Shinshu Med J, 68⑸：235～242, 2020

綜説Treatment Strategy for Pancreatic Neuroendocrine Neoplasms (pNEN)
Koji Kubota, Akira Shimizu＊, Tsuyoshi Notake, Shinsuke Sugenoya, Kiyotaka Hosoda
Koya Yasukawa, Hikaru Hayashi, Ryoichiro Kobayashi and Yuji Soejima
Division of Gastroenterological, Hepato-Billiary-Pancreatic, Transplantation and Pediatric Surgery,
Department of Surgery, Shinshu University School of Medicine

Key words : non-functioning neuroendocrine tumor of the pancreas,functioning neuroendocrine tumor of the pancreas, enucleation, standard pancreatectomy,
lymph node dissection

Ⅰ Introduction

for some of the non-functional pancreatic neuroendo­
crine tumors, although conditional. There have also

Neuroendocrine neoplasms (NEN) were previously

been changes to surgical treatments, including theclassified under the disease concept vaguely referred

addition of surgical indications to the newly proposed

to as carcinoids. The term carcinoids were removed

G3 NET. Given the differences between the Nationalfrom the 2000 World Health Organization (WHO)Comprehensive Cancer Network (NCCN) guidelines2）classification of pancreatic and gastrointestinal tract

and the European Neuroendocrine Tumor Societydiseases and the disease concept of neuroendocrine(ENET) guidelines3）, this article provides a review oftumors (NET) was defined. In the 2010 WHO classifi­

surgical treatments for pancreatic NEN (pNEN).

cation, tissue grading was reconsidered using the Ki67 index and mitotic count, which represents mitotic

Ⅱ Pancreatic Neuroendocrine Neoplasms (pNEN)

cell patterns that correlate with clinical symptoms.

The generic term for neuroendocrine tumors ofMoreover, the notation in the 2017 WHO classifica­

the pancreas is pNEN. For pNEN, the degree of differ­tion of gastrointestinal and pancreatic neuroendo­

entiation is first evaluated pathologically. Well-differ­crine tumors was changed from NET to NEN. New

entiated tumors are classified as pancreatic neuro­

concepts were also proposed, including the reclassi­

endocrine tumors (pNET), and poorly-differentiated tu‑

fication of neuroendocrine carcinomas (NEC) intomors as pancreatic neuroendocrine carcinomas (pNEC).

well-differentiated G3 NET and poorly-differentiatedWithin pNET, tumors are divided into functional

NEC. This was accompanied by a revision of thepancreatic endocrine tumors with clinical manifesta­

Clinical Practice Guidelines for Gastroenteropancre­

tions of excess hormone production of tumors andatic Neuroendocrine Neoplasms (GEP-NEN) 2019 innon-functional pancreatic endocrine tumors without1）(hereinafter, Japan NeuroEndocrine Tumor

clinical manifestations. Mixed neuroendocrine-non-Society ; JNETS Guidelines, 2nd Edition). An obser­

neuroendocrine neoplasms (MiNEN) were defined asvation approach was included as a treatment option

tumors where the same tumor contains at least 30%Japaneach of pNEN and another epithelial tumor (Fig. 1).
＊Corresponding author : Akira Shimizu	Division of Gastroenterological, Hepato-Billiary-Pancreatic,
Transplantation and Pediatric Surgery, Department of Sur­gery, Shinshu University School of Medicine, 3-1-1 Asahi,Matsumoto, Nagano 390-8621, Japan
E-mail : ashimizu@shinshu-u.ac.jp

No. 5, 2020

Ⅲ

Functional Pancreatic Neuroendocrine Tumor ;F-pNET

Treatment concepts for F-pNETs have two objec­
tives : (1) improving hormonal symptoms through235

Kubota・Shimizu・Notake et al.

Fig. 1

Concept of pNEN

tumor resection (occasionally reducing the dose), andarterial secretagogue injection (SASI) testing with(2) radical resection of the tumor.

calcium be performed preoperatively. If tumors can­Insulinoma : This condition triggers hypoglycemic

not be identified intraoperatively without SASI tests,

symptoms, as represented by the triad of Whipple

intraoperative ultrasonography may be helpful. How­symptoms that are caused by excessive secretions ofever, there is still a possibility that tumors may not

insulin. Many patients experience some interference

be detected. Resection of the pancreas is not recom­in their daily life due to chronic high insulin status.

mended if SASI tests are not performed preopera­

Surgical treatment is indicated when the diagnosis istively, the location of the intraoperative tumor (orconfirmed, and surgery is recommended in all ofeven if it can be identified as a tumor) is not under­

1）-3）

the guidelines. Approximately 90 ％ of insulinomas

stood, or the culprit site is unclear. After abdominal

are benign tumors and are likely to be cured by sur­closure, SASI tests must be performed to identify

4）5）gery. There are some differences in the interpre­the culprit site and map the extent of resection. Iftations in each of the guidelines. In the 2nd edition

the lesions cannot be confirmed to be tumors, lesionsof the JNETS guidelines, enucleation is recommend­causing hyperinsulinemia, such as minute insulinoma,

ed for tumors without distant metastases, without

hyperplasia of the islets of Langerhans, and non-invasive findings, and that are distant from the main

insulinoma pancreatogenous hypoglycemia syndrome

6）7）. If damage to the main pancreatic(NIPHS), may be identified within the resected spec­

duct is suspected, a procedure that preserves theimen8）9）. Standard pancreatectomy with lympha­

pancreas as much as possible (including partial pan­denectomy is recommended for invasive findings,

createctomy, segmentectomy, distal pancreatectomy

multiple lesions, lesions with dilated pancreatic ducts,with/without spleen preservation) may be selected.

and positive lymph node metastases. For the mostLess invasive laparoscopic surgery is also an option

part, surgical method selection is the same as de­at some medical institutions. Even if the tumor can­scribed in the NCCN guidelines. Somatostatin recep­

not be identified intraoperatively, surgery should be

tor scintigraphy (SRS) or positron emission tomogra­

pancreatic duct

performed on that assumption. The recommendation

phy/computed tomography (PET/CT) or PET/magnet-

is that not only diagnostic imaging but also selective

ic resonance imaging (MRI) is also recommended

236

Shinshu Med J

l. 68

Treatment strategy for pancreatic neuroendocrine neoplasms (pNEN)

Fig. 2

Surgical treatment algorithm for insulinoma

preoperatively2）. In addition to resection, the ENET

5.6 ％ of instances arise outside the pancreas andguidelines introduce endoscopic ultrasonography (EUS)-

duodenum18）, systemic evaluation such as with SRS isguided ethanol injection and CT-guided radiofrequency

required prior to surgery. Surgical procedures are10）-12）ablation (RFA)(Fig. 2). For insulinomas, treatment

almost identical to those described in the 2nd edition

is difficult since whether or not the hyperinsulinemiaof the JNETS guidelines and the NCCN guidelines,

improves intraoperatively even after the resection ofand evaluations are performed depending on thetumors is not known. Based on this finding as well,location, the presence or absence of invasion, and theconfirming the localization of culprit lesions preoper­

number of tumors. If neither pancreas or duodenum

atively by SASI tests provides reassurance. Although

are invaded, enucleation and partial resection are

not mentioned in the guidelines, there have been re­chosen ; however, lymphadenectomy is required forports of increases in glucose from continuous intra­

all procedures. Moreover, in patients with invasion or13）

or an insulin/glucose

multiple lesions, pancreaticoduodenectomy, total duo­

ratio of 0.3 or less as being a guide for resection ofdenectomy, distal pancreatectomy, and central pan­operative glucose monitoring
14）

createctomy are considered. However, the ENET

culprit lesions .

Gastrinoma : Refractory peptic ulcers and reflux

guidelines do not recommend extensive surgery,esophagitis due to gastric hyperacidity are observ­

such as pancreaticoduodenectomy, in gastrinomas

ed since the condition presents with the so-called

complicated with multiple endocrine neoplasia

Zollinger-Ellison syndrome (ZES). Gastrinoma is atype 1 (MEN1). The reason for this is that ZES canhighly malignant tumor with a high rate of lymph

be controlled with pharmacotherapy19）20）and there is anode metastases. Resection of the primary lesion andpossibility of numerous early and late complications15）
16）

lymphadenectomy are necessary. Surgery is thewith pancreaticoduodenectomy. This point signifi­

only treatment method that can be expected to leadcantly differs from the 2nd edition of the JNETS

to a cure. Gastrinomas are often seen within the gas­guidelines. Total pancreatectomy should be avoided

trinoma triangle comprising the duodenum and pan­for patients with glucagonoma associated with MEN,

creas and adjacent lymph nodes17）. However, since

but the recommendation is that curative outcomes are

No. 5, 2020237

Kubota・Shimizu・Notake et al.

Fig. 3

Surgical treatment algorithm for gastrinoma

focused on when selecting the procedure21）22） (Fig. 3).

of the JNETS guidelines, the recommendation is to

Rare functional pancreatic NET : In addition tofollow-up patients with tumors less than 1 cm ininsulinoma and gastrinomas, there are rare F-pNET,

diameter and no incidental findings of metastases orsuch as glucagonomas, vasoactive intestinal peptide

invasion every 6 to 12 months and to consider sur­(VIP) omas, somatostatinomas, growth hormone

gery if the tumor grows larger24）25）. Follow-up isreleasing factor (GRF) omas, pancreatic polypeptide

included as an option other than surgery for tumors(PP) omas, adrenocorticotropic hormone (ACTH)

less than 1 cm in the NCCN guidelines2） and foromas, and parathyroid hormone (PTH) omas. All oftumors 2 cm or less in the ENETS guidelines3）. Since

these tumors are highly malignant and are associat­

highly invasive procedures such as pancreaticoduo­23）

ed with poor prognoses . Surgery is the only cura­denectomy are an option, particularly when thetive treatment. Lymph node metastases are frequent

tumor is located in the head of the pancreas, follow-in all of these tumors, and standard pancreatectomy

up may be selected if preferred after providing awith lymphadenectomy is recommended. Althoughthorough explanation to the patient. Naturally, if

these tumors are often large, spleen-preserving dis­such a course is taken, there must be no imaging

tal pancreatectomy and partial pancreatectomy orfindings that are suggestive of malignancies. There isenucleation should be performed to preserve organ

also a need to determine whether follow-up is appro­

function in small tumors less than 2 cm. Lymph­

priate considering age and whether the patient has

adenectomy should not be omitted.

any complications. Standard pancreatectomy andⅣNon-functional Pancreatic Neuroendocrine
Tumor ; NF-pNET

regional lymphadenectomy are also indisputably indi­cated for large tumors 2 cm or more in diameter.
However, for small tumors less than 2 cm, various

Surgery is the fundamental treatment mentioned

pancreatic resection techniques can be chosen, rang­

in all of the guidelines. However, there is no consen­

ing from enucleation to standard pancreatectomy,

sus as to whether resection should be performed forconsidering such factors as the location of the tumor

all patients with small NF-pNETs. In the 2nd edition

and the main pancreatic duct (Fig. 4). There is, how­

238Shinshu Med Jl. 68

Treatment strategy for pancreatic neuroendocrine neoplasms (pNEN)

Fig. 4

Surgical treatment algorithm for NF-pNET

ever, no consensus on the extent of lymphadenecto­

the prognosis is relatively good. Conversely, the Ki-my required. The 2nd edition of the JNETS guide­

67 index for pNEC (G3) is usually at least 50 ％ and,lines also states that there is a need to investigate

although platinum-based pharmacotherapies are suc­whether pancreatectomy with lymphadenectomy will

cessful in some cases, survival prognoses are report­

lead to improved outcomes and quality of life (QOL)

ed to be extremely poor30）31）. Furthermore, a reportin all patients. This is because while there are nu­

on an investigation of gene expression patterns

merous reports of very few nodal metastases in G1

in both groups indicated that the gene expression26）-28）, G1 pNETs less than 1 cm

patterns for pNET G3 were similar to those of pNET

are also reportedly associated with widespread me­

G1 and G2, whereas that for pNEC (G3) was similarpNETs less than 1 cm29）

tastases . At this point in time, the recommendation

to that of pancreatic ductal carcinoma32）. The two

is to sample the surrounding lymph nodes, even iftumor types did not show continuity in their devel­

limited surgery is performed on NF-pNETs 2 cm oropment and malignant transformation as tumors,less.

since the tumors were considered to have developed
ⅤG3 pNET and pNEC

and originated from completely different cells. Prior
to the 2017 WHO classification, NECs (known as

As previously mentioned, well-differentiated tu­

pNET G3 and pNEC (G3) from 2017 onwards) weremors with a Ki-67 index higher than 20 ％ are de­not indicated for surgery and the recommended

fined as pNET G3 and poorly-differentiated tumors

treatment was platinum-based pharmacotherapy.

as pNEC (G3) in the 2017 WHO classification. Within

However, following the 2017 revision of the WHO

conventional NEC, there were groups respondingclassification, the JNETS guidelines1） recommenda­

differently to pharmacotherapy, and these were di­tions were also updated to state that the treatment

vided in two groups. The Ki-67 index for pNET G3 ispolicy for pNET G3 should conform to that of pNET

modestly low, ranging from 20 ％ to 50 ％ , and re­

G1/G2. This meant that surgery was added as asponse rates to platinum-based anticancer therapy,treatment option. Nevertheless, the prognoses forthe standard treatment for NEC, are low. However,pNEC (G3) after resection remain extremely poor,

No. 5, 2020

239

Kubota・Shimizu・Notake et al.

even in patients with resectable lesions, and the me­

lymphadenectomy were performed38）-40）. Thus, stan­

dian overall survival does not exceed 12 months 33）-

dard pancreatectomy with hepatectomy and regional35）. Since there have been no reports evaluating thelymphadenectomy is indicated in pNET patients

outcomes of resection and prognostic factors forwith liver metastases. However, since simultaneous

resection in only pNEC patients, whether surgery

hepato-pancreatectomy is associated with excessive

should be indicated or not and, if so, in which pa­

surgical invasiveness, not all patients are eligible

tients has not been clarified.

for this procedure and it should be considered on aⅥ

pNETs with Metastatic or Recurrent Lesionscase-by-case basis considering the risks41）. Even inlesions for which curative resection is not feasible,

If resection is feasible without the risk of leaving asurgery is indicated when improvements in progno­

residual lesion, multidisciplinary treatment with re­sis and QOL are desired. In the United States, favor­

section as the main treatment is indicated. An analy­

able prognosis was reportedly obtained with liver

sis of the vast amount of data in the United Statestransplantation42）.

Surveillance Epidemiology and End Results (SEER)

Ⅶ Conclusions

registry revealed that surgical treatment that in­cluded the primary tumor and distant metastases36）

This article focused on describing surgical options

was associated with improved outcomes . However,for pNEN. The extent and indications of lymph­

most patients require multidisciplinary treatment

adenectomy and the role of hepatectomy in multidis­

and surgery alone is not expected to lead to a cure.

ciplinary treatment are controversial. The guidelines

In patients with pNET and liver metastases, recur­

reported to date have been mainly from Europe andrences within 3 years were reportedly associatedthe United States, and the accumulation of more data37）

with more lymph node metastases , and favorablefrom Japan is anticipated to lead to the dissemination

overall survival when hepatectomy and regionalof new evidence.

References
1） Japan NeuroEndocrine Tumor Society (JNETS) : Clinical Practice Guidelines for Gastroenteropancreatic Neuroendo­
crine Neoplasms (GEP-NEN) 20192） NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®
) Neuroendocrine and Adrenal Tumors Version
1.2019-March 5, 20193） Falconi M, Eriksson B, Kaltsas G, et al : ENETS Consensus Guidelines Update for the Management of Patients with
Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendo­
crinology 103 : 153-171, 20164） Metz DC, Jensen RT : Gastrointestinal neuroendocrine tumors : pancreatic endocrine tumors. Gastroenterology 135 :1469-1492, 2008
5） Vanderveen K, Grant C : Insulinoma. Cancer Treat Res 153 : 235-252, 2010
6） Hirshberg B, Cochran C, Skarulis MC, et al : Malignant insulinoma : spectrum of unusual clinical features. Cancer
104 : 264-272, 2005
7） Roldo C, Missiaglia E, Hagan JP, et al : MicroRNA expression abnormalities in pancreatic endocrine and acinar
tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol 24 : 4677-4684, 20068） Jensen RT, Berna MJ, Bingham DB, et al : Inherited pancreatic endocrine tumor syndromes : advances in molecularpathogenesis, diagnosis, management, and controversies. Cancer 113 : 1807-1843, 20089） Fendrich V, Waldmann J, Bartsch DK, et al : Surgical management of pancreatic endocrine tumors. Nat Rev ClinOncol 6 : 419-428, 200910） Mehrabi A, Fischer L, Hafezi M, et al : A systematic review of localization, surgical treatment options, and outcome
240

Shinshu Med Jl. 68

Treatment strategy for pancreatic neuroendocrine neoplasms (pNEN)of insulinoma. Pancreas 43 : 675-686, 201411） Guo Q, Wu Y : Surgical treatment of pancreatic islet cell tumor : report of 44 cases. Hepatogastroenterology 60 :2099-2102, 201312） Knigge U, Hansen CP : Surgery for GEP-NETs. Best Pract Res Clin Gastroenterol 26 : 819-831, 201213） Sugiyama Y, Kiuchi C, Suzuki M, et al : Glucose Management during Insulinoma Resection Using Real-Time Subcu­
taneous Continuous Glucose Monitoring. Case Rep Anesthesiol 2018 : 6248467, 201814） Tonelli F, Giudici F, Nesi G, et al : Operation for insulinomas in multiple endocrine neoplasia type 1 : When pancre­
atoduodenectomy is appropriate. Surgery 161 : 727-734, 201715） Bartsch DK, Waldmann J, Fendrich V, et al : Impact of lymphadenectomy on survival after surgery for sporadic
gastrinoma. Br J Surg 99 : 1234-1240, 201216） Giovinazzo F, Butturini G, Monsellato D, et al : Lymph nodes metastasis and recurrences justify an aggressive
treatment of gastrinoma. Updates Surg 65 : 19-24, 201317） Howard TJ, Stabile BE, Zinner MJ, et al : Anatomic distribution of pancreatic endocrine tumors. Am J Surg 159 :258-264, 1990
18） Wu PC, Alexander HR, Bartlett DL, et al : A prospective analysis of the frequency, location, and curability of ectopic(nonpancreaticoduodenal, nonnodal) gastrinoma. Surgery 122 : 1176-1182, 199719） Ito T, Igarashi H, Jensen RT : Pancreatic neuroendocrine tumors : clinical features, diagnosis and medical treat­ment : advances. Best Pract Res Clin Gastroenterol 26 : 737-753, 201220） Ito T, Igarashi H, Uehara H, et al : Pharmacotherapy of Zollinger-Ellison syndrome. Expert Opin Pharmacother
14 : 307-321, 201321） Imamura M, Komoto I, Ota S, et al : Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia
type 1 patients. World J Gastroenterol 17 : 1343-1353, 201122） Bartsch DK, Fendrich V, Langer P, et al : Outcome of duodenopancreatic resections in patients with multiple endo­
crine neoplasia type 1. Ann Surg 242 : 757-764, discussion 764-756, 200523） Oberg K : Pancreatic endocrine tumors. Semin Oncol 37 : 594-618, 201024） Sadot E, Reidy-Lagunes DL, Tang LH, et al : Observation versus Resection for Small Asymptomatic Pancreatic Neu­roendocrine Tumors : A Matched Case-Control Study. Ann Surg Oncol 23 : 1361-1370, 201625） Sallinen V, Haglund C, Seppanen H : Outcomes of resected nonfunctional pancreatic neuroendocrine tumors : Do sizeand symptoms matter ? Surgery 158 : 1556-1563, 201526） Tsutsumi K, Ohtsuka T, Mori Y, et al : Analysis of lymph node metastasis in pancreatic neuroendocrine tumors(PNETs) based on the tumor size and hormonal production. J Gastroenterol 47 : 678-685, 201227） Partelli S, Gaujoux S, Boninsegna L, et al : Pattern and clinical predictors of lymph node involvement in nonfunction­
ing pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg 148 : 932-939, 201328） Furukori M, Imai K, Karasaki H, et al : Clinicopathological features of small nonfunctioning pancreatic neuroendo­
crine tumors. World J Gastroenterol 20 : 17949-17954, 201429） Gratian L, Pura J, Dinan M, et al : Impact of extent of surgery on survival in patients with small nonfunctional pan­creatic neuroendocrine tumors in the United States. Ann Surg Oncol 21 : 3515-3521, 201430） Sorbye H, Welin S, Langer SW, et al : Predictive and prognostic factors for treatment and survival in 305 patientswith advanced gastrointestinal neuroendocrine carcinoma (WHO G3) : the NORDIC NEC study. Ann Oncol 24 : 152160, 201331） Hijioka S, Hosoda W, Matsuo K, et al : Rb Loss and KRAS Mutation Are Predictors of the Response to PlatinumBased Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3 : A Japanese Multicenter PancreaticNEN-G3 Study. Clin Cancer Res 23 : 4625-4632, 201732） Hijioka S, Hosoda W, Mizuno N, et al : Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms
No. 5, 2020

241

Kubota・Shimizu・Notake et al.
accurately characterize pancreatic neuroendocrine carcinomas ? J Gastroenterol 50 : 564-572, 201533） Dasari A, Shen C, Halperin D, et al : Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With
Neuroendocrine Tumors in the United States. JAMA Oncol 3 : 1335-1342, 201734） Haugvik SP, Janson ET, Österlund P, et al : Surgical Treatment as a Principle for Patients with High-Grade Pancre­
atic Neuroendocrine Carcinoma : A Nordic Multicenter Comparative Study. Ann Surg Oncol 23 : 1721-1728, 201635） Han X, Xu X, Ma H, et al : Clinical relevance of different WHO grade 3 pancreatic neuroendocrine neoplasms basedon morphology. Endocr Connect 7 : 355-363, 201836） Hill JS, McPhee JT, McDade TP, et al : Pancreatic neuroendocrine tumors : the impact of surgical resection on sur­vival. Cancer 115 : 741-751, 200937） Zhang XF, Beal EW, Chakedis J, et al : Early Recurrence of Neuroendocrine Liver Metastasis After Curative Hepa­
tectomy : Risk Factors, Prognosis, and Treatment. J Gastrointest Surg 21 : 1821-1830, 201738） Fendrich V, Langer P, Celik I, et al : An aggressive surgical approach leads to long-term survival in patients withpancreatic endocrine tumors. Ann Surg 244 : 845-851 ; discussion 852-843, 200639） Cho CS, Labow DM, Tang L, et al : Histologic grade is correlated with outcome after resection of hepatic neuroendo­
crine neoplasms. Cancer 113 : 126-134, 200840） Sarmiento JM, Que FG, Grant CS, et al : Concurrent resections of pancreatic islet cell cancers with synchronous
hepatic metastases : outcomes of an aggressive approach. Surgery 132 : 976-982 ; discussion 982-973, 200241） De Jong MC, Farnell MB, Sclabas G, et al : Liver-directed therapy for hepatic metastases in patients undergoing
pancreaticoduodenectomy : a dual-center analysis. Ann Surg 252 : 142-148, 201042） Moris D, Tsilimigras DI, Ntanasis-Stathopoulos I, et al : Liver transplantation in patients with liver metastases fromneuroendocrine tumors : A systematic review. Surgery 162 : 525-536, 2017（2020. 6. 9 received）

242

Shinshu Med J

l. 68