Masui et al. BMC Cancer(2020) 20:1104
https://doi.org/10.1186/s12885-020-07581-y

RESEARCH ARTICLE

Open Access

Recent epidemiology of patients withgastro-entero-pancreatic neuroendocrine
neoplasms (GEP-NEN) in Japan: apopulation-based study
Toshihiko Masui1,2, Tetsuhide Ito2,3,4, Izumi Komoto2,5,6, Shinji Uemoto1,2* and JNETS Project Study Group

Abstract
Background: The worldwide prevalence and incidence of neuroendocrine neoplasms (NEN) have been increasing
recently, although few studies have analyzed data on the current situation of NENs in Japan. Here, the Japan
Neuroendocrine Tumor Society (JNETS) planned to investigate the recent incidence and distribution of thesetumors using data from the national cancer registry started in 2016. This study examined the incidence anddistribution of primary sites as well as rate of advanced disease from this population-based registry.
Methods: A retrospective, population-based study using data from the national cancer registry in Japan (NCR) was
conducted to evaluate patients with gastro-entero-pancreatic NEN (GEP-NEN) in 2016. Associated population data
were used to determine annual age-adjusted incidences.
Results: A total of 6735 individuals were diagnosed with GEP-NEN in Japan in 2016. Annual onset incidence was
0.70/100,000 for pancreatic NEN and 2.84/100,000 for gastrointestinal NEN. NEN in the ileum accounted for only 1%of total GEP-NENs in Japan. Most NENs in the esophagus or lungs were neuroendocrine carcinomas (NECs), while
the majority of those in the duodenum, ileum, appendix and rectum were grade 1 neuroendocrine tumors (NETs).
Median age at initial diagnosis was in between 60 to 65. Tumors in the duodenum, appendix and rectum were
mostly limited to local, while those in the esophagus, stomach and colon tended to show distant metastasis. In
Japan, initial treatment for GEP-NENs was resection even if the tumor was NEC.
Conclusions: This is the first report of a national registry-based incidence and distribution of GEP-NEN in Japan.
These data will serve as an important first step to determining the exact etiology and trends for this pathology inJapan.
Keywords: National registry, Neuroendocrine neoplasm, Japan, Incidence, Distribution* Correspondence: jnets-office@umin.ac.jp
1
Division of Hepato-Biliary-Pancreatic Surgery and Transplantation,
Department of Surgery, Kyoto University, 54 Shogoin Kawaracho, Sakyo,
Kyoto, Japan
2
Japan Neuroendocrine Tumor Society, Kyoto, Japan
Full list of author information is available at the end of the article© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
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Masui et al. BMC Cancer(2020) 20:1104

Background
Neuroendocrine neoplasm (NEN) was called a carcinoid(carcinoma-like tumor) before and has been considereda rare and indolent tumor [1, 2]. According to the Surveillance, Epidemiology and End Results (SEER) programin the United States, the number of patients with thispathology has been increasing, with an annual incidenceof 6.98 per 100,000 population in 2012 [3], approximately 7 times greater than the 1.09 per 100,000 population reported in 1973.
In Japan, only two studies have reported on the incidence of NEN. Ito et al. estimated annual incidences in2005 of 1.01 per 100,000 population for pancreatic NEN(PanNEN), and 2.10 per 100,000 for gastrointestinal
NEN (GI-NEN) in Japan [4]. The same group conducteda second survey in 2010 and reported increased incidences of 1.25 per 100,000 for PanNEN and 4.35 per 10,
000 for GI-NEN [5]. Although these analyses provided
numerous important new insights, such as the low incidence of ileal NEN in Japan, the data were based onquestionnaire surveys. A more precise analysis of NEN
patients in Japan has thus been necessary to clarify thestatus quo of NEN diagnosis/treatment in Japan.
In 2016, the Cancer Registry Promotion Act took effect which required all hospitals in Japan to submit thebasic data of newly encountered cancer patients to thenational cancer registry. Since NEN is rare and displays
a comparatively indolent phenotype, these data have notbeen presented as annual reports. The Cancer Registry
Promotion Act recommends utilizing these data for theinvestigation of cancer epidemiology in Japan, and thesedata could provide an excellent resource for evaluating
the incidence and distribution of NEN in Japan. For accuracy. National Cancer Center asks the facility concerned if they found an inconsistency. Therefore, it takes
3 years to settle the data at present, resulting in analyzing the data in 2016 in this study.
The present study employed 2016 data from the National Cancer Registry to evaluate the number and distribution of primary sites as well as the malignant
potential, to elucidate the status quo of NEN in Japan.
Methods
Data source

All 2016 submissions to the National Cancer Registry inJapan were used for this study. The Japan NCR is a coordinated system of population-based cancer registries collecting incidence and survival data on cases reported
from every hospital in Japan. The pertinent population
data are obtained from the Ministry of Health, Laborand Welfare. We collected data from patients with pulmonary and gastro-entero-pancreatic (GEP)-NETs using
histologic codes from the International Classification of
Diseases for Oncology, 3rd Edition, that identified

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patients with NENs (8013/3, 8041/3, 8042/3, 8043/3,
8044/3, 8045/3, 8150/3, 8151/3, 8152/3, 8153/3, 8154/3,
8155/3, 8156/3, 8240/3, 8241/3, 8242/3, 8243/3, 8244/3,
8245/3, 8246/3, 8247/3, 8249/3, 8240/3, 8241/3, 8242/3,
8243/3, 8244/4, 8245/3, 8246/3, 8247/3, and 8249/3).
The staging system used for analysis was that adopted
by the SEER program. Tumors were classified as localized, regional, or distant. Localized NEN was defined as
an invasive neoplasm confined entirely to the organ oforigin. Regional NEN was defined as a neoplasm that: 1)
extended beyond the limits of the organ of origin directly into surrounding organs or tissue; 2) involved regional lymph nodes; or 3) fulfilled both theaforementioned criteria 1) and 2). Finally, distant NEN
was defined as a neoplasm that had spread to parts ofthe body remote from the primary tumor such as metastasized to the liver, lung, bone and/or distant lymph
nodes. In total, analyzed factors included gender, age,primary sites, NETG1, G2 and NEC, stage at diagnosis,
methods of discovery and treatment.
The Kyoto University institutional review board approved all study protocols (approval number R2010,
September 2019). Data analysis was conducted between
December 2019 and February 2020.
Statistical analysis

NCR histological grade information is designed to beclassified according to WHO2010 criteria as: grade (G)1,
well-differentiated, Ki67 0–3%; G2, well-differentiated,
Ki67 3–20%; neuroendocrine carcinoma (NEC), Ki67 >20%; or mixed adenoneuroendocrine carcinoma (MANEC), co-localization of NEC with adenocarcinoma.
NENs were classified according to the anatomical location, with the diagnosis of NENs left to the judgment ofeach institution. Data on disease stage were collectedfrom the final diagnosis at the time of pathological/
radiographical analysis. Age-adjusted incidence rates
were analyzed using weighted proportions of corresponding age groups according to the 1985 Japan standard population. If the initial treatments included
resection, the treatment were dealt as resection, therefore, resection with pharmacotherapy were counted as
resection, and pharmacotherapy was counted as pharmacotherapy alone.
All other statistical analyses were performed using
JMP version 14.0 (SAS Institute, Cary, NC). Comparative
differences were considered significant at P < 0.05.

Results
Epidemiology of GEP-NEN in Japan in 2016

Based on data derived from the NCR2016, the total
number of patients treated for GEP-NENs in 2016
was recorded as 6735 and the age-adjusted overall incidence was 3.53 per 100,000 population. Age-

Masui et al. BMC Cancer(2020) 20:1104

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adjusted incidences of each primary NEN are shownin Table 1 and the ratio is shown in Fig. 1a. Abouthalf of GEP-NENs involved the rectum (1.82 per 100,000 population), followed by the pancreas (0.697 per
100,000 population). The incidence of ileal NEN was
1% of total GEP-NENs. For tumor location of PanNEN, 36.0% of all PanNEN patients had the lesion in
the pancreatic head, 29.7% in the pancreatic body,and 28.7% in the pancreatic tail.
An apparent male predominance tended to be seen in
the incidence of NENs, especially in the upper GI. The
overall incidence of NENs among males was 2.09 per
100,000 population and that in females was 1.39 per 100,000 population.
With regard to the age of onset, 65.8% of patients developed NENs in their 60s–70s (Fig. 1b). Age distributions also differed within GEP-NENs according toprimary site (Fig. 1c). In the younger patients, the mostcommon primary sites for NEN were the rectum or appendix, and gradually decreased with increasing age.
Conversely, the ratio of NENs in the stomach and in theesophagus increased with age. The ratio of NENs in thepancreas was sustained at around 20% in all ages.
The disease was incidentally diagnosed in 51.8% of patients with no symptoms on a visit to the hospital for ahealth checkup or by chance (Fig. 1d). In pancreatic
NEN, only 31.5% of patients showed symptoms on admission, while in GI-NEN, more than half of the esophagus, jejunum/ileum and colon NENs were diagnosed bysymptoms.
Disease grade, stage and metastasis of GEP-NEN in Japan(Fig. 2)NENs showed various grade distributions for different
primary sites. As reported before, most esophageal
NENs showed high Ki67 > 20% (WHO2010 NEC), andaround half of stomach NENs and colonic NENs were

WHO2010 NEC. In contrast, at least 90% of duodenal,
ileal, appendiceal and rectal NENs were welldifferentiated type, and around 80% of NENs were G1.
In the pancreas, at least 79.5% were well-differentiatedtype and G1 comprised 58.2% of low grade NEN.
Disease stage at the time of diagnosis also differedamong primary sites and correlated with higher grade.
Esophageal NEN showed distant metastasis in half, while
over 70% of duodenal, appendiceal, and rectal NENs
remained confined to a local site. In the pancreas, 23.2%
exhibited distant metastasis at the time of diagnosis.
Initial treatment for GEP-NEN in Japan (Fig. 3)

Initial treatment was different among the primary sitesof the tumor and the tumor grades. Most GEP-NENs except esophageal NEN were initially treated with endoscopic or surgical resection even if the tumor was
WHO2010 NEC. In pancreatic NEN, 29.2% of theWHO2010 NEC were resected initially, although someof the tumors might be diagnosed as NEC in theresected specimens. Because of the tumor characteristics,
24% of esophageal NENs was treated with radiotherapy.

Discussion
This study found that the overall incidence of GEPNENs in Japan was 3.53 per 100,000 population in 2016.
Median age at onset was around the 60s, but patientswith rectal NEN were younger than NEN patients withother primary sites. In terms of malignant potential,
NENs in the esophagus, stomach and colon were likely
to show a more aggressive phenotype, while most NENs
in the duodenum, ileum, appendix and rectum were of
low grade. Accordingly, distant metastasis was morecommon with the former NENs, while the latter NENs
were likely to remain at a local site.
The number of NEN patients appears to be increasing
recently worldwide [3, 6]. In Japan, two reports by Ito

Table 1 Incidence of NEN in Japan in 2016
Primarytumor site

Newly diagnosed number in 2016
Male

FemaleAll cases

Male

Adjusted incidence /100,000 population in 2016
FemaleAll cases

Pancreas

707

629

1336

0.362

0.335

0.697

Esophagus

200

62

262

0.074

0.025

0.098

Stomach

775

267

1042

0.309

0.120

0.482

Duodenum

264

178

442

0.112

0.083

0.195

Jejunum/Ileum

65

32

97

0.031

0.016

0.046

Appendix

55

50

105

0.039

0.035

0.074

Colon

157

121

278

0.069

0.050

0.118

Rectum

1911

1262

3173

1.099

0.723

1.822

GI-NEN

3427

1972

5399

1.733

1.051

2.835

All cases

4134

2601

6735

2.094

1.385

3.532

Incidence was age-adjusted annual incidence per 100,000 to the standard population in Japan

Masui et al. BMC Cancer(2020) 20:1104

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Fig. 1 Distribution of primary sites of NENs and age in Japan. a Pie chart of GEP-NENs. Rectal NENs comprise 53% of GEP-NENs, followed by thepancreas at 20%, then stomach. b Age distributions of GEP-NENs in Japan. The scale is incidence /100,000 per year. c Primary site distribution of
GEP-NENs for every age decade. d Diagnostic opportunity for NENs

et al. in 2005 and 2010 used questionnaire surveys to estimate the incidence of newly diagnosed GEP-NENs as
1.27 per 100,000 population in PanNENs and 3.51 per
100,000 population in GI-NENs in 2010 [4, 5]. Ourcurrent estimation was 0.70 per 100,000 population in
PanNENs and 2.83 per 100,000 population in GI-NENs,
slightly lower than the estimations of Ito et al.

These discrepancies might be attributable to the different methods of estimating incidence, resulting in difficulty in estimating trends for NEN patients in Japan.
However, when referring to the age distribution and primary site distribution within NEN patients, median age
at onset for individuals with PanNEN and GI-NEN in2005 was 57.6 years and 59.8 years [5], compared to 65

Masui et al. BMC Cancer(2020) 20:1104

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Fig. 2 Disease stage of NENs in relation to grade at the time of diagnosis. Faint gray rectangles show localized tumor, gray rectangles depict
regional tumor and black rectangles represent tumor with distant metastasis. White rectangles are unknown

Fig. 3 Initial treatment for NENs in relation to grade at the time of diagnosis. Faint gray rectangles represent treatment with tumor resection
including endoscopic resection, thick gray rectangles depict treatment with irradiation and black rectangles are pharmacotherapy. Gray rectangles
represent no treatment described. White rectangles are other treatments or unknown

Masui et al. BMC Cancer(2020) 20:1104

years for GEP-NEN in the current study. This differenceof approximately 5 years could be attributable to theaging of the population in Japan. Indeed, median age inJapan was 42.9 years in 2005, compared to 46.5 years in2016 according to a population survey by the Statistics
Bureau of Japan, representing an increase similar to thatseen in NEN patients.
The incidence of GEP-NENs in each age provided
three categories according to primary site: 1) decreasegroup: appendix and rectum; 2) increase group: esophagus, stomach and colon; and 3) steady group: pancreas,
ileum and duodenum. Because the increasing group
showed a high proportion of NEC (Fig. 2), these different tendencies might imply different mechanisms of development for NENs.
In the 2010 survey, Pancreatic NEC (WHO2010)accounted for 7.5% and GI-NEC for 6.2% [5]. The
current analysis revealed that 20.4% of PanNENs and26.6% of GI-NENs were NEC, including MANEC, suggesting that aggressive phenotypes are more prevalentthan expected. Compared to the SEER database as reported by Dasari [3], the overall incidence of GEP-NEC
is around 15–20%, comparable to that in our study.
The distribution of primary tumor sites was similar tothat in a previous survey from Japan. Half of GEP-NENs
were rectal NENs, followed by PanNEN. Comparing toanalyses from Europe [7–10], the ileum was much lessfrequent as a primary site, at 1%. This is consistent witha report from Taiwan [11], which suggested interactions
with ethnic and/or regional factors in the developmentof NENs. Yao et al. [12] presented the incidence of ileal/
jejunal NENs among Asian/Pacific Islander and Indian/
Alaskan natives as 0.09 per 100,000 population, compared to that in White and African-American individuals
as 0.71 and 0.88 per 100,000 population, respectively,
suggesting ethnic impacts on the development of NENs.
A tendency toward a male predominance was identified among newly developed GEP-NENs in Japan. The
overall incidence among males was 1.73 per 100,000
population, as compared to 1.05 per 100,000 population
among females. This is similar to two results using the
SEER database in the United States, with 3.65 per 100,000 population among males vs. 3.08 per 100,000 amongfemales in 2000–2004 [12] and males representing
57.75% compared to 42.25% females in 2010–2015 [13].
The current NCR includes data for initial treatment
for every patient. As in the Fig. 3, most of the initial
treatments for GEP-NEN were surgical or endoscopic
resection in every NEN grade even in NEC. It is reasonable that the tumor was resected palliatively or curatively
in GI-NEN, because the tumor could cause bowel obstruction. However, even in pancreatic NEC, 29.2% of
the tumor were resected. Because 32.9% of the pancreatic NEC was within regionally invasive (Fig. 2), more

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than 80% of the pancreatic NEC without metastasis were
initially resected in Japan. In contrast, treatment of
10.6% of the pancreatic NETG1 was not registered as resection, radiation, chemotherapy, other treatments or
unknown. Because NCR registered every element with
yes, no or unknown, no treatments above suggest undersurveillance or best supportive care. Therefore, for pancreatic NETG1, it is likely that around 10% of the tumor
were carefully under surveillance for some reasons inJapan.
This study had several limitations that require consideration when interpreting the results. First, given that
NENs may not have been reported to cancer registries
unless considered malignant, we have likely underestimated the true incidences and prevalences. This might
affect the high incidence of NEC in this registry. Second,
the NCR was started in 2016 and we currently lack asystem for checking and omitting cases mistakenly registered as newly identified NEN before 2015, implying a
potential for overestimation of incidence. In addition,
because the registry started at 2016, we could notanalyze data except 2016, which may have led to a selective bias. Third, because the NCR was started in 2016,
we do not yet have sufficient data on survival. We plan
to clarify these issues after we accumulate sufficiently
mature data. Finally, several important epidemiologicalfactors are not captured by the NCR. For example, thedatabase does not provide information regarding thehormonal functional status of the NEN, as well as thegenetic background. These may affect treatment decisions and survival outcomes that will be analyzed later.
Such drawbacks are inherent to any retrospective,
population-based study and raise obvious concerns
about the generalizability of the findings. However, thesize of the present study compensates for this weakness
to a great extent and provides a comprehensive epidemiological understanding of NENs in Japan.

Conclusions
In conclusion, we have provided information on the epidemiological status quo among GEP-NEN patients inJapan by utilizing population-based NCR data for the
first time. We plan to expand this study to serial years,
and to analyze survivals and trends in mortality afterwards. The current study serves as an important firststep to determine the exact etiology and trends in Japan.
Abbreviations
NEN: Neuroendocrine neoplasm; JNETS: Japan Neuroendocrine Tumor
Society; NCR: National Cancer Registry; GEP: Gastroenteropancreatic;
NEC: Neuroendocrine carcinoma; NET: Neuroendocrine tumor;
SEER: Surveillance, Epidemiology and End Results; GI: Gastrointestinal; MANE
C: Mixed adenoneuroendocrine carcinoma; PanNEN: Pancreatic
neuroendocrine neoplasm

Masui et al. BMC Cancer(2020) 20:1104

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Acknowledgements
We thank Dr. Takahiro Higashi and Dr. Akiko Shibata for comments on the
manuscript. This work was supported by the Japan Neuroendocrine Society.

8.

Authors’ contributions
MT, IT, KI, and US conceived and designed the study, and were responsible
for the final decision to submit for publication. All authors were involved in
the development, review, and approval of the manuscript. All authors readand approved the final manuscript.

9.

10.
11.

Funding
This study was financially supported by Japan Neuroendocrine Tumor
Society (JNETS).
Availability of data and materials
The datasets during and/or analyzed during the current study available fromthe corresponding author on reasonable request.
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki
and Ethical Guidelines for Clinical Research.
The protocol of this cohort study was created in June 2019 and approved by
the ethics review committee of Kyoto University Hospital (approval no.
R2032, dated July 1st, 2019). Consent is waived for publication of this article,
because the data in this manuscript has been registered under the Cancer
Registry Promotion Act for the purpose of ascertaining the reality ofmalignant tumors in Japan.
The authors applied to National Cancer Registry Information ProvisionCouncil to access the raw data from National Cancer Registry in Japan andreceived administrative permission to access and use the data.
Consent for publication
Not applicable.
Competing interests
Not applicable.
Author details
1
Division of Hepato-Biliary-Pancreatic Surgery and Transplantation,
Department of Surgery, Kyoto University, 54 Shogoin Kawaracho, Sakyo,
Kyoto, Japan. 2Japan Neuroendocrine Tumor Society, Kyoto, Japan. 3Schoolof Nursing at Fukuoka, International University of Health and Welfare,
Fukuoka, Japan. 4Hepato-Biliary-Pancreatic-Neuroendocrine-Tumor Center,
Fukuoka Sanno Hospital, Fukuoka, Japan. 5Department of Surgery, Kansai
Electric Power Hospital, Osaka, Japan. 6Division of Neuroendocrine Tumor
Science, Kansai Electric Power Medical Research Institute, Osaka, Japan.
Received: 22 March 2020 Accepted: 28 October 2020

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