Investigation of Fluorodeoxyglucose Positron Emission Tomography for the Diagnosis of Solid Pseudopapillary Neoplasm of the Pancreas:A Study Associated With a National Survey of Solid Pseudopapillary Neoplasms

概要

ORIGINAL ARTICLE

Investigation of Fluorodeoxyglucose Positron Emission
Tomography for the Diagnosis of Solid Pseudopapillary
Neoplasm of the Pancreas
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A Study Associated With a National Survey of Solid Pseudopapillary Neoplasms
Keisuke Kurihara, MD,* Keiji Hanada, MD, PhD,† Masahiro Serikawa, MD, PhD,* Yasutaka Ishii, MD, PhD,*
Tomofumi Tsuboi, MD, PhD,* Ryota Kawamura, MD,* Tsuyoshi Sekitou, MD,* Shinya Nakamura, MD,*
Takeshi Mori, MD,* Tetsuro Hirano, MD,* Juri Ikemoto, MD,* and Kazuaki Chayama, MD, PhD*

Objectives: This study aimed to investigate the utility of fluorodeoxyglucose
(FDG) positron emission tomography for solid pseudopapillary neoplasm
(SPN) diagnosis.
Methods: The subjects included 53 cases of SPN. We compared the
maximal standardized uptake volume (SUVmax) with those of 25 cases
of pancreatic duct cancer and 18 cases of pancreatic neuroendocrine
neoplasm. In addition, immunopathological testing for SPN with regard
to FDG uptake was undertaken.
Results: An increase in SUVmax was observed in all tumors with increased tumor diameter. Among tumors of 20 mm or smaller, the SUVmax
of SPN was significantly higher than those of pancreatic duct cancer and
pancreatic neuroendocrine neoplasm. The results of a pathological study
of FDG uptake in SPN revealed increased glucose transporter protein type
1 expression with tumor enlargement. Furthermore, increased hypoxiainducible factor-1 and vascular endothelial growth factor expression under
hypoxic conditions were observed in the areas of necrosis.
Conclusions: In cases in which high FDG uptake is observed in small
pancreatic tumors, FDG positron emission tomography is potentially useful
for SPN differentiation. The factors involved in FDG uptake in SPN include cell density and glucose transporter protein expression, as well as
hypoxia-inducible factor and vascular endothelia growth factor expression
in the hypoxic environment of necrotic areas.
Key Words: solid pseudopapillary neoplasm, FDG-PET, pancreas,
pancreatic duct cancer, pancreatic neuroendocrine neoplasm, tumor
Abbreviations:
FDG-PET - fluorodeoxyglucose positron emission tomography,
SPN - solid pseudopapillary neoplasm,
SUVmax - maximal standardized uptake volume,
From the *Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University; and
†Department of Gastroenterology, Onomichi General Hospital, Hiroshima, Japan.
Received for publication March 11, 2019; accepted September 12, 2019.
Address correspondence to: Keisuke Kurihara, MD, Department of
Gastroenterology and Metabolism, Applied Life Sciences, Institute of
Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi,
Hiroshima 734-8551, Japan (e‐mail: k.kurihara@onomichi-gh.jp).
This study was supported by Japan Pancreas Society. The design and conduct of
the study, interpretation of the data, and decision to submit the manuscript
for publication were the responsibilities of the authors listed.
This study was approved by the ethics committees of Hiroshima University
(E-817).
The authors declare no conflict of interest.
Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NCND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
DOI: 10.1097/MPA.0000000000001424

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www.pancreasjournal.com

PDC - pancreatic duct cancer,
PNEN - pancreatic neuroendocrine neoplasm,
GLUT1 - glucose transporter protein type 1,
HIF - hypoxia-inducible factor, VEGF - vascular endothelial growth factor,
JPS - Japan Pancreas Society, CT - contrast computed tomography
(Pancreas 2019;48: 1312–1320)

S

olid pseudopapillary neoplasm (SPN) in the pancreas is a
relatively rare pancreatic epithelial tumor that often occurs
in young women and is reported to occur in 0.17% to 2.7% of
all pancreatic tumors.1 With advances in imaging examinations,
reports of SPN have increased in recent years.2–5 We conducted
our own investigation using data from the Japan Pancreas Society
(JPS) SPN National Survey to study the clinical pathology of this
disease. The results of the National Survey revealed that the typical macroscopic findings of SPN included a mixture of cysts and
solid components, calcification, and bleeding. Contrast computed
tomography (CT) examinations revealed prolonged, uneven staining, with tumors depicted with cysts and calcification. However,
in small SPNs, the tumors may not have cysts, calcification, or
bleeding. Therefore, it is often difficult to differentiate SPN from
pancreatic duct cancer (PDC).2
Fluorodeoxyglucose positron emission tomography (FDGPET) is useful for the differential diagnosis of malignancies or
otherwise of tumorous lesions in various organs. In pancreatic tumors, high FDG uptake is observed in PDC; thus, it has been reported as a marker of malignancy.6 Furthermore, although World
Health Organization classifications consider SPN to have low malignant potential, there are many reports of high FDG uptake.7–13
The degree of FDG uptake by tumors generally depends on the
tumor size, histologic type, and microvessel density at the
molecular level,6 and associations have been reported with
glucose transporter-1 (GLUT-1) related to glucose metabolism,13–15
hypoxia-inducible factor-1 (HIF-1) related to hypoxic environments, and vascular endothelial growth factor (VEGF) related
to neovascularization.16–20
A National Survey of SPN of the pancreas was conducted by
the JPS; we additionally conducted a study to clarify the utility of
FDG-PET for the diagnosis of SPN, as well as an investigation of
the molecular mechanisms related to FDG uptake.

Committee
The JPS established a committee (Drs Keiji Hanada, Keisueke
Kurihara, Takao Itoi, Akio Katanuma, Tamito Sasaki, and Kazuo
Hara as endoscopists; Drs Masafumi Nakamura, Wataru Kimura
Pancreas • Volume 48, Number 10, November/December 2019

Pancreas • Volume 48, Number 10, November/December 2019

Yutaka Suzuki, and Masanori Sugiyama as surgeons; Drs Nobuyuki
Ohike, Noriyoshi Fukushima, and Michio Shimizu as pathologists;
and Drs Kousei Ishigami and Toshifumi Gabata as radiologists) to
evaluate the clinical and pathological problems associated with SPNs.

Solid Pseudopapillary Neoplasms of the Pancreas

CD31 was measured in 4 random sites with high vessel density in
a visual field of 1:200 (0.8 mm2) for each sample to measure the
microvessel density based on the average value.

Statistical Analysis
MATERIALS AND METHODS
National Survey of SPN of the Pancreas by the JPS
The study subjects included 288 cases that were diagnosed
with SPN using postoperative specimens at 33 facilities with
councilors on the Board of the JPS, along with a questionnairebased survey related to the clinical findings. The maximal standardized uptake volume (SUVmax) of the tumor was measured
in 53 cases in which FDG-PETwas performed and a study was carried out on the utility of FDG-PET in SPN diagnosis and its relationship to the clinical findings. We then compared the FDG
uptake in 25 cases of PDC and 18 cases of pancreatic neuroendocrine neoplasm (PNEN) in which surgery had been conducted at
our hospital and PET had been performed before surgery.2

FDG-PET Contrast Method
The 18F-FDG PET scans were performed on a Biograph
mCT-S PET/CT scanner (Siemens, Milwaukee, Wis). The patients
fasted for at least 5 hours before the injection of 18F-FDG. Data
acquisition was started approximately 60 minutes after the injection of 71 to 333 MBq (range, 1.40–3.67 MBq/kg) of FDG. The
imaging range was from the thigh to the head with both arms
raised; the imaging length fell within the range of 8 bed positions. The emission acquisition time was 2 minutes in list
mode per bed position. The PET images were reconstructed
using a 3-dimensional ordered subsets expectation maximization algorithm in a 128  128 matrix with a field of view of
200  200 mm and a slice thickness of 3 mm.

Immunostaining
To study the molecular mechanisms relating to FDG uptake
in SPN, we conducted GLUT-1, VEGF, HIF-1, and CD31 immunostaining using the paraffin-embedded section protocol
for 6 cases of SPN in which surgery had been conducted at our
hospital and investigated the relationship of the findings with
the SUVmax.
Immunostaining was performed using a polymer method and
ImmPRESS reagent (Vector Laboratories, Burlingame, Calif ).
After deparaffinization and hydration, the macrophage method
using a citrate buffer Target Retrieval Solution (Dako, Carpinteria,
Calif ) was used, which included heat treatment for 10 minutes before antigen retrieval. Endogenous enzyme blocking was conducted for 30 minutes with a 0.3% hydrogen peroxide/methanol
solution, followed by blocking with 2.5% normal horse serum.
The primary antibodies used were as follows: GLUT1 (1:300
dilution, ab652; Abcam, Cambridge, United Kingdom), VEGF-A
(1:200 dilution, ab46154; Abcam), HIF-1 (1:500 dilution, ab85886;
Abcam), Ki67 (1:50 dilution, ab8191; Abcam), and CD31 (1:300
dilution, bs0195R; Bioss, Woburn, Mass). The antibodies were all
left overnight for a response, followed by the use of the ImmPRESS
reagent for the secondary antibody reaction. Staining was conducted with the ImmPACT DAB enzyme substrate solution.
Immunostaining was evaluated on the basis of staining concentration and the ratio of tissue stained. The degrees of staining
of the GLUT-1, VEGF, and HIF-1 of the cytoplasm and cell membranes were classified into 4 levels: negative (−) or positive (+, ++,
or +++). ...

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