DOI: 10.1002/jhbp.956|

Revised: 3 March 2021|

Accepted: 30 March 2021

ORIGINAL ARTICLE

Survey of surgical resections for neuroendocrine liver metastases:
A project study of the Japan Neuroendocrine Tumor Society(JNETS)
Taku Aoki1| Keiichi Kubota1 | Sho Kiritani2 | Junichi Arita2|
3
4
5
Chigusa Morizane | Toshihiko Masui | Atsushi Kudo | Izumi Komoto6 |Etsuro Hatano7 | Tetsuhide Ito8 | Robert Y. Osamura9,10 | Michiaki Unno11|
4
12
Shinji Uemoto | Norihiro Kokudo| The Japanese Neuroendocrine Tumor Society (JNETS)
1

Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan2

Hepato-­Biliary-­Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine,
University of Tokyo, Tokyo, Japan3

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan

4

Division of Hepato-­Biliary-­Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan

5

Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

6

Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan

7

Department of Gastroenterological Surgery, Hyogo College of Medicine, Hyogo, Japan

8

Neuroendocrine Tumor Center, Fukuoka Sanno Hospital, International University of Health and Welfare, Fukuoka, Japan

9

Division of Diagnostic Pathology, Nippon Koukan Hospital, Kanagawa, Japan10

Department of Pathology, Keio University School of Medicine, Tokyo, Japan

11

Department of Surgery, Tohoku University School of Medicine, Miyagi, Japan

12

Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan

Correspondence
Taku Aoki, Second Department ofSurgery, Dokkyo Medical University, 880
Kitakobayashi, Mibu, Tochigi 321-­0293,
Japan.
Email: aoki-2su@dokkyomed.ac.jp

Abstract
Background/Purpose: Hepatic resection is considered the treatment of choice forneuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study
was to collect real-­world data regarding hepatic resections for NELM.
Methods: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative
details, pathological findings, and patient outcomes were investigated.
Results: A total of 222 patients were enrolled from 30 institutions. The primary tumor
site was the pancreas in 58.6%, and the presentation of NELM was synchronous in
63.1% of the cases. Concomitant resection of the primary tumor and liver metastases
was performed for 66.4% of the synchronous metastases, and the 90-­day morbidity
and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2021 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.
J Hepatobiliary Pancreat Sci. 2021;28:489–497.	﻿	

wileyonlinelibrary.com/journal/jhbp| 489

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Received: 22 February 2021

|   

AOKI et al.

resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence
after R0/1 resections. However, the patients were treated using multiple modalities
after R2 resection or recurrence, and the overall survival rate was relatively favorable,with 5-­year and 10-­year survival rates of 70.2%, and 43.4%, respectively. Univariable
and multivariable analyses identified the tumor grading (G3) of the primary tumor
as a significant prognostic factor for both the recurrence-­free and overall survivals.
Conclusions: The present data confirmed the safety of the surgical resection of
NELM. Although recurrences were frequent, the survival outcomes after resection
were favorable when a multi-­disciplinary treatment approach was used.
KEYWORDS

neuroendocrine liver metastasis, overall survival, postoperative complication, surgery, tumor
recurrence

1|

IN TRO D U C T ION

Neuroendocrine neoplasms (NENs) are rare neoplasms that
include a wide spectrum of disease sites and histologicalsubgroups. The incidence of NENs has reportedly increased
during the last decade.1,2 The current WHO classification3,4
first stratifies NEN into well-­differentiated NEN (NET) andpoorly differentiated NEN (NEC); then, NET is sub-­grouped
into G1, G2, and G3 according to the Ki-­67 index, and recent
epidemiologic data from the United States has documented
striking increases in localized-­stage NENs as well as NET G1.2
In contrast to the aggressive behavior of NEC, NET reportedly
follows a relatively indolent clinical course; however, some
NET tumors are found with distant metastases, especially liver
metastases, at their presentation, and more than half of NET
cases reportedly develop liver metastases during their clinicalcourse.5 The presence of liver metastasis adversely affects patient outcomes; thus, the management of liver metastases is ofprime importance in the treatment of NEN patients.6
At present, surgical resection is the treatment of choicefor neuroendocrine liver metastasis (NELM) whenever feasible, since patient outcomes after surgical resection have beenreported to be favorable compared with those with unresectable tumors.6,7 However, clinical trials comparing surgicalresection and other treatment modalities are lacking, andreal-­world data surrounding NELM remains scarce. In thepresent study, we conducted a nationwide survey in Japan andcollected clinical information regarding surgical resection toclarify the status of treatment for NELM.

2
2.1

|

METHODS|

Study design

This retrospective, multicenter survey was planned as aproject of the Japanese Neuroendocrine Tumor Society(JNETS). This study was conducted with the approval of
the ethical committee of the JNETS as well as of Dokkyo
Medical University Hospital (registration number: 27111)
and each participating institution. Questionnaires were sent
to the participating institutions, and the replies were collected
and analyzed at the Second Department of Surgery, Dokkyo
Medical University. The data collection was performed from
June to September 2017.

2.2|

Patients

Patients undergoing an initial hepatic resection for NELM
between January 2000 and June 2017 were enrolled in thepresent study. The collected data included background patient characteristics (age, sex, date of diagnosis, backgrounddisease [sporadic or hereditary], primary tumor site, functionality of the tumor, presentation of liver metastasis [synchronous or metachronous], and treatments prior to the liverresection), operative details (order of the operation [primary
first, liver first, concomitant resection], extent of liver resection, tumor number, maximum tumor size, and radicality ofthe operation [R0, R1, or R2]), pathological results (differentiation of the primary tumor, grading of the primary tumor,
differentiation of liver metastasis, grading of liver metastasis, and Ki-­67 index of the primary tumor and liver metastasis), and surgical outcomes (90-­day morbidity and mortality
rates, presence of recurrence, recurrence-­free survival [RFS]
period after liver resection, treatments after R2 resection orrecurrence, and overall survival [OS] period after liver resection). Postoperative complications classified as Clavien-­
Dindo grade 3 or more were recorded as morbidities.8

2.3|

Statistical analysis

The Ki-­67 index of the primary tumor and liver metastasis were compared using the Wilcoxon signed-­rank test.

18686982, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jhbp.956 by Cochrane Japan, Wiley Online Library on [28/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License490

Univariable and multivariable analyses were performed toinvestigate the significant clinicopathological factors associated with recurrence-­free and overall survivals. The survival
curves were generated using the Kaplan-­Meier method. The
analyses were conducted using SPSS version 25.0 (SPSS Inc)
and BellCurve for Excel (Social Survey Research Information
Co., Ltd.). Differences with P < .05 were considered as being
significant.

3|

R E S U LTS

Thirty institutions participated in the present study, and a
total of 222 patients were enrolled in the analyses. The namesof the participating institutions are listed in Appendix S1.

3.1|

Background patient characteristics

Patient age ranged from 22 to 84 years (median, 56.0 years)
at the diagnosis of NEN and from 22 to 84 years (median, 59.0 years) at the time of the first hepatic resection(Table 1). Nine patients had hereditary diseases; five had
multiple endocrine neoplasia type 1, three had Von Hippel-­
Lindau disease, and one had Li-­Fraumeni syndrome. The
dominant primary tumor site was the pancreas in 130(58.6%) patients, followed by the rectum in 28 (12.6%),
the duodenum in 19 (8.6%), and the small intestine in 10(4.5%). The primary tumor was functional in 29 cases.
The presentation of liver metastasis was synchronous in
140 cases (63.1%) and metachronous in 82 cases (36.9%).
Treatment prior to hepatic resection was performed in 51
patients (23.0%); somatostatin analogue therapy was performed in 15, molecular-­targeting therapy was performed
in 13, chemotherapy was performed in 21, and transcatheter arterial chemoembolization (TACE) was performed in
16. The number of modalities used before hepatic resection
ranged from one to four.

3.2 | Operative procedures and short-­
term outcomes
Concomitant resection of the primary tumor and liver metastases was performed in 93 cases (66.4%) (Table 2), andthe pancreas was the dominant concomitantly resected organ(n = 67). The pancreatectomy procedure consisted of a distal
pancreatectomy in 49 patients, a pancreaticoduodenectomyin 16 patients, and a total pancreatectomy in two patients. In
the other 47 patients, a liver first (n = 27) or a primary first(n = 20) approach was selected. The hepatic resection procedure consisted of a partial resection in 115 (51.8%) patients,a hemi-­hepatectomy or more in 51 (23.0%), a segmentectomy| 491

TABLE 1(n = 222)

Clinical characteristics of the enrolled patients

VariableData

Age at the diagnosis of NEN, y, median (range)

56.0 (22-­84)

Age at the hepatic resection, y, median (range)

59.0 (22-­84)

Sex, male/female

113/109

Hereditary disease, yes/no

9/213

MEN type1, n5

VHL, n3

Li-­Fraumeni syndrome, n1Primary site, n (%)
Pancreas, n

130 (58.6)

Rectum, n

28 (12.6)

Duodenum, n

19 (8.6)

Small intestine, n

10 (4.5)

Stomach, n

9 (4.1)

Lung/bronchus, n

8 (3.6)

Bile duct, n

3 (1.4)

Colon, n

2 (0.9)Others, n

13 (5.9)

Functional tumour, yes/no

29/193

Pancreas, n26

Rectum, n1

Small intestine, n1

Stomach, n1

Presentation of liver metastasis, n (%)
Synchronous

140 (63.1)

Metachronous

82 (36.9)

Treatments prior to hepatic resection, yes/no

51/171

Somatostatin analogue, n

15

Molecular-­targeting agents, n

13

Chemotherapy, n

21

TACE, n16

RFA, n5

Radiation, n1

Number of treatment modalities performed prior to hepatic
resection, n
1

30

2

14

3

6

4

1

Abbreviations: N/A, not assessed; NEN, neuroendocrine neoplasm; RFA,
radiofrequency ablation; TACE, transcatheter arterial chemembolization; VHL,Von Hippel-­Lindau disease.

in 33 (14.9%), and a sub-­segmentectomy in 19 (8.6%). As aresult, an anatomical resection was performed in 103 cases(46.4%). The number of resected tumors was one in 53(24.1%) cases, 2-­3 in 50 (22.7%), 4-­10 in 58 (26.4%), and 11

18686982, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jhbp.956 by Cochrane Japan, Wiley Online Library on [28/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License   

AOKI et al.

AOKI et al.

TABLE 2TABLE 3

Surgery-­related variables

Variable

Data

Time-­sequence of the resection of the liver and the primary inpatients with synchronous metastasis, n (%)
Concomitant resection

93 (66.4)

Liver first

27 (19.3)

Primary first

20 (14.3)

The organ(s) concomitantly resected with the liver, nPancreas (PD/DP/TP)

67 (16/49/2)

Stomach/duodenum

9

Small intestine

8

Colon/rectum

4

Others4

Procedure of hepatic resection, n (%)
Partial resection

115 (51.8)

Hemi-­hepatectomy or more

51 (23.0)

Segmentectomy

33 (14.9)

Sub-­segmentectomy

19 (8.6)

N/A

4 (1.8)Tumor number, n (%)
1

53 (24.1)

2-­3

50 (22.7)

4-­10

58 (26.4)

11-­2020 (9.1)

21-­

39 (17.7)

Maximum tumor size, cm, median (range)

3.0 (0.2-­35.0)

Radicality of the operation, n (%)
R0

140 (63.1)

R1

21 (9.5)

R2

58 (26.1)

N/A

3 (1.4)90-­day morbidity (Clavien-­Dindo grade 3 ormore), yes/no/unknown

28 (12.6)/191(86.0)/3 (1.4)

90-­day mortality, yes/ no/ unknown (n, %)2 (0.9)/ 217(97.7)/3 (1.4)

Abbreviations: DP, distal pancreatectomy; N/A, not assessed; PD,pancreaticoduodenectomy; TP, total pancreatectomy.

or more in 59 (26.8%), with a median size of 3.0 cm among
the largest tumors. The operation was cytoreductive (non-­curative) in 58 (26.1%) patients. The 90-­day morbidity andmortality rates were 12.6% and 0.9%, respectively.

3.3|

Pathological results

Pathological variables

Variable

Data

Differentiation of the primary tumor, n (%)
Well differentiated177 (79.7)

Poorly differentiated

12 (5.4)

N/A

33 (14.9)

Grading of the primary tumor (WHO2010), n (%)
G1

28 (12.6)

G2

82 (36.9)

G3

14 (6.3)

N/A

98 (44.1)

Differentiation of the liver metastasis, n (%)
Well differentiated97 (43.7)

Poorly differentiated

12 (5.4)

N/A

113 (50.9)

Grading of the liver metastasis (WHO2010), n (%)
G1

13 (5.9)G2

56 (25.2)

G3

12 (5.4)

N/A

141 (63.5)

Abbreviation: N/A, not assessed.

The grading of the primary tumor based on the WHO 2010classification9 was G1 in 28 (12.6%) cases, G2 in 82 (36.9%)
cases, G3 in 14 (6.3%) cases, and unknown in 98 (44.1%)
cases. The differentiation of the liver metastases was well-­
differentiated in 97 (43.7%) cases, poorly differentiated in 12(5.4%) cases, and unknown in 113 (50.9%) cases. The grading of the liver metastases was G1 in 13 (5.9%) cases, G2 in
56 (25.2%) cases, G3 in 12 (5.4%) cases, and unknown in 141(63.5%) cases.
Information regarding the grading of both the primarytumor and the liver metastasis were available in 46 cases. The
results showed that an up-­grading from the primary tumor
to the liver metastasis was found in seven cases (15.2%;
G1→G2, six cases; G1→G3, one case) and down-­grading
was found in five cases (10.8%; G2→G1, two cases; G3→G2,
three cases).
Among the seven cases with up-­grading, the presentationof liver metastasis was synchronous in four cases and metachronous in three cases. Information regarding the actual Ki-­
67 index values were available in 46 cases. The difference
between the Ki-­67 index of the primary tumor and that of theliver metastasis was insignificant (P = .63).

3.4|

Recurrence-­free and overall survivals

The differentiation of the primary tumor was well-­
differentiated in 177 (79.7%) cases, poorly differentiated in
After a median follow-­up period of 42 months (range, 0-­
12 (5.4%) cases, and unknown in 33 (14.9%) cases (Table 3).
274 months; mean, 54.0 months), tumor recurrence had

18686982, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jhbp.956 by Cochrane Japan, Wiley Online Library on [28/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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492

occurred in 146 (83.4%) cases among the patients who received R0/1 resections (Tables 4 and 5). The median RFS
period after hepatic resection was 14.0 months, and the 1-­
year, 3-­year, and 5-­year RFS rates were 54.7%, 23.9%, and13.4%, respectively (Figure 1A). The recurrence site wasintra-­hepatic only in 90 (63.4%) cases, extra-­hepatic onlyin 11 (7.7%) cases, and both intra-­hepatic and extra-­hepatic
in 40 (28.2%) cases. Treatments for residual tumors afterR2 resection or recurrent tumors were conducted in 175
cases (91.1%) and included various modalities such as repeat hepatic resection, somatostatin analogue therapy, andmolecular-­targeting therapy. The median OS period after hepatic resection was 113 months, and 1-­year, 3-­year, 5-­year,
and 10-­year OS rates were 91.8%, 83.1%, 70.2%, and 43.4%,
respectively (Figure 1B). The OS curves stratified by the status of radicality (R0 vs R1 vs R2) showed that R2 resection
was associated with unfavorable patient outcomes (R0/1 vs
R2: P = .03) (Figure 2).
Regarding the grading of the liver metastasis and the primary tumor, there were no significant differences in overall
survivals among the three subgroups (same grading, up-­
grading, and down-­grading, P = .82). No significant differences were found when the results were stratified by thegrading of the primary tumor (Figure S1).
TABLE 4

Patient outcomes

Variable

Data

Tumor recurrence after R0/1 resection, yes/no, n, (%)

146 (83.4)/ 29 (16.6)

Site of recurrence, n (%)
Intra-­hepatic only

90 (63.4)

Extra-­hepatic only

11 (7.7)

Intra-­ and extra-­hepatic

40 (28.2)

N/A

1 (0.7)

Treatment(s) after R2 resection orrecurrence, yes/ no/ unknown, n (%)

175 (91.1) /14 (7.3)/
3 (1.6)

Treatment modality after R2 resection or recurrence, yes/ no, n (%)
Surgical resection

67 (38.3)/ 108 (61.7)

Somatostatin analogue

82 (46.9)/ 93 (53.1)

Everolimus

54 (30.9)/ 121 (69.1)

Sunitinib

30 (17.1)/ 145 (82.9)

Streptozocin

29 (16.6)/ 146 (83.4)

Platinum-­based chemotherapy

13 (7.4)/ 162 (92.6)

IVR (including TACE)

53 (30.3)/ 122 (69.7)

Liver-­directed local therapy (includingRFA)

20 (11.4)/ 155 (88.6)

Radiation

19 (10.9)/ 156 (89.1)

Abbreviations: IVR, interventional radiology; N/A, not assessed; NEN,
neuroendocrine neoplasm; RFA, radiofrequency ablation; TACE, transcatheter
arterial chemoembolization.

| 493

Univariable and multivariable analyses revealed that a
grade G3 primary tumor was significantly associated with
the RFS, and patient age and a grade G3 primary tumor
were significantly associated with the OS. Other variables,such as the primary tumor site, synchronous presentation(Figure S2), and tumor number and size, were not identified
as significant factors.

4|

DISCUSSION

In the present study, the authors conducted a nationwide survey of patients receiving surgical resections for NELM andenrolled 222 cases from 30 institutions. To our knowledge,
this is one of the largest cohort studies examining surgicalresection for NELM.
The epidemiology of NEN differs widely between Asianand Western countries. Previous Japanese survey data havedocumented that the dominant primary sites of gastroenteropancreatic NEN were the pancreas and the rectum;10 meanwhile, the incidence of NEN originating from the midgut
is relatively low in Asian countries, compared with that inWestern countries. In addition, the malignant potential of
NEN also differs widely according to the primary site, andthe pancreas and the rectum are stratified into the intermediate and unfavorable strata, respectively, while the small intestine is stratified into the favorable stratum.2,11 Reflecting
these epidemiological and biological backgrounds, the pancreas and the rectum were the dominant primary tumor sites
in the present cohort. The results of the background characteristics also revealed that non-­functioning tumors werepredominant in this series, and two-­thirds of the patients
had synchronous liver metastases at the time of their presentation. As a result, only one-­third of the patients received
non-­surgical treatments, including somatostatin analogue
therapy and preoperative TACE, prior to hepatic resection;in other words, most of the patients in this study receivedup-­front surgery.
A remarkable finding of this study was that the primary tumor and liver metastases were often resected concomitantly. In particular, a pancreatectomy with multiple
partial resections of the liver was frequently performed.
Furthermore, the morbidity and mortality rates were minimal. The surgical risk of combined pancreatectomy andhepatectomy procedures has been previously discussed12,13;
the present results, however, showed that the concomitantresection of both the primary pancreatic tumor and liver
metastases are justifiable. In addition, the survival outcomes were similar between synchronous and metachronous liver metastases (Figure S2). The result also supports
this aggressive surgical approach.
On the other hand, up-­front surgery resulted in R2 resections in 26.1% of the cases, and R2 resection was associated18686982, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jhbp.956 by Cochrane Japan, Wiley Online Library on [28/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License   

AOKI et al.

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TABLE 5AOKI et al.

Univariable and multivariable analyses for (A) recurrence-­free survival and (B) overall survival
Univariable Analysis

Variables

N (%)

Hazardratio

Multivariable Analysis

95% CI

P value

Hazardratio

95% CIP
value(A) Recurrence-­free survivalAge, ≥ 60

79 (35.6)

1.178

0.600-­1.201

0.354

Sex, male

113 (50.9)

0.873

0.620-­1.233

0.44

Functional tumor, yes

29 (13.1)

0.948

0.571-­1.494

0.826

Presentation ofliver metastasis,
metachronous

82 (36.9)

1.333

0.939-­1.884

0.107

Primary site, pancreas

129 (58.1)

1.02

0.722-­1.451

0.911

Grading, G3

14 (86.3)

2.477

1.064-­5.093

0.037

2.449

1.052-­5.040

0.039

Tumor number, ≥10

58 (26.1)

1.975

1.276-­2.964

0.003

1.662

0.914-­2.863

0.093

Maximum tumor size,≥5cm

70 (31.5)

1.147

0.788-­1.643

0.467

Anatomical resection, no

150 (67.6)

0.964

0.677-­1.389

0.84

Age, ≥ 60

79 (35.6)

1.941

1.227-­3.085

0.005

2.024

1.036-­3.982

0.039

Sex, male

113 (50.9)

1.392

0.872-­2.267

0.167

4.172

1.720-­9.165

0.003

1.557

0.701-­3.224

0.264(B) Overall survival

Functional tumor, yes

29 (13.1)

1.231

0.669-­2.127

0.486

Presentation ofliver metastasis,
metachronous

82 (36.9)

1.107

0.691-­1.751

0.669

Primary site, pancreas

129 (58.1)

0.716

0.451-­1.138

0.158

Grading, G3

14 (86.3)

3.892

1.623-­8.405

0.004

Tumor number, ≥10

58 (26.1)

1.044

0.588-­1.757

0.877

Maximum tumor size,≥5cm

70 (31.5)

1.538

0.953-­2.442

0.077

R2 resection, yes

58 (26.1)

1.77

1.013-­2.967

0.045

Anatomical resection, no

150 (67.6)

1.556

0.941-­2.673

0.086

with an unfavorable OS in a univariable analysis, although
it was not identified as a significant prognostic factor ina multivariable analysis. Other previous reports have addressed the impact of cytoreductive surgery on patient outcome, and a consensus has not yet been reached.6,14-­17 The
present findings suggest a need for neoadjuvant or conversion therapy for multiple NELM, and the significance of
preoperative treatments should be clarified in future clinical trials.
After R0/1 resection, 83.4% of the patients experienced
recurrence during the follow-­up period and most of thepatients developed intra-­hepatic recurrence. The high recurrence rate found in this study was similar to the resultsof previous reports from Western series,18,19 although the
distribution of the primary tumor site in our series differedfrom that in the Western series. On the other hand, evenafter R2 resection or recurrence, 91.1% of the patients

received additional treatments including repeat resection,
somatostatin analogue therapy, molecular-­targeting therapy, chemotherapy, and/or liver-­directed local treatments.
These results confirmed that NELM should be treated using
a multi-­disciplinary approach, and surgical resection canplay a role, if performed in a timely manner, in this multi-­
disciplinary strategy. In fact, the long-­term outcomes ofthis study cohort were favorable, with 5-­year and 10-­year
survival rates of 70.2% and 43.4%, respectively. Therefore,
timely introduction of surgical intervention may be an optimal strategy in the relatively long treatment courses of
NEN patients.
Recently, the significance of repeat resection for recurrent
NELM has been reported.19,20 Repeat hepatectomy, if feasible, can be a good option for intra-­hepatic recurrence and canprovide long-­term survival. Therefore, the treatment policy
for recurrences should be decided on a case-­by-­case basis and18686982, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jhbp.956 by Cochrane Japan, Wiley Online Library on [28/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License494

F I G U R E 1 (A) Recurrence-­free survival (RFS) curve after
hepatic resection. The 1-­year, 3-­year, and 5-­year RFS rates were
54.7%, 23.9%, and 13.4%, respectively. (B) Overall survival (OS)curve after hepatic resection. The 1-­year, 3-­year, 5-­year, and 10-­year
OS rates were 91.8%, 83.1%, 70.2%, and 43.4%, respectively

should be a product of discussions among oncologists, gastroenterologists, and surgeons.
Multivariable analyses revealed that a G3 primary tumor
was significantly associated with a short RFS and OS. In thisseries, G3 primary tumors included both well-­differentiatedNET (NET G3 in the WHO 2017 classification) and poorly
differentiated NEC, and the two categories cannot be discussed separately. In any case, the surgical indications forliver resection should be cautiously determined for NELMs
with high Ki-­67 index values. On the other hand, other variables including the primary tumor site, tumor number, tumor
size, and R2 resection were not identified as being significant

   

| 495

in multivariable analyses, although these factors have beenreported as prognostic factors in previous reports.5-­7,21-­24
These results may be attributable to a bias in the cohort, suchas the fact that the primary tumor site was the pancreas inmore than half of the tumors and that about half of the patients underwent multiple partial hepatic resections for relatively small tumors. Nevertheless, R2 resections, especiallyfor G3 tumors, are not good indications for surgical resection,and therefore, cytoreductive surgery should be attempted as apart of a multi-­disciplinary treatment approach.
The present results showed that up-­grading and down-­
grading between the primary tumor and the liver metastasis sometimes occurred (15.2% and 10.8%, respectively),
although only 46 pairs of specimens could be assessed inthis series. Of note, this phenomenon was found in caseswith both synchronous and metachronous metastases.
Recent reports have documented that up-­grading from theprimary tumor to liver metastases, as well as heterogeneity among the liver metastases, are frequently found, andthese reports have recommended a re-­evaluation of theKi-­67 index prior to the start of anti-­tumor treatments fortumor progreesion.25-­27 Our results may support their recommendations, and the Ki-­67 index should be evaluated forboth the primary site and the metastatic site. Previous reports suggested that the survival outcomes were favorable
in patients with a lower Ki-­67 index in the metastases thanthe primary tumor when compared with the patients witha higher Ki-­67 index in the metastases than the primarytumor, and up-­grading of the Ki-­67 index in the metastases was more frequently observed when the disease became
progressive.26,27 On the other hand, there was no significant
difference in overall survival among the three subgroups ofsame grading, up-­grading, and down-­grading in the present
analyses (Figure S1). These conflicting results may be ascribed to the small number of patients in each group, andas a result, a definite conclusion cannot be drawn. Further
investigation is needed to clarify the significance of up-­anddown-­grading of the liver metastasis.
This study had several limitations. First, detailed information about the clinical course of each patient was
not available because of the nature of the survey data.
Therefore, the efficacy of each treatment modality could
not be assessed. Second, the examinations of pathological variables were insufficient, as information regarding
tumor differentiation, tumor grading, and the actual Ki-­67
index value were only available for a limited number ofpatients. The current WHO classification recommends thata description of the actual Ki-­67 index value be included
on pathological reports; if more sophisticated information
becomes available in the near future, researchers will beable to discuss interesting topics, such as NELM grade migration from that of the primary tumor and a comparisonof NET G3 and NEC.

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AOKI et al.

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AOKI et al.

F I G U R E 2 Overall survival (OS)curves stratified by the radicality of theoperation (R0 vs R1 vs R2). R2 resection
was associated with an unfavorable OS

ACKNOWLEDGEMENTS
The authors thank all the colleagues who participated in thissurvey project. The context of this study was presented at
the 13th IHPBA World Congress 2018, Geneva, Switzerland.

5.

CONFLICTS OF INTEREST
We have no conflicts of interest to declare.

6.

AUTHORS’ CONTRIBUTIONSTA and KK conceived the study. TA searched the publishedliterature. JA, CM, TM, AK, IK, EH, TI, RYO, MU, and NK
are members of the Committee on Treatment of NEN Liver
Metastasis of JNETS. TA and KK performed the data analyses and interpreted the data. TA and KS performed the statistical analyses. TA wrote the first draft of the report. All theauthors approved the final version of the report.

7.

ORCID
https://orcid.org/0000-0002-2868-5246
Taku Aoki
https://orcid.org/0000-0003-1929-8479
Junichi Arita
Michiaki Unno
https://orcid.org/0000-0002-2145-6416
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section.

How to cite this article: Aoki T, Kubota K, Kiritani S,
et al. Survey of surgical resections for neuroendocrine
liver metastases: A project study of the Japan
Neuroendocrine Tumor Society (JNETS). J
Hepatobiliary Pancreat Sci. 2021;28:489–­497. https://doi.org/10.1002/jhbp.956

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AOKI et al.