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ORIGINAL ARTICLE—LIVER, PANCREAS, AND BILIARY TRACT
JNETS clinical practice guidelines for gastroenteropancreatic
neuroendocrine neoplasms: diagnosis, treatment, and follow-up:
a synopsis
Tetsuhide Ito
1,2
•Toshihiko Masui
1,2
•Izumi Komoto
1,2
•Ryuichiro Doi
1,2
•
Robert Y. Osamura
1,2
•Akihiro Sakurai
1,2
•Masafumi Ikeda
1,2
•Koji Takano
1,2
•
Hisato Igarashi
1,2
•Akira Shimatsu
1,2
•Kazuhiko Nakamura
1,2
•Yuji Nakamoto
1,2
•
Susumu Hijioka
1,2
•Koji Morita
1,2
•Yuichi Ishikawa
1,2
•Nobuyuki Ohike
1,2
•
Atsuko Kasajima
1,2
•Ryoji Kushima
1,2
•Motohiro Kojima
1,2
•Hironobu Sasano
1,2
•
Satoshi Hirano
1,2
•Nobumasa Mizuno
1,2
•Taku Aoki
1,2
•Takeshi Aoki
1,2
•
Takao Ohtsuka
1,2
•Tomoyuki Okumura
1,2
•Yasutoshi Kimura
1,2
•Atsushi Kudo
1,2
•
Tsuyoshi Konishi
1,2
•Ippei Matsumoto
1,2
•Noritoshi Kobayashi
1,2
•
Nao Fujimori
1,2
•Yoshitaka Honma
1,2
•Chigusa Morizane
1,2
•Shinya Uchino
1,2
•
Kiyomi Horiuchi
1,2
•Masanori Yamasaki
1,2
•Jun Matsubayashi
1,2
•
Yuichi Sato
1,2
•Masau Sekiguchi
1,2
•Shinichi Abe
1,2
•Takuji Okusaka
1,2
•
Mitsuhiro Kida
1,2
•Wataru Kimura
1,2
•Masao Tanaka
1,2
•Yoshiyuki Majima
1,2
•
Robert T. Jensen
1,2
•Koichi Hirata
1,2
•Masayuki Imamura
1,2
•Shinji Uemoto
1,2
Received: 31 May 2021 / Accepted: 13 September 2021
ÓThe Author(s) 2021
Abstract Neuroendocrine neoplasms (NENs) are rare
neoplasms that occur in various organs and present with
diverse clinical manifestations. Pathological classification
is important in the diagnosis of NENs. Treatment strategies
must be selected according to the status of differentiation
and malignancy by accurately determining whether the
neoplasm is functioning or nonfunctioning, degree of dis-
ease progression, and presence of metastasis. The newly
revised Clinical Practice Guidelines for Gastroenteropan-
creatic Neuroendocrine Neoplasms (GEP-NENs) com-
prises 5 chapters—diagnosis, pathology, surgical
treatment, medical and multidisciplinary treatment, and
multiple endocrine neoplasia type 1 (MEN1)/von Hippel–
Lindau (VHL) disease—and includes 51 clinical questions
and 19 columns. These guidelines aim to provide direction
and practical clinical content for the management of GEP-
NEN preferentially based on clinically useful reports.
These revised guidelines also refer to the new concept of
‘‘neuroendocrine tumor’’ (NET) grade 3, which is based on
the 2017 and 2019 WHO criteria; this includes health
The original version of this article appeared in Japanese as ‘‘Sui-
Syoukakan Shinkeinaibunpitsushuyo Shinryo Guideline’’ from the
Japanese Neuroendocrine Tumor Society (JNETS), published by
Kanehara-Shuppan, Tokyo, 2019. Please see the article on the
standards, methods, and process of developing the guidelines
(ISBN978/4-307-20401-9).
Tetsuhide Ito, Toshihiko Masui, Izumi Komoto, Ryuichiro Doi,
Robert Y. Osamura, Akihiro Sakurai, Masafumi Ikeda, Koji Takano,
Hisato Igarashi, Akira Shimatsu, Kazuhiko Nakamura, Yuji
Nakamoto, Susumu Hijioka, Koji Morita, Yuichi Ishikawa, Nobuyuki
Ohike, Atsuko Kasajima, Ryoji Kushima, Motohiro Kojima,
Hironobu Sasano, Satoshi Hirano, Nobumasa Mizuno, Taku Aoki,
Takeshi Aoki, Takao Ohtsuka, Tomoyuki Okumura, Yasutoshi
Kimura, Atsushi Kudo, Tsuyoshi Konishi, Ippei Matsumoto,
Noritoshi Kobayashi, Nao Fujimori, Yoshitaka Honma, Chigusa
Morizane, Shinya Uchino, Kiyomi Horiuchi, Masanori Yamasaki,
Yuichi Sato, Masau Sekiguchi, Takuji Okusaka, Mitsuhiro Kida,
Wataru Kimura, Masao Tanaka, Yoshiyuki Majima, Robert T. Jensen,
Koichi Hirata, Masayuki Imamura and Shinji Uemoto: Guidelines
Committee for creating and evaluating the ‘‘Clinical practice
guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms
(GEP-NEN)2019’’, The Japanese Neuroendocrine Tumor Society
(JNETS), 54 Kawaramachi, Shougoin, Sakyouku, Kyoto 104-0061,
Japan.
The members of the Guidelines Committee are listed in the Appendix
in the text.
&Tetsuhide Ito
itopapa@kouhoukai.or.jp
1
Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, 3-
6-45 Momochihama, Sawara-ku, Fukuoka 814-0001, Japan
2
Department of Gastroenterology, Graduate School of Medical
Sciences, Internal University of Health and Welfare, 3-6-45
Momochihama, Sawara-ku, Fukuoka 814-0001, Japan
123
J Gastroenterol
https://doi.org/10.1007/s00535-021-01827-7
insurance coverage of somatostatin receptor scintigraphy
for NEN, everolimus for lung and gastrointestinal NET,
and lanreotide for GEP-NET. The guidelines also newly
refer to the diagnosis, treatment, and surveillance of NEN
associated with VHL disease and MEN1. The accuracy of
these guidelines has been improved by examining and
adopting new evidence obtained after the first edition was
published.
Keywords Clinical practice guideline
Gastroenteropancreatic neuroendocrine neoplasm
Japanese Neuroendocrine Tumor Society
Introduction
To standardize the diagnosis and treatment of gastroen-
teropancreatic neuroendocrine neoplasms (GEP-NENs) in
Japan, the Japanese Neuroendocrine Tumor Society
(JNETS) published the first Clinical Practice Guidelines for
Gastroenteropancreatic Neuroendocrine Neoplasms in
Japan in 2015 [1]. However, several subsequent develop-
ments regarding neuroendocrine neoplasms (NENs)
necessitate the revision of clinical practice guidelines. The
Guidelines Revision Committee was established at JNETS
and began working on the revised guidelines in January
2018.
After making updates to reflect the assessment com-
mittee members’ suggestions, public hearings were held at
various academic societies starting April 2019, culminating
in the publication of the second edition in September 2019
[2]. This revised edition encompasses diagnosis, pathology,
surgical treatment, medical and multidisciplinary treat-
ment, and multiple endocrine neoplasia type 1 (MEN1)/von
Hippel–Lindau (VHL) disease and includes 51 clinical
questions and 19 columns. Topics under exploration are
introduced in the ‘‘Columns’’ in the guideline based on
expert consensus and evidence.
As a new development in the treatment of NEN in
Japan, somatostatin receptor scintigraphy (SRS) [3,4] was
approved for insurance coverage in 2015 for the general
diagnosis of NEN. In addition, the WHO classification for
GEP-NENs was revised in 2017 and 2019, adding the new
grade 3 (G3) well-differentiated neuroendocrine tumors
(NETs), which are characterized by well-differentiated
tissue and a Ki-67 index exceeding 20% [5,6]. Regarding
surgical treatment, the first edition of the guidelines did not
include explicit recommendations for nonfunctioning pan-
creatic NETs 1–2 cm in size. However, the revised edition
specifies indications for surgery and recommends surgical
approaches for well-differentiated nonfunctioning pancre-
atic NETs and specifically covers the management of small
pancreatic NETs from a broad perspective. The revised
guidelines also newly include indications for surgery for
poorly differentiated pancreatic neuroendocrine carcino-
mas (NECs). Regarding drug therapy, the molecular tar-
geted drug everolimus is now covered by insurance for the
treatment of well-differentiated NENs of the lungs and
gastrointestinal tract [7]. In addition, the somatostatin
analogue lanreotide is now covered by insurance for the
treatment of well-differentiated GEP-NENs [8–10], sub-
stantially broadening treatment options. Moreover, while
the first edition covered the diagnosis and treatment of
NENs associated with MEN1, the revised edition also
covers pancreatic NENs associated with VHL disease [11].
In this article, we explain the changes described above in
the sequential order of the 5 chapters of the guidelines.
Diagnosis
A GEP-NEN can be functioning or nonfunctioning. A Ja-
panese epidemiological study reports that approximately
35% of pancreatic NETs are functioning, indicating that
most pancreatic NETs are nonfunctioning [12]. Meanwhile,
approximately 1% of gastrointestinal NETs present with
carcinoid syndrome, which differs considerably from the
trends in Europe and the U.S. [12]. This is likely because
hindgut NENs are more prevalent in Japan, while midgut
NENs, which have higher rates of carcinoid syndrome
complication, are more prevalent in Europe and the U.S.
[12,13].
Functional NENs are often diagnosed on the basis of
endocrine symptoms due to hormonal hypersecretion.
Insulinoma primarily presents with fasting hypoglycemia
episodes and includes autonomic and neurologic symp-
toms. In cases in which hypoglycemic symptoms are
unrecognized, symptoms such as seizures and dementia
may be the earliest symptoms [14,15]. Testing such as a
72-h fasting test and a mixed-meal test are recommended
for definitive diagnosis [16], although there are recent
reports of a 48-h fasting test combined with a glucagon test
[17]. Symptoms of gastrinoma include peptic ulcer and
reflux esophagitis due to gastric hypersecretion and diar-
rhea due to pancreatic enzyme inactivation [18]. Mea-
surement of fasting serum gastrin level and gastric acid pH
are required for definitive diagnosis, while a calcium
infusion test is useful [19,20]. Determination of MEN1
complication is also recommended [21,22]. Symptoms and
recommended tests for functional NENs including other
relatively rare neoplasms are shown in Table 1.
Nonfunctional pancreatic NENs have no specific
symptoms and may present with jaundice, pancreatitis,
bloating, abdominal pain, or intestinal obstruction symp-
toms associated with tumor growth. Advanced cases are
often identified owing to the detection of distant metastases
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J Gastroenterol
[13]. Pathological diagnosis such as histology and cytology
is recommended for differential diagnosis.
To determine the localization of pancreatic NENs, it is
recommended to consider and perform imaging such as
ultrasonography (US), computed tomography (CT), mag-
netic resonance imaging (MRI), endoscopic ultrasonogra-
phy (EUS), or SRS on a case-by-case basis. When
performing histology, endoscopic ultrasound-guided fine-
needle aspiration (EUS-FNA) is recommended [3,23]. If
microscopic insulinomas and gastrinomas cannot be
localized by imaging, then selective arterial secretagogue
injection (SASI) test is useful [24,25].
Endoscopic findings of gastrointestinal NETs are round,
submucosal, tumor-like protrusions, which when grown are
accompanied by central depression and ulceration [26].
Meanwhile, gastrointestinal NECs often appear as
advanced cancer. The next recommended tests are endo-
scopic biopsy, EUS-FNA, and imaging to rule out distant
metastases [27].
When testing for metastases, US, CT, MRI, positron
emission tomography (PET) with 18F-fluorodeoxyglucose
(FDG), or SRS should be performed as appropriate. For
liver metastases, the rate of detection by US can be
improved by the use of contrast media, and multiphasic
imaging using contrast media is recommended for CT [28].
Contrast-enhanced MRI using Gd-DOTA yields higher
detectability than CT or SRS [29]. Although only some
well-differentiated NETs are positive on FDG-PET, FDG-
PET is useful for finding metastases and recurrent lesions
of tumors with high proliferative potential, such as NECs;
this method is inversely correlated with and complemen-
tary to SRS. Although the sensitivity of SRS is not nec-
essarily high at 52%, it has a high specificity of 93% [30].
Histopathology
The WHO Classification of Endocrine Organs (2017) [5]
and Digestive System (2019) [6] categorizes NENs as well-
differentiated NENs (termed ‘‘NETs’’) or poorly differen-
tiated NECs. NENs are graded according to morphology
(i.e., well or poorly differentiated) and proliferative
Table 1 Symptoms and recommended tests for functional NENs
Functional
neuroendocrine
neoplasm
Symptoms and findings Differential diagnosis (presence diagnosis)
Insulinoma Central nervous system symptoms: impaired consciousness
(67–80%), abnormal vision (42–59%), amnesia (47%),
personality changes (16–38%), epilepsy (16–17%),
headache (7%)
Autonomic symptoms: sweating (30–69%), malaise
(28–56%), hyperphagia/obesity (14–50%), tremor
(12–14%), palpitation (5–12%), anxiety (12%)
Differentiating hypoglycemia: Whipple’s triad, exogenous
insulin, oral hypoglycemic agents, endogenous insulin
dyssecretion, insulin autoimmune syndrome
Definitive diagnosis: 72-h fasting test, mixed-meal test, 48-h
fasting test ?glucagon tolerance test
Gastrinoma Peptic ulcers: duodenal bulb (75%), distal duodenum (14%),
jejunum (11%)
Abdominal pain, steatorrhea
Fasting serum gastrin measurement, gastric pH measurement,
intravenous calcium injection test (MEN1 differential
diagnostics: blood calcium measurement, intact PTH
measurement)
Glucagonoma Glucose intolerance/diabetes (30–90%), weight loss
(60–90%), necrotizing erythema migrans (55–90%),
mucosal symptoms (30–40%), diarrhea (10–15%), anemia
(30–90%), hypoaminoacidemia (30–100%), venous
thrombosis, psychoneurotic symptoms
Plasma glucagon measurement, serum albumin
measurement, amino acid fraction measurement
VIPoma Profuse watery diarrhea, hypokalemia, fatigue, muscle
weakness, shortness of breath, muscle cramps
Diarrhea: dark brown, odorless, low osmotic gap and
secretory
Stool osmotic gap measurement
Blood VIP cannot be measured in Japan
Somatostatinoma Weight loss, abdominal pain, diabetes, cholelithiasis,
steatorrhea, diarrhea, hypoacidity, anemia (often
asymptomatic)
Blood somatostatin cannot be measured in Japan Diagnosis
by biopsy
Carcinoid
syndrome
Skin flushing (without sweating), diarrhea, pellagra
symptoms, psychiatric symptoms (i.e., confusion), heart
failure (especially right heart failure), bronchospasm,
intra-abdominal fibrosis
Urinary 5-HIAA excretion measurement, intake of serotonin-
containing foods and drugs
MEN1, multiple endocrine neoplasia type 1
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activities (i.e., mitotic rate measured as mitoses/2 mm
2
or
Ki-67 index by counting 500 tumor cells in hotspots).
Well-differentiated NETs with proliferative activi-
ties \3%, 3–20%, and [20% are graded as G1, G2, and
G3, respectively. In contrast, poorly differentiated NECs
usually exhibit a higher Ki-67 index (i.e., [20%) and
lower expression of somatostatin receptor 2 (Table 2).
It can be difficult to distinguish NET G3 from NECs.
However, the pathology of NET G3 is essentially similar to
that of NET G1 and G2 in that it forms well-demarcated,
medullary, expansive, solid masses; grows relatively
slowly; and has a compact organoid structure (e.g., funic-
ular, alveolar, pseudoglandular, etc.) with neuroendocrine
differentiation on histology (Figure S1). Cytologic atypia
remains mild to moderate, and components corresponding
to NET G1 and G2 coexist inside the tumor. On the other
hand, NECs form poorly demarcated medullary masses and
grow rapidly. Histologically, highly atypical cells exhibit
large alveolar to sheet-like and diffuse proliferation with an
ill-defined organoid structure. NET G3 and NECs both
have Ki-67 indices [20%, but NECs usually have a Ki-67
index [50% often with extensive necrotic foci; mean-
while, NET G3 rarely has a Ki-67 index [50% or necrotic
foci. Somatostatin receptor expression is often positive in
NET G3 but weakly positive or negative in NECs. As
NECs exhibit p53 overexpression and deletion of Rb pro-
tein, which are characteristic of extremely malignant
tumors, immunostaining for these markers is helpful for
differentiating NET G3 and NECs [3,32,34].
The WHO 2010 classification includes a category for
mixed adeno-neuroendocrine carcinoma (MANEC) as
combined adenocarcinoma and NET, although this did not
include combinations such as acinar cell carcinoma and
NET. In the new classification, such combinations are
instead described as tumors involving both neuroendocrine
and non-neuroendocrine cells, and are classified as mixed
neuroendocrine–non-neuroendocrine neoplasm (MiNEN)
[6].
Surgical treatment
The surgical treatment of pancreatic NENs varies
depending on the type of tumor. Pancreatectomy with
lymphadenectomy is generally recommended for non-
functioning pancreatic NENs [34,35]. Meanwhile, for
incidentally discovered asymptomatic tumors \10 mm
with no evidence of metastasis/invasion (e.g., hepatic or
lymphatic involvement, pancreatic duct stenosis, and bil-
iary stricture) on imaging, follow-up every 6–12 months
may be an option with the patient’s informed consent
(Fig. 1)[36–39]. Surgery is generally recommended for
insulinomas; when indicated, a minimally invasive
approach is preferable [40,41]. Pancreatectomy with
lymphadenectomy is recommended for malignant insuli-
nomas [42]. For gastrinomas, the high malignant potential
is assumed, and resection with lymphadenectomy is rec-
ommended. Gastrinomas with MEN1 exhibit metachronous
recurrences, so care must be taken to avoid excessive
surgery [43]. As rare functional pancreatic NENs other
than insulinomas and gastrinomas (e.g., glucagonomas,
VIPomas, somatostatinomas, GRFomas, PPomas,
ACTHomas, and PTHomas) are highly malignant, pan-
createctomy with lymphadenectomy is recommended [44].
When feasible, macroscopic curative resection is rec-
ommended for pancreatic NET G3 as for NET G1 and G2,
whereas the indications for surgery are unclear for pan-
creatic NECs [45].
Surgical treatment of gastrointestinal NENs varies by
organ. More than 90% of esophageal NENs are NECs.
Endoscopic resection or surgical resection is indicated for
NETs according to stage, and drug therapy is indicated for
nonresectable cases. Esophageal NECs are frequently
accompanied by lymph node metastases (30%) and distant
metastases (50%), requiring more careful decisions on
surgery than that for esophageal cancers [46,47]. For
gastric NENs, the decision on surgical indications and
selection of a surgical procedure according to Rindi’s
classification [48] is recommended. For small intestinal
NENs, small intestine resection with lymphadenectomy is
Table 2 WHO grading criteria
for GEP-NENs (2017/2019) Classification Differentiation Grade Ki-67 index Mitotic index (/2mm
2
)
NET G1
NET G2
Well differentiated Low
Intermediate
\3%
3–20%
\2
2–20
NET G3 High [20% [20
NEC
Small-cell type
Large-cell type
Poorly differentiated High [20% [20
MiNEN Well or poorly differentiated Variable Variable Variable
GEP-NEN, gastroenteropancreatic neuroendocrine neoplasm; MiNEN, mixed neuroendocrine-–non-neu-
roendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor
123
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recommended when curative resection is feasible [49].
Surgery is indicated for all appendiceal NENs, and the
surgical approach should be selected by taking tumor
localization, tumor size, and the presence of risk factors
into account [50,51]. Endoscopic resection is often indi-
cated for colonic NENs, but colectomy with lym-
phadenectomy is recommended for the following: tumor
size C1 cm or G2 or higher; muscularis propria invasion;
suspected lymph node metastasis; or endoscopic resection
specimens indicative of vascular invasion, muscularis
propria invasion, positive surgical margins, or G2 or
higher. Proctectomy with lymphadenectomy or rectal
amputation is recommended for rectal NENs for the fol-
lowing: tumor size C1 cm or G2 or higher; muscularis
propria invasion; suspected local lymph node involvement;
or endoscopic resection specimens indicative of the need
for additional treatment (Fig. 2)[52–54].
Medical and multidisciplinary treatment (Fig. 3)
Treatment modalities for GEP-NENs differ for NETs and
NECs, and treatment approaches differ for NETs origi-
nating in the pancreas and gastrointestinal tract (Table 3).
Resection is indicated for NETs when feasible; endoscopic
treatment can also be considered for gastrointestinal NETs.
Moreover, radiofrequency ablation and transarterial
chemoembolization are used for liver metastases. How-
ever, adjuvant chemotherapy to prevent recurrence of
NETs has not been established [55–57]. For functional
NETs with hormonal symptoms, somatostatin analogues
such as octreotide and lanreotide are used to control
symptoms [55–58]. For tumor control, somatostatin ana-
logues, molecular targeted drugs, and cytotoxic anticancer
agents are indicated [55–57]. Regarding somatostatin
analogues, insurance covers lanreotide [8] for pancreatic
NETs as well as octreotide [59] and lanreotide [8] for
gastrointestinal NETs. Regarding molecular targeted drugs,
insurance covers everolimus [60] and sunitinib [61] for
pancreatic NETs as well as everolimus [7] for gastroin-
testinal NETs. Regarding cytotoxic anticancer agents,
Fig. 1 Surgical approach for nonfunctioning pancreatic NETs.
(Superscript a) Check the swelling and firmness of the regional
lymph nodes and dissect if lymph node metastases are suspected; if
the tumor is discovered incidentally and there is no radiographic
evidence of metastasis or invasion, follow-up may be an option with
adequate explanation. PanNEC, pancreatic neuroendocrine carci-
noma; PanNEN, pancreatic neuroendocrine neoplasm; PanNET,
pancreatic neuroendocrine tumor
123
J Gastroenterol
insurance covers streptozocin [62,63] for both pancreatic
and gastrointestinal NETs; in addition, temozolomide [64]
is considered promising in Europe and the U.S. Temo-
zolomide combination therapy is one of the useful treat-
ments, but it is not approved for insurance in Japan.
Furthermore, radiation therapy may be used for palliative
purposes for bone and brain metastases. Moreover,
radionuclide-labeling peptide therapy (PRRT) [65] is often
used in Europe and the U.S. PRRT has recently been
covered by insurance in Japan, but at present, it should be
given priority to patients who are ineffective with other
drugs after the second treatment and need immediate PRRT
treatment. For that purpose, it is considered necessary to
build a network with feasible facilities.
While there is no established strategy for selecting
appropriate treatment modalities, Japanese experts have
proposed guidelines for NETs originating in the pancreas
[66], although future validation is required.
For NECs, resection is indicated when feasible, and
adjuvant chemotherapy can be used to prevent recurrence
after surgery. Resection is not recommended for liver
metastases in NECs. In nonresectable cases, platinum-
based chemotherapy is indicated, such as etoposide/cis-
platin, irinotecan/cisplatin, and etoposide/carboplatin
[1–3]. However, no effective drug therapy has been
established for cases refractory to these therapies [1–3].
Although GEP-NENs are rare, there are effective local
therapies such as resection, radiofrequency ablation, and
transarterial chemoembolization [55–57]. Several ran-
domized controlled trials have demonstrated the usefulness
of various drugs—many of which have been approved for
use. In practice, the multidisciplinary treatment that takes
advantage of these therapies is offered.
MEN1/VHL disease
Some pancreatic NENs develop in settings of hereditary
neoplasms, specifically MEN1 and VHL disease. Epi-
demiological studies report the frequencies of these
Fig. 2 Surgical approach for NENs of the colon and rectum. NEC, neuroendocrine carcinoma; NEN, neuroendocrine neoplasm; NET,
neuroendocrine tumor
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J Gastroenterol
hereditary neoplasms among all pancreatic NENs, and
whole-genomic sequencing revealed that approximately
6% and 1% of pancreatic NENs carry germline mutations
in MEN1 and VHL, respectively [67], suggesting that the
actual frequency is within this range.
Pancreatic NENs in settings of hereditary neoplasms
require different treatment approaches and surveillance
compared to nonhereditary cases and also lead to preclin-
ical diagnosis in family members. Therefore, it is important
to appropriately screen patients with suspected hereditary
neoplasia. In settings of MEN1, GEP-NEN is an important
prognostic factor along with thymic NEN [68,69].
Meanwhile, VHL disease rarely affects prognosis.
Regarding diagnosis, MEN1 or VHL disease is sus-
pected in cases of GEP-NENs that meet the criteria in
Table 4, thus requiring further assessment including
searching for associated pathologies and genetic testing.
MEN1 or VHL disease may also be associated with
multiple small pancreatic NENs, and EUS-FNA with CT or
MRI is recommended for localization. If a functional tumor
is suspected, other nonfunctioning tumors are also often
present; therefore, a SASI test is recommended [70].
The indications for surgery for GEP-NENs in settings of
MEN1 or VHL disease are essentially the same as those for
sporadic cases. However, because they involve multifocal
and recurrent tumors, follow-up is generally recommended
for nonfunctioning tumors \2 cm in a setting of MEN1
[71]. Surgery is considered for tumors that are C2cmor
have a high growth rate. If surgery is indicated, a procedure
that preserves as much pancreatic function as possible is
recommended. In a setting of VHL disease, surgery is
considered for tumors that are C2 cm and have a doubling
time \500 days [72].
Regarding surveillance, the growth rate of GEP-NETs
associated with MEN1 is slow (0.1–1.3 mm/year);
tumors \1 cm, in particular, show little growth [73]. In
patients with MEN1, annual follow-up including exami-
nation, imaging with CT or MRI, and biochemistry (i.e.,
fasting glucose, insulin, and gastrin) is recommended,
keeping functional NENs in mind [74]. In patients with
VHL disease, follow-up with dynamic CT every 2–3 years
is recommended for tumors that are \2 cm and have a
doubling time C500 days and every 6 months to 1 year
for tumors meeting only 1 of the 2 conditions.
Table 3 Treatment approaches for gastroenteropancreatic neuroendocrine neoplasms
NETs NECs
Pancreatic origin Gastrointestinal origin Pancreatic
origin
Gastrointestinal
origin
Local therapy Primary: resection Primary: resection, endoscopic treatment Resection ±adjuvant
chemotherapy
a
Metastasis: resection, RFA (for liver
metastasis), TACE (for liver
metastasis)
Metastasis: resection, RFA (for liver
metastasis), TACE (for liver
metastasis)
Symptom management:
somatostatin
analogues
Octreotide Octreotide
Lanreotide Lanreotide
Tumor control:
somatostatin
analogues
Lanreotide Octreotide – –
Lanreotide
Tumor control:
molecular targeted
drugs
Everolimus Everolimus – –
Sunitinib
Tumor control:
cytotoxic anticancer
agents
Streptozocin Etoposide/cisplatin
Temozolomide
a
Irinotecan/cisplatin
– Etoposide/carboplatin
Tumor control: radiation Radiation (for bone metastases, brain metastases): PRRT* Radiation (for bone or brain
metastasis)
a
Off-label in Japan
In recent years, a high response rate of temozolomide therapy for pancreatic NET has been reported overseas [64]. Based on these results,
guidelines also recommend temozolomide combination therapy is recommend as options for patients with large tumors and symptomatic patients
in Europe and the U.S. Temozolomide combination therapy is one of the useful treatments, but it is not approved for insurance in Japan.
Furthermore, radionuclide-labeling peptide therapy (PRRT) [65] is often used in Europe and the U.S. as well. PRRT has recently been covered by
insurance in Japan, but at present, it should be given priority to patients who are ineffective with other drugs after the second treatment and need
immediate PRRT treatment.
123
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Conclusions
The revised clinical practice guidelines encompass the
revised WHO classification for new diagnostic modalities,
pathological diagnosis, surgical and
medical/multidisciplinary treatments for pancreatic NETs,
and the management of pancreatic NETs in a setting of
hereditary diseases by addressing issues encountered in
daily clinical practice.
Compared to countries other than Japan, the frequency
of rectal NETs among gastrointestinal NETs is high in
Japan, whereas the frequency of midgut NETs is high in
Europe and the U.S. In addition, the frequency of MEN1 in
cases of pancreatic NET is lower in Japan than that in
Europe and the U.S. Accordingly, diagnostic and treatment
approaches differ between patients from Japan and Europe
or the U.S., requiring specific guidelines for patients in
Japan. Thus, the revised guidelines contain specific
strategies for GEP-NEN care in Japan, emphasizing clini-
cal practicality.
Fig. 3 Treatment strategy for metastatic/recurrent GEP-NEN. GEP-
NEN: gastroenteropancreatic neuroendocrine neoplasm; NEC: neu-
roendocrine carcinoma; NET: neuroendocrine tumor; PPI: proton
pump inhibitor; RFA: radiofrequency ablation; SSA: somatostatin
analogue; TACE: transarterial chemoembolization; TAE: tran-
scatheter arterial embolization
Table 4 Criteria for suspected MEN1 or VHL disease in cases of
gastroenteropancreatic neuroendocrine neoplasms
1. Multiple pancreatic NETs
2. Recurrent pancreatic NETs
3. Gastrinomas (particularly of duodenal origin) (NEN-1)
4. Insulinomas in younger patients (MEN-1)
5. Complicated by hypercalcemia (MEN-1)
6. Presence and history of MEN1 or VHL-associated neoplasms
7. Familial history of MEN1 or VHL-associated neoplasms
MEN1, multiple endocrine neoplasia type 1; NET, neuroendocrine
tumor; VHL, von Hippel–Lindau
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J Gastroenterol
Appendix
Members of the Guidelines Committee who created and
evaluated the JNETS ‘‘Clinical practice guidelines for
Gastroenteropancreatic Neuroendocrine Neoplasms’’ are
listed below.
Executive Committee: Chair: Tetsuhide ITO (Neuroen-
docrine Tumor Centre, Fukuoka Sanno Hospital.
Department of Gastroenterology, Graduate School of
Medical Sciences, Internal University of Health and
Welfare).
Vice-Chair: Toshihiko Masui (Department of Surgery,
Graduate School of Medicine, Kyoto University), and
Izumi Komoto (Neuroendorine Tumor Center, Kansai
Electric Power Hospital).
Members: Ryuichiro Doi (Department of Surgery, Otsu
Red Cross Shiga Hospital), Robert Y. Osamura (Depart-
ment of Diagnostic Pathology Nippon Koukan Hospital),
Akihiro Sakurai (Department of Medical Genetics and
Genomics, Sapporo Medical University School of Medi-
cine), Masafumi Ikeda (Department of Hepatobiliary and
Pancreatic Oncology, National Cancer Center Hospital
East), Koji Takano (Department of Endocrinology, Dia-
betes and Metabolism, Kitasato University School of
Medicine), Hisato Igarashi (Igarashi Medical Clinic), Akira
Shimatsu (Advanced Medical Care Center, Kusatsu Gen-
eral Hospital), Kazuhiko Nakamura (Department of Gas-
troenterology and Hepatology, National Hospital
Organization Fukuokahigashi Medical Center), Yuji
Nakamoto (Department of Diagnostic Imaging and Nuclear
Medicine, Graduate School of Medicine Kyoto University),
Susumu Hijioka (Department of Hepatobiliary and Pan-
creatic Oncology, National Cancer Center Hospital), Koji
Morita(Division of Endocrinology and Metabolism,
Department of Internal Medicine, Teikyo University
School of Medicine), Yuichi Ishikawa (Department of
Pathology, School of Medicine, International University of
Health and Welfare), Nobuyuki Ohike (Division of
Pathology, Shizuoka Cancer Center), Atsuko Kasajima
(Department of Pathology, Technical University Munich),
Ryoji Kushima (Department of Pathology, Shiga Univer-
sity of Medical Science), Motohiro Kojima (Division of
Pathology, Exploratory Oncology Research and Clinical
Trial Center, National Cancer Center), Hironobu Sasano
(Department of Pathology, Tohoku University School of
Medicine), Satoshi Hirano (Department of Gastroentero-
logical Surgery II, Hokkaido University Faculty of Medi-
cine), Nobumasa Mizuno (Department of
Gastroenterology, Aichi Cancer Center Hospital), Taku
Aoki (Second Department of Surgery, Dokkyo Medical
University), Takeshi Aoki (Department of Surgery, Tohoku
University Graduate School of Medicine), Takao Ohtsuka
(Department of Digestive Surgery, Breast and Thyroid
Surgery, Graduate School of Medical Sciences, Kagoshima
University), Tomoyuki Okumura (Department of Surgery
and Science, Faculty of Medicine, Academic Assembly,
University of Toyama), Yasutoshi Kimura (Department of
Surgery, Surgical Oncology and Science, Sapporo Medical
University), Atsushi Kudo (Department of Hepatobiliary
and Pancreatic Surgery, Graduate School of Medicine,
Tokyo Medical and Dental University), Tsuyoshi Konishi
(Cancer Institute Hospital of the Japanese Foundation for
Cancer Research), Ippei Matsumoto (Department of Sur-
gery, Kindai University Faculty of Medicine), Noritoshi
Kobayashi (Department of Oncology, Yokohama City
University Graduate School of Medicine), Nao Fujimori
(Department of Medicine and Bioregulatory Science,
Graduate School of Medical Sciences, Kyushu University),
Yoshitaka Honma (Department of Head and Neck, Eso-
phageal Medical Oncology, National Cancer Center
Hospital), Chigusa Morizane (Department of Hepatobiliary
and Pancreatic Oncology, National Cancer Center Hospi-
tal), Shinya Uchino (Noguchi Thyroid Clinic and Hospital
Foundation), Kiyomi Horiuchi (Department of Breast and
Endocrine Surgery, Tokyo Women’s Medical University),
Masanori Yamasaki (Division of Diabetes, Endocrinology
and Metabolism, Department of Internal Medicine, Shinshu
University School of Medicine).
Evaluation Committee: Chair: Masayuki Imamura
(Neuroendorine Tumor Center, Kansai Electric Power
Hospital).
Members: Koichi Hirata (Department of Surgery, JR
Sapporo Hospital), Takuji Okusaka (Department of Hepa-
tobiliary and Pancreatic Oncology, National Cancer Center
Hospital), Mitsuhiro Kida (Department of Gastroenterol-
ogy, Kitasato University School of Medicine), Wataru
Kimura (Toto Kasukabe Hospital), Masao Tanaka
(Department of Surgery, Shimonoseki City Hospital),
Yoshiyuki Majima (NPO PanCAN Japan).
Main Collaborators: Jun Matsubayashi (Department of
Surgery, Otsu Red Cross Shiga Hospital), Yuichi Sato
(Nagaoka central general Hospital), Masau Sekiguchi
(Cancer Screening Center/Endoscopy Division, National
Cancer Center Hospital), Shinichi Abe (Japan Medical
Library Association).
Observer: Robert T. Jensen (Cell Biology Section,
Digestive Diseases Branch, National Institutes of Diabetes,
Digestive and Kidney Diseases. National Institutes of
Health, USA.).
The Japanese Neuroendocrine Tumor Society: Presi-
dent, Shinji Uemoto (Department of Hepato-Biliary-Pan-
creatic Surgery and Transplantation, Graduate School of
Medicine, Kyoto University).
123
J Gastroenterol
Declarations
Conflict of interest Any financial relationship with enterprises,
businesses, or academic institutions in the subject matter or materials
discussed in the manuscript are listed as follows; Tetsuhide Ito
received speaker’s honoraria from Teijin Pharma Limited, Novartis
Pharma and Mylan EPD. Robert Y. Osamura received speaker’s
honoraria from Teijin Pharma Limited and Novartis Pharma. Akihiro
Sakurai received speaker’s honoraria from AstraZeneca. Masafumi
Ikeda received speaker’s honoraria from Novartis Pharma, Chugai
Pharmaceutical Co. Ltd. and Bayer Pharma. Susumu Hijioka received
speaker’s honoraria from Teijin Pharma Limited, Novartis Pharma
and Novel Pharma. Taku Aoki received speaker’s honoraria from
Novartis Pharma. Atsuko Kasajima received speaker’s honoraria from
Teijin Pharma Limited. Ryoji Kushima received speaker’s honoraria
from Takeda Pharmaceutical Co. Ltd. Hironobu Sasano received
speaker’s honoraria from Novartis Pharma. Tsuyoshi Konishi
received speaker’s honoraria from Olympus and Johnson & Johnson.
The authors, the spouse, partner or immediate relatives of the authors
report no other conflicts of interest in this work.
Supplementary InformationThe online version contains
supplementary material available at https://doi.org/10.1007/s00535-
021-01827-7.
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 appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate
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use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.
org/licenses/by/4.0/.
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