital, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China; 50Department
of Hepatobiliary Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China; 51Department
of Surgery, Seoul National University Hospital Bundang, Seoul National University College of Medicine, Seoul, Korea;
52
Department of Hepatopancreatobiliary Surgery, University Medical Center, University of Medicine and Pharmacy,
Ho Chi Minh City, Vietnam; 53Department of Surgery, Fondazione Poliambulanza, Brescia, Italy; 54Surgery Academic
Clinical Programme, Duke-National University of Singapore Medical School, Singapore, Singapore

ABSTRACT Methods. This was a post-hoc analysis of 3008 patients

Introduction. Although tumor size (TS) is known to affect
surgical outcomes in laparoscopic liver resection (LLR), its
impact on laparoscopic major hepatectomy (L-MH) is not
well studied. The objectives of this study were to investigate
the impact of TS on the perioperative outcomes of L-MH
and to elucidate the optimal TS cutoff for stratifying the
difficulty of L-MH.
who underwent L-MH at 48 international centers. A total
1396 patients met study criteria and were included. The
impact of TS cutoffs was investigated by stratifying TS at
each 10-mm interval. The optimal cutoffs were determined
taking into consideration the number of endpoints which
showed a statistically significant split around the cut-points
Impact of Tumor Size on …
of interest and the magnitude of relative risk after correction
for multiple risk factors.
Results. We identified 2 optimal TS cutoffs, 50 mm and
100 mm, which segregated L-MH into 3 groups. An increas-
ing TS across these 3 groups (≤ 50 mm, 51–100 mm, >
100 mm), was significantly associated with a higher open
conversion rate (11.2%, 14.7%, 23.0%, P < 0.001), longer
operating time (median, 340 min, 346 min, 365 min, P =
0.025), increased blood loss (median, 300 ml, ml, 400 ml, P
= 0.002) and higher rate of intraoperative blood transfusion
(13.1%, 15.9%, 27.6%, P < 0.001). Postoperative outcomes
such as overall morbidity, major morbidity, and length of
stay were comparable across the three groups.
Conclusion. Increasing TS was associated with poorer
intraoperative but not postoperative outcomes after L-MH.
We determined 2 TS cutoffs (50 mm and 10 mm) which
could optimally stratify the surgical difficulty of L-MH.
Keywords Laparoscopic liver resection · Major
hepatectomy · Size · Difficulty · Minimally invasive liver
Laparoscopic liver resection (LLR) has increasingly
become a standard approach for all types and extents of
LR.1–4 The preoperative evaluation of surgical difficulty is
important in LLR in terms of appropriate patient selection as
well as surgical approach and planning. As a result, several
scoring systems have been devised by assessing the impact
of various tumor and patient factors to obtain a precise and
uniform difficulty scale that can guide surgeons performing
LLRs to select cases appropriate for their level of experi-
ence.5–10 These difficulty scoring s­ ystems11 are also useful
when assessing and comparing outcomes during the perfor-
mance of surgical audits.
Although tumor size is well known to affect the diffi-
culty of LLR and is included in several scoring systems,11
the optimal size cutoff to stratify the difficulty of LLR has
not been established. The BAN and Iwate scoring systems
subjectively proposed 3 cm as a size cutoff for all types
of LLRs without any strong supporting ­evidence5,6 while
the Southampton scoring system utilized 3 cm and 5 cm as
size cutoffs to stratify LLR.7 In a recent single institution
study, Kabir et al. demonstrated that a trichotomy of less
than 30 mm, 30–69 mm, and more than 70 mm might pro-
vide better granularity in the assessment of the difficulty
of LLR.12 Although differing in their conclusions, these
studies share the same major pitfall of indiscriminately
considering all types of liver resections, from wedge resec-
tions to extended hepatectomies, in their analyses.
Intuitively, one would expect the impact of tumor size
to differ according to the extent of the LLR. For example, a
3-cm cutoff would likely have an impact on the difficulty of
a wedge resection or monosegmentectomy, but is less likely
to significantly impact a major hepatectomy.13 Bearing in
mind the limitations of previous studies, we therefore per-
formed the present study to investigate the impact of tumor
size on the difficulty and outcomes of laparoscopic major
hepatectomy (L-MH), and to elucidate the optimal tumor
size cutoff(s) affecting its difficulty. Furthermore, we also
investigated a potential gradation in perioperative outcomes
depending on the tumor size with regards to L-MH.
METHODS
This is a post-hoc analysis of 17,602 patients who under-
went pure LLR at 48 international centers between 2004
and 2020. Among these, 3008 pure L-MH were performed.
After excluding patients who underwent concomitant major
surgical procedures (such as colectomies, gastrectomies,
hilar lymphadenectomies, and bile duct resections), repeat
liver resections, and resections for gallbladder cancer, cysts/
cystic tumors or abscesses, there were 2186 patients remain-
ing. MH were defined as resections of 3 or more segments
according to the 2000 Brisbane classification.14 The L-MH
were classified according to the Institut Mutualiste Mont-
souris (IMM) ­classification8,11 and in order to analyze a
more uniform cohort of patients, only IMM grade 3 MH
were included. Hence, 790 left hepatectomies, which are
well accepted to be technically simpler, were excluded. This
resulted in a total of 1396 IMM-3 L-MH (right hepatectomy,
extended right hepatectomy, extended left hepatectomy, and
central hepatectomy) included in the final analysis.
All institutions obtained their respective approvals
according to their local center’s requirements. This study
was approved by the Singapore General Hospital Institution
Review Board and the need for patient consent was waived.
The anonymized data were collected in the individual cent-
ers. These were collated and analyzed centrally at the Sin-
gapore General Hospital.
Definitions
The diameter of the largest lesion was used in the cases
of multiple tumors. The difficulty of resection was graded
according to the Iwate scoring system.6 Postoperative com-
plications were classified according to the Clavien-Dindo
classification and recorded for up to 30 days or during the
same hospitalization.15
Statistical Analysis
We systematically investigated the univariate impact
of tumor size cutoffs, in intervals of 10 mm, by iteratively
dichotomizing the tumor size at each 10-mm interval and
 Y. Kato et al.

computing two-sample treatment effect sizes local to that
cutoff. This was accomplished using a user-written Stata
implementation of the ‘Cutoff_Finder’ R package,16 with
modifications to permit the estimation of adjusted relative
risks and median differences from Poisson and quantile
regression models (Table 1, Fig. 1). To adjust for baseline
imbalances and confounders, treatment effects were condi-
tioned on inverse probability-weights, which were estimated
from a multivariate Firth logistic regression incorporating
age, gender, year of surgery, previous abdominal surgery,
American Society of Anesthesiologists (ASA) performance
status, concomitant minor surgery, cirrhosis, multifocality,
posterosuperior segments, malignant pathology, and all
components of the Iwate score, excluding tumor size. As the
aforementioned analysis reported a different set of possible
optimal tumor sizes for each individual outcome (i.e., uni-
variate), we also sought to obtain a single set of tumor size
cutoffs (rounded to the nearest 10 mm) that would be appli-
cable to all relevant outcomes simultaneously (i.e., multi-
variate), which were selected based on the multivariate influ-
ence function from the R ‘party’ p­ ackage17 that combines the
influence functions from each univariate response variable.
We considered intraoperative outcomes to be surrogates for
laparoscopic difficulty; hence, the multivariate responses of

TABLE 1  Cutoff analysis for nine selected endpoints

Tumor size Open con- Operation Estimated Blood trans- Pringle Post-op Post-op Major com- 90-day mor-
(cm) version time (min) blood loss fusion maneuver length of complica- plications tality
RR (95% MD (95% (ml) RR (95% RR (95% stay tions RR (95% RR (95% CI)
CI) CI) MD (95% CI) CI) MD (95% RR (95% CI)
CI) CI) CI)

>1.0 versus 1.86 (0.7 to 10 (− 18 to − 12 (− 114 1.05 (0.5 to 0.89 (0.51 to 1.8 (0 to 3.7) 1.52 (0.82 to 1.52 (0.62 to 2.58 (0.16 to
≤1.0 4.93) 38) to 91) 2.2) 1.54) 2.78) 3.71) 42.77)
>2.0 versus 1.49 (0.91 to 4 (− 12 to 20) 9 (− 52 to 70) 1.33 (0.85 to 0.98 (0.72 to 0.9 (− 0.2 to 1.23 (0.89 to 1.08 (0.69 to 10.0 (0.61 to
≤2.0 2.44) 2.09) 1.34) 1.9) 1.71) 1.69) 164)
>3.0 versus 1.5 (1.04 to 13 (1 to 26) 33 (− 13 to 1.38 (0.98 to 0.94 (0.74 to 0.4 (− 0.5 to 0.97 (0.75 to 0.83 (0.6 to 1.45 (0.61 to
≤3.0 2.17) 79) 1.94) 1.2) 1.2) 1.23) 1.16) 3.47)
>4.0 versus 1.43 (1.04 to 12 (1 to 23) 35 (− 9 to 79) 1.31 (0.98 to 0.99 (0.8 to 0.1 (− 0.6 to 0.97 (0.78 to 0.95 (0.7 to 0.86 (0.42 to
≤4.0 1.96) 1.77) 1.23) 0.9) 1.21) 1.29) 1.75)
>5.0 versus 1.59 (1.17 to 11 (0 to 22) 56 (12 to 101) 1.52 (1.14 to 1.13 (0.91 to 0 (− 0.7 to 0.96 (0.77 to 0.98 (0.73 to 0.92 (0.45 to
≤5.0 2.16) 2.03) 1.4) 0.7) 1.2) 1.33) 1.89)
>6.0 versus 1.56 (1.14 to 12 (1 to 23) 56 (9 to 103) 1.57 (1.17 to 1.12 (0.9 to 0.3 (− 0.5 1 (0.8 to 1.03 (0.76 to 1.11 (0.54 to
≤6.0 2.11) 2.09) 1.4) to 1) 1.25) 1.41) 2.29)
>7.0 versus 1.49 (1.08 to 11 (− 1 to 23) 50 (− 1 to 1.6 (1.19 to 1.01 (0.8 to 0.6 (− 0.2 to 1.07 (0.84 to 1.25 (0.91 to 1.24 (0.59 to
≤7.0 2.05) 101) 2.16) 1.28) 1.4) 1.36) 1.73) 2.64)
>8.0 versus 1.72 (1.22 to 11 (− 3 to 24) 52 (− 4 to 1.82 (1.32 to 1.07 (0.83 to 0.4 (− 0.5 to 1.09 (0.83 to 1.14 (0.79 to 1.92 (0.9 to
≤8.0 2.41) 108) 2.51) 1.4) 1.3) 1.42) 1.63) 4.09)
>9.0 versus 1.82 (1.27 to 13 (− 2 to 28) 47 (− 16 to 2.03 (1.45 to 1.3 (0.97 to 0.6 (− 0.4 to 1.1 (0.82 to 1.13 (0.76 to 1.62 (0.71 to
≤9.0 2.62) 109) 2.86) 1.74) 1.6) 1.47) 1.68) 3.74)
>10.0 ver- 2.1 (1.39 to 23 (5 to 40) 134 (50 to 2.31 (1.57 to 1.05 (0.75 to 1.4 (0.2 to 1.42 (1.01 to 1.55 (1 to 2.21 (0.92 to
sus ≤10.0 3.17) 218) 3.41) 1.49) 2.5) 1.99) 2.39) 5.34)
>11.0 ver- 1.99 (1.26 to 29 (10 to 49) 122 (30 to 2.35 (1.54 to 0.91 (0.62 to 1.9 (0.7 to 1.53 (1.05 to 1.93 (1.23 to 2.9 (1.2 to
sus ≤11.0 3.14) 215) 3.59) 1.33) 3.2) 2.23) 3.05) 7.04)
>12.0 ver- 2.03 (1.19 to 42 (19 to 65) 173 (50 to 2.25 (1.36 to 1 (0.64 to 2.1 (0.6 to 1.63 (1.04 to 1.98 (1.16 to 3.59 (1.39 to
sus ≤12.0 3.46) 295) 3.71) 1.56) 3.6) 2.55) 3.37) 9.28)
>13.0 ver- 2.01 (1.11 to 46 (20 to 72) 190 (53 to 2.19 (1.25 to 1.03 (0.62 to 2.2 (0.5 to 1.59 (0.96 to 2.14 (1.2 to 3.6 (1.28 to
sus ≤13.0 3.63) 326) 3.82) 1.7) 3.9) 2.61) 3.82) 10.11)
>14.0 ver- 2.44 (1.25 to 64 (33 to 95) 216 (69 to 2.85 (1.52 to 1.05 (0.58 to 3.6 (1.6 to 1.88 (1.04 to 2.97 (1.56 to 5.42 (1.91 to
sus ≤14.0 4.76) 362) 5.35) 1.91) 5.7) 3.38) 5.64) 15.44)
>15.0 ver- 3.04 (1.44 to 60 (23 to 96) 184 (12 to 2.57 (1.22 to 1.26 (0.61 to 4 (1.6 to 6.4) 1.95 (0.98 to 2.97 (1.4 to 5.77 (1.79 to
sus ≤15.0 6.44) 356) 5.43) 2.57) 3.9) 6.27) 18.6)

Modified Poisson regression with robust variance and quantile regression models were fitted to estimate relative risks (RR) and median differ-
ences (MD). Effect sizes were computed by dichotomizing the tumor size at every 10-mm interval (for example, at the tumor size cutoff of 10
cm, the effect size of RR 2.10 [95% CI 1.39–3.17] for the outcome of open conversion represents the risk ratio obtained when comparing the
rate of open conversion amongst patients with tumor size >100 mm versus patients with tumor size ≤ 100 mm). Effect sizes were adjusted using
inverse probability-weights from a logistic regression incorporating the following as covariates: age, gender, year of surgery, ASA status, previ-
ous abdominal surgery, concomitant minor surgery, cirrhosis, multifocality, difficult posterosuperior segment, malignant pathology, and all com-
ponents of the Iwate score, excluding tumor size
Impact of Tumor Size on …

Open conversion OT time (min) Estimated blood loss (ml)

75 100
10

300
Median difference

Median difference
Relative risk

200
50
4

25

100
2

0
-50 -25
1

-100
0 10 20 30 40 50 60 70 80 90 100110120130140150 0 10 20 30 40 50 60 70 80 90 100110120130140150 0 10 20 30 40 50 60 70 80 90 100110120130140150
Tumor size cutoff (mm) Tumor size cutoff (mm) Tumor size cutoff (mm)
Effect size dichotomized at > T vs ≤T cutoff Effect size dichotomized at > T vs ≤T cutoff Effect size dichotomized at > T vs ≤T cutoff

Blood transfusion Pringle maneuver Post-op length of stay (days)

10

6
Median difference
5
Relative risk

Relative risk
4

4
2

3
2

2
1

1
1

0
-1
.5

.5

0 10 20 30 40 50 60 70 80 90 100110120130140150 0 10 20 30 40 50 60 70 80 90 100110120130140150 0 10 20 30 40 50 60 70 80 90 100110120130140150

Tumor size cutoff (mm) Tumor size cutoff (mm) Tumor size cutoff (mm)
Effect size dichotomized at > T vs ≤T cutoff Effect size dichotomized at > T vs ≤T cutoff Effect size dichotomized at > T vs ≤T cutoff

Any-grade morbidity Major complicants 90 day mortality

10

10

5 10 25 50 100
Relative risk

Relative risk

Relative risk
4
4

2
2

0.25 .5 1 2
1
1

0 10 20 30 40 50 60 70 80 90 100110120130140150 0 10 20 30 40 50 60 70 80 90 100110120130140150 0 10 20 30 40 50 60 70 80 90 100110120130140150

Tumor size cutoff (mm) Tumor size cutoff (mm) Tumor size cutoff (mm)
Effect size dichotomized at > T vs ≤T cutoff Effect size dichotomized at > T vs ≤T cutoff Effect size dichotomized at > T vs ≤T cutoff

FIG. 1  Cutoff analysis. Impact of tumor size cutoffs in intervals of using a modified version of the ‘Cutoff_Finder’ R package to permit
10 mm on perioperative outcomes. Effect sizes were computed by the estimation of adjusted relative risks and median differences from
iteratively dichotomizing the tumor size at each 10-mm interval and Poisson and quantile regression models
computing two-sample treatment effect sizes local to that cutoff,

interest were namely the rates of open conversion, operative worsen (or improve) as the tumor size category increased.
time, estimated blood loss, application of Pringle’s maneuver, For example, we would expect a consistent and stepwise
and requirement for intraoperative blood transfusion. increase in the estimated blood loss as the tumor size
The aforementioned analysis identified two tumor size category increases from ‘0–50 mm’ to ‘51–100 mm’ and
cutoffs (50 mm and 100 mm) which segregated L-MHs to ‘> 100 mm’. Statistical analyses were conducted in R
into three categories. Tests of inequality across tumor size version 4.0.2 (R Foundation) or Stata 16.1 (StataCorp),
categories were performed using Kruskal-Wallis and Fish- and P < 0.05 were regarded to indicate nominal statistical
er’s exact tests for continuous and categorical variables, significance.
respectively. We assessed for the strength of monotonic
rank ordering using two-sided Jonckheere–Terpstra and RESULTS
Cochran–Armitage trend tests for continuous and binary
dependent variables respectively, with tumor size category Identification of Optimal Tumor Size Cutoffs
as an ordinal independent variable. The alternative hypoth-
esis of interest is that there exists a gradation in outcomes The analyses identified two tumor size cutoffs, 50 mm
whereby perioperative outcomes should consistently and 100 mm, respectively, which significantly affected

intraoperative outcomes during L-MH, including the rates
of open conversion, operative time, estimated blood loss,
application of Pringle’s maneuver, and requirement for intra-
operative blood transfusion. Therefore, the trichotomized
tumor-size groups (≤ 50 mm, 51–100 mm, > 100 mm) were
devised and studied for the next sets of analysis.
Comparison of Baseline Clinical and Surgical
Characteristics Among the Stratified Tumor‑Size Groups
Baseline clinical and surgical characteristics of patients
who underwent L-MH were compared among those with
tumor size ≤ 50 mm (n = 761), 51–100 mm (n = 483) and >
100 mm (n = 152) (Table 2). As shown, statistically signifi-
cant differences were found in year of surgery (2004–2012
vs. 2013–2021, P = 0.005), previous abdominal surgery (P
< 0.001), malignant pathology (P < 0.001), median tumor
size (P < 0.001), multiple tumors (P < 0.001), Iwate dif-
ficulty score including (P < 0.001), and excluding (P <
0.001), tumor size, Iwate difficulty levels (P < 0.001) and
IMM-3 procedures (P = 0.019). The impact of patient age,
sex, concomitant minor surgery, ASA score, presence of cir-
rhosis or portal hypertension, tumor location at the postero-
superior segments, and performance of multiple resections
were comparable among the three tumor size groups.
Comparison Between Perioperative Outcomes Across the 3
Groups Stratified by Tumor Size
In the next sets of analysis, we compared intraoperative
and postoperative short-term outcomes among the three
tumor size groups, and investigated the potential existence
of a monotonic trend among the groups regarding each
variable (Table 3). As tumor size increases (from ≤ 50 to
51–100 mm and >100 mm), the open conversion rate (from
11.2 to 14.7% and 23.0%, P < 0.001), operating time (from
340 to 346 min and 365 min, P = 0.025), blood loss (from
300 to 300 ml and 400 ml, P = 0.002), and the rate of intra-
operative blood transfusion (from 13.1 to 15.9% and 27.6%,
P < 0.001) all significantly increased in a monotonous and
stepwise fashion. The rate of Pringle’s maneuver application
was comparable among the three groups.
On the other hand, overall and major (≥ Clavien-Dindo
grade 2) postoperative morbidity, postoperative length of
hospital stays, 30-day readmission, and 30-day and 90-day
mortality, as well as the rate of surgical close margins, were
comparable among the three tumor size groups.
DISCUSSION
In this large international multi-center study, we exam-
ined the impact of tumor size and determined optimal TS
cutoffs for stratifying the surgical difficulty of IMM-3 L-MH
Y. Kato et al.
utilizing surrogate perioperative outcome measures such as
blood loss, blood transfusion rate, open conversion, post-
operative morbidity, and length of stay. Using our analysis
based on tumor size stratified at each 10-mm interval, we
identified two distinct size cutoffs (50 mm and 100 mm),
which stratified L-MH according to perioperative outcomes.
We determined 3 different TS categories stratified by these
two cutoffs, which had a significant impact on the intraop-
erative outcomes and difficulty of L-MH as shown by the
significant difference in open conversion rate, operative
time, estimated blood loss, and the rate of blood transfu-
sion. Moreover, by utilizing these same two cutoff sizes,
a monotonous gradation of these intraoperative outcomes
was shown as tumor size increased. However, increasing
tumor size did not have a significant impact on postopera-
tive outcomes such as morbidity, mortality, hospital stay, or
surgical margins. To the best of our knowledge, this is the
first study to date to analyze the correlation between tumor
size and perioperative outcomes of L-MH.
Previous studies have suggested several possible TS
cutoffs that impact the operative difficulty as well as post-
operative outcomes of LLR.5,7–9 The Iwate criteria uses 3
cm while the Southampton system applies 3 cm and 5 cm,
respectively, as cutoffs.6,7 Kabir et al. determined that 30 mm
and 70 mm were optimal size cutoffs and showed signifi-
cantly longer operating times, increased blood loss, and
longer hospital stays between the 3 groups. There was also
a monotonous trend in the transfusion rates, overall morbid-
ity, and 90-day mortality rates, with increasing tumor size.12
A study by Levi Sandri et al., analyzing 172 LLR cases that
were trichotomized into 3 groups (< 3 cm, 3–5 cm, and ≥
5 cm), also demonstrated that a larger TS was associated
with significantly higher conversion rates, longer opera-
tive times, greater blood loss, more frequent and prolonged
Pringle maneuver, and longer hospital stay.18 Another study
by Shelat et al. on 52 patients undergoing LLRs for malig-
nant tumors ≥ 5 cm, showed that a subgroup of 10 patients
with tumors ≥ 10 cm had longer operative time and signifi-
cantly greater blood loss than those with tumors < 10 cm.19
Kabir et al. compared 15 LLR cases of hepatocellular car-
cinoma (HCC) ≥ 10 cm with 101 cases of HCC < 10 cm
and demonstrated a significantly longer operative time and
a trend towards increased blood loss and increased use of
Pringle maneuver in the former group, although postopera-
tive morbidity and mortality were comparable.20
However, a major limitation of these previous studies was
that all types and extent of LLR were included in the analy-
ses. It is intuitive to most liver surgeons that the impact of
TS on the difficulty of an LR would be dependent on the
extent of the LR.13 To highlight this point, for example dur-
ing a monosegmentectomy, resection of a tumor of 4 cm in
size would be much more challenging than for a 1-cm tumor.
However, when performing a right hepatectomy, there would
Impact of Tumor Size on …

TABLE 2  Comparison of baseline clinical and surgical characteristics of patients who underwent L-MH, stratified by tumor size
All Tumor size ≤ 50 mm Tumor size 51–100 mm Tumor size >100 mm P-value (inequality
N = 1396 N = 761 N = 483 N = 152 between groups)†

Median age (IQR), years 62 (53–71) 63 (54–71) 62 (52–71) 62 (50–72) 0.186

Male sex, n (%) 863 (61.8%) 488 (64.1%) 291 (60.2%) 84 (55.3%) 0.082
Year of surgery 0.005
2004-2012 242 (17.3%) 155 (20.4) 66 (13.7%) 21 (13.8%)
2013-2021 1154 (82.7%) 606 (79.6%) 417 (86.3%) 131 (86.2%)
Previous abdominal surgery, 498/1386 (35.9%) 317/756 (41.9%) 135/478 (28.2%) 46/152 (30.3%) < 0.001
n/total (%)
Concomitant minor surgery, 79 (5.7%) 40 (5.3%) 31 (6.4%) 8 (5.3%) 0.691
n (%)
ASA score, n/total (%) 0.224
1 190 (13.6%) 87 (11.4%) 80 (16.6%) 23 (15.1%)
2 843 (60.4%) 473 (62.2%) 282 (58.4%) 88 (57.9%)
3 354 (25.4%) 195 (25.6%) 118 (24.4%) 41 (27.0%)
4 9 (0.6%) 6 (0.8%) 3 (0.6%) 0 (0.0%)
Malignant neoplasm, n (%) 1270 (91.0%) 718 (94.3%) 428 (88.6%) 124 (81.6%) < 0.001
Cirrhosis, n/total (%) 338 (24.2%) 176 (23.1%) 127 (26.3%) 35 (23.0%) 0.43
Portal hypertension, n/total 52/1391 (3.7%) 31/759 (4.1%) 15/480 (3.1%) 6/152 (3.9%) 0.672
(%)
Median tumor size, mm 50 (30–80) 30 (20–40) 75 (65–85) 130 (116–150) < 0.001
(IQR)
Multiple tumors, n (%) 554 (39.7%) 352 (46.3%) 158 (32.7%) 44 (28.9%) < 0.001
Posterosuperior segments (I, 1241 (88.9%) 665 (87.4%) 437 (90.5%) 139 (91.4%) 0.147
IVa, VII, VIII), n (%)
Multiple resections, n (%) 134 (9.6%) 86 (11.3%) 38 (7.9%) 10 (6.6%) 0.06
Median Iwate difficulty 10 (10–11) 10 (9–11) 11 (10–11) 11 (10–11) < 0.001
score, (IQR)
Median Iwate difficulty score 10 (9–10) 9 (9–10) 10 (9–10) 10 (9–10) < 0.001
excluding tumor size, (IQR)
Iwate difficulty, n (%) < 0.001
Low 0/1392 (0.0%) 0/758 (0.0%) 0/482 (0.0%) 0/152 (0.0%)
Intermediate 10/1392 (0.7%) 10/758 (1.3%) 0/482 (0.0%) 0/152 (0.0%)
High 284/1392 (78.9%) 223/758 (29.4%) 49/482 (10.2%) 12/152 (7.9%)
Expert 1098/1392 (78.9%) 525/758 (69.3%) 433/482 (89.8%) 140/152 (92.1%)
IMM-3 procedure, n (%) 0.019
Right hepatectomy 1083 (77.6%) 580 (76.2%) 382 (79.1%) 121 (79.6%)
Extended Rt hepatectomy 114 (8.2%) 57 (7.5%) 37 (7.7%) 20 (13.2%)
Central hepatectomy 109 (7.8%) 67 (8.8%) 38 (7.9%) 4 (2.6%)
Extended Lt hepatectomy 90 (6.4%) 57 (7.5%) 26 (5.4%) 7 (4.6%)
†
Kruskal-Wallis test for continuous variables and Fisher’s exact test for categorical variables

be minimal impact on the technical difficulty of resecting a
2-cm tumor compared with a 5-cm tumor.
It is important to note that, in this study, although increas-
ing TS had a significant impact on intraoperative outcomes
such as open conversion rate, operation time, blood loss, and
blood transfusion rate, it did not have a significant impact
on postoperative outcomes such as morbidity, mortality,
or length of stay. These favorable postoperative outcomes
observed in this analysis attest to the feasibility and safety
of L-MH in specialized centers, even when performed for
large tumors. This observation also suggests that TS alone
is not an important factor in determining postoperative out-
comes after L-MH in well-selected patients. Other factors
such as patient co-morbidities and severity of liver disease
would likely have a more significant impact on postoperative
outcomes compared with tumor size alone.
There are several limitations associated with this study
which should be highlighted. Firstly, this is a retrospective
 Y. Kato et al.

TABLE 3  Comparison of perioperative outcomes of patients who underwent L-MH, stratified by tumor size

All Tumor size ≤ 50 mm Tumor size 51-100 mm Tumor size >100 mm P-value for
N = 1396 N = 761 N = 483 N = 152 monotonic
trend†

Open conversion, n (%) 191 (13.7%) 85 (11.2%) 71 (14.7%) 35 (23.0%) < 0.001
Mean operating time (SD), min 345 (122) 340 (114) 346 (132) 365 (125) 0.025
Median blood loss (IQR), ml 300 (200–600) 300 (184–600) 300 (200–500) 400 (200–800) 0.002
Intraoperative blood transfusion, 219 (15.7%) 100 (13.1%) 77 (15.9%) 42 (27.6%) < 0.001
n (%)
Pringle maneuver applied, n (%) 750/1350 (55.6%) 398/734 (54.2%) 268/468 (57.3%) 84/148 (56.8%) 0.312
Median postoperative stay (IQR), 7 (5–10) 7 (5–10) 7 (5–10) 7 (5–12) 0.684
days
Overall morbidity, n (%) 478 (34.2%) 264 (34.7%) 151 (31.3%) 63 (41.4%) 0.833
Major morbidity (Clavien-Dindo 195 (14.0%) 107 (14.1%) 59 (12.2%) 29 (19.1%) 0.663
grade >2)
30-day readmission, n (%) 69/1371 (5.0%) 36/751 (4.8%) 23 (4.9%) 10 (0.8%) 0.504
30-day mortality, n (%) 17 (1.22%) 9 (1.2%) 3 (0.6%) 5 (3.3%) 0.429
90-day mortality, n (%) 30 (2.1%) 17 (2.2%) 7 (1.4%) 6 (3.9%) 0.811
Close margins, n (%) 234/1388 (16.9%) 129 (17.0%) 18/479 (3.8%) 20/152 (13.2%) 0.598
†
Two-sided Cochran-Armitage or Jonckheere-Terpstra tests were used to evaluate the presence of a monotonic increasing or decreasing trend
over the four tumor size categories, which was treated as an ordinal variable (i.e., Group 1: < 40 mm, Group 2: 40–69 mm, Group 3: 70–99 mm,
Group 4: ≥ 100 mm)

study with inherent biases. Secondly, as an international
multicenter study, there would be inevitable inter-center var-
iations in operative indications, surgical technique, surgeon/
center experience, and perioperative management strategies.
Nonetheless, the relatively large sample size enabled us to
perform a robust statistical analysis.
In conclusion, increasing TS was associated with poorer
intraoperative but not postoperative outcomes after L-MH.
We determined two tumor size cutoffs (50 mm and 10 mm)
which could optimally stratify the surgical difficulty of
L-MH. These two size cutoffs should be considered when
formulating a new difficulty scoring system for L-MH.
Development of a more accurate difficulty scoring system
would enable better stratification of L-MH, allowing sur-
geons to better select patients for L-MH according to their
experience level. This would also allow fairer comparison
when auditing outcomes and benchmarking L-MH.
ACKNOWLEDGEMENTS International Robotic and Laparoscopic
Liver Resection Study Group investigators: Mikel Prieto: (Hepatobil-
iary Surgery and Liver Transplantation Unit, Biocruces Bizkaia Health
Research Institute, Cruces University Hospital, University of the Basque
Country, Bilbao, Spain). Celine De Meyere: (Department of Digestive
and Hepatobiliary/Pancreatic Surgery, Groeninge Hospital, Kortrijk,
Belgium). Juul Meurs: (Department of Digestive and Hepatobiliary/
Pancreatic Surgery, Groeninge Hospital, Kortrijk, Belgium). Kit-Fai
Lee: (Division of Hepatobiliary and Pancreatic Surgery, Department
of Surgery, Prince of Wales Hospital, The Chinese University of Hong
Kong, New Territories, Hong Kong SAR, China). Diana Salimgereeva:
(Department of Hepato-Pancreato-Biliary Surgery, Moscow Clinical
Scientific Center, Moscow, Russia). Ruslan Alikhanov: (Department of
Hepato-Pancreato-Biliary Surgery, Moscow Clinical Scientific Center,
Moscow, Russia). Lip-Seng Lee: (Hepatopancreatobiliary Unit, Depart-
ment of Surgery, Changi General Hospital, Singapore). Jae Young
Jang: (Department of General Surgery, CHA Bundang Medical Center,
CHA University School of Medicine, Seongnam, Korea). Jaime Arthur
Pirola Kruger: (Liver Surgery Unit, Department of Gastroenterology,
University of Sao Paulo School of Medicine, Sao Paulo, Brazil). Victor
Lopez-Lopez: (Department of Surgery, Virgen de la Arrixaca University
Hospital, Murcia, Spain). Margarida Casellas I Robert: (Hepatobiliary
and Pancreatic Surgery Unit, Department of Surgery, Dr. Josep Trueta
Hospital, IdIBGi, Girona, Spain). Roberto Montalti: (Department of
Public Health, Division of HPB, Minimally Invasive and Robotic Sur-
gery, Federico II University Hospital Naples, Naples, Italy). Boram Lee:
(Department of Surgery, Seoul National University Bundang Hospital,
Seoul National University College of Medicine, Seoul, Korea). Hao-
Ping Wang: Department of Surgery, Chang Gung Memorial Hospital,
Kaohsiung. Mansour Saleh: (Department of Hepatobiliary Surgery,
Assistance Publique Hopitaux de Paris, Centre Hepato-Biliaire, Paul-
Brousse Hospital, Villejuif, France). Simone Vani: (Hepatobiliary Sur-
gery Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS,
Catholic University of the Sacred Heart, Rome, Italy). Francesco Ardito:
(Hepatobiliary Surgery Unit, Fondazione Policlinico Universitario A.
Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy).
Ugo Giustizieri: (HPB Surgery, Hepatology and Liver Transplantation,
Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy).
Davide Citterio: (HPB Surgery, Hepatology and Liver Transplantation,
Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy).
Federico Mocchegiani: (HPB Surgery and Transplantation Unit, United
Hospital of Ancona, Department of Experimental and Clinical Medicine
Polytechnic University of Marche). Marco Colasanti: (Division of Gen-
eral Surgery and Liver Transplantation, San Camillo Forlanini Hospital,
Rome, Italy). Yoelimar Guzmán: (General & Digestive Surgery, Hospi-
tal Clínic, Barcelona, Spain). Kevin P. Labadie: (Department of Surgery,
University of Washington Medical Center. Seattle, USA). Paolo Magis-
tri: (HPB Surgery and Liver Transplant Unit, University of Modena and
Reggio Emilia, Modena, Italy). Kohei Mishima: (Center for Advanced
Impact of Tumor Size on …
Treatment of Hepatobiliary and Pancreatic Diseases, Ageo Central Gen-
eral Hospital, Saitama, Japan). Felix Krenzien: (Department of Sur-
gery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-
Universitätsmedizin, Corporate Member of Freie Universität Berlin,
and Berlin Institute of Health, Berlin, Germany). Prashant Kadam:
(Department of Hepatopancreatobiliary and Liver Transplant Surgery,
University Hospitals Birmingham NHS Foundation Trust, Birmingham,
United Kingdom). Chung Ngai Tang: (Department of Surgery, Pamela
Youde Nethersole Eastern Hospital, Hong Kong SAR, China). Jacob
Ghotbi: (The Intervention Centre and Department of HPB Surgery, Oslo
University Hospital, Institute of Clinical Medicine, University of Oslo,
Oslo, Norway). Åsmund Avdem Fretland: (The Intervention Centre
and Department of HPB Surgery, Oslo University Hospital, Institute of
Clinical Medicine, University of Oslo, Oslo, Norway). Mariano Giglio:
(Department of Clinical Medicine and Surgery, Division of HPB, Mini-
mally Invasive and Robotic Surgery, Federico II University Hospital
Naples, Naples, Italy). Alessandro Mazzotta: (Department of Diges-
tive, Oncologic and Metabolic Surgery, Institute Mutualiste Montsouris,
Universite Paris Descartes, Paris, France). Qu Liu: (Faculty of Hepato-
pancreatobiliary Surgery, the First Medical Center of Chinese People’s
Liberation Army (PLA) General Hospital, Beijing, China). Shian Yu:
(Department of Hepatobiliary Surgery, Affiliated Jinhua Hospital, Zhe-
jiang University School of Medicine, Jinhua, China).
FUNDING Dr T. P. Kingham was partially supported by the US
National Cancer Institute MSKCC Core Grant number P30 CA008747
for this study. Dr M. Yin was partially funded by the Research Project
of Zhejiang Provincial Public Welfare Fund project in the Field of
Social development (LGF20H160028).
DISCLOSURE Dr Goh BK has received travel grants and hono-
raria from Johnson & Johnson, Olympus, and Transmedic, the local
distributor for the Da Vinci Robot. Dr Marino MV is a consultant
for CAVA robotics LLC. Johann Pratschke reports a research grant
from Intuitive Surgical Deutschland GmbH and personal fees or non-
financial support from Johnson & Johnson, Medtronic, AFS Medical,
Astellas, CHG Meridian, Chiesi, Falk Foundation, La Fource Group,
Merck, Neovii, NOGGO, pharma-consult Peterson, and Promedicis.
Moritz Schmelzle reports personal fees or other support outside of the
submitted work from Merck, Bayer, ERBE, Amgen, Johnson & John-
son, Takeda, Olympus, Medtronic, Intuitive. Asmund Fretland reports
receiving speaker fees from Bayer. Fernando Rotellar reports speaker
fees and support outside the submitted work from Integra, Medtronic,
Olympus, Corza, Sirtex and Johnson & Johnson.
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