Additional information gained by positron emission tomography with 68Ga-DOTATOC for suspected unknown primary or recurrent neuroendocrine tumors
Ann Nucl Med
Additional information gained by positron emission tomography with 68Ga-DOTATOC for suspected unknown primary or recurrent neuroendocrine tumors
Yuji Nakamoto 0 1 2
Kohei Sano 0 1 2
Takayoshi Ishimori 0 1 2
Masashi Ueda 0 1 2
Takashi Temma 0 1 2
Hideo Saji 0 1 2
Kaori Togashi 0 1 2
0 Radioisotopes Research Laboratory, Kyoto University Hospital , Kyoto , Japan
1 Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences , Kyoto , Japan
2 & Yuji Nakamoto
Objective Positron emission tomography (PET)/computed tomography (CT) using 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N0,N00,N¢¢¢-tetraacetic acid-D-Phe1-Tyr3octreotide (DOTATOC) has been used to detect neuroendocrine tumors (NETs). The purpose of this study was to investigate the clinical efficacy of DOTATOC-PET/CT for detecting clinically suspected NETs when conventional imaging modalities were negative or inconclusive, in terms of additional value. Methods A total of 46 patients were analyzed retrospectively. Among them, 14 patients underwent a DOTATOCPET/CT scan for detecting unknown primary tumors after histopathological confirmation of a NET at metastatic sites (group A): 7 patients for detecting metastasis or recurrence after surgery for NET because of their high hormone levels but with no recurrence detected by other imaging modalities (group B); the remaining 25 patients for detecting suspected NETs because their hormone levels were high with no history of histopathologically proven NET (group C). Additional information was assessed, according to each situation.
PET/CT; Neuroendocrine tumor
Department of Diagnostic Imaging and Nuclear Medicine,
Kyoto University Graduate School of Medicine, 54
Shogoinkawahara-cho, Sakyo-Ku, Kyoto 606-8507, Japan
Positron emission tomography computed tomography
using 18F-fluorodeoxyglucose (FDG-PET/CT) has been
widely accepted for clinical tumor imaging [
]. Primary or
metastatic lesions are depicted as a hypermetabolic area of
glucose in many cancers, which is helpful for staging,
restaging, and monitoring the response to therapy. Despite
dramatic spread of FDG-PET/CT use during the past
decade, neuroendocrine tumors (NETs), which commonly
express somatostatin receptors, are often not FDG-avid, for
which conventional FDG-PET/CT does not always provide
useful information for therapeutic management. For these
tumors, 111In-octreotide has been used in Europe and the
United States for somatostatin receptor scintigraphy [
but it is not routinely available in Japan.
68Ga-labeled octreotide, including 68Ga-labeled
acid-D-Phe1Tyr3-octreotide (DOTATOC), has been used as a PET tracer
for somatostatin receptor imaging mainly in Europe [
Compared with 111In-labeled compounds, more promising
results have been reported, especially for detecting lung or
bone metastasis [
]. There have already been a few articles
demonstrating the clinical efficacy of DOTATOC-PET/CT
for unknown primary NETs [
]. The data are limited,
however, and the value of PET/CT with 68Ga-labeled
compounds clinically has not been investigated in Japan,
although there has been one article that elucidated
characteristics of NETs quantitatively with 111In-labeled octreotide
investigation . Because it has been reported that there
are large differences in the features of
gastroenteropancreatic NETs in Japan and Western countries [
], the clinical
efficacy of DOTATOC-PET/CT should be evaluated in a
The aim of this study was to evaluate the clinical
usefulness of PET/CT using 68Ga-DOTATOC in NET patients
with suspected unknown primary or recurrent tumors in
each situation when other conventional imaging modalities
were negative or inconclusive, from a view point of
Patients and methods
A total of 46 consecutive patients (male/female ratio 12:34;
mean age 56 years, range 27–80 years) who underwent
DOTATOC-PET/CT at our institution were analyzed. The
patients were divided into three groups according to their
scanning records. In group A, PET/CT was performed after
metastatic NETs were confirmed histopathologically, but
primary tumors had not been identified by other imaging
modalities. In group B, DOTATOC-PET/CT scan was
performed to evaluate suspected recurrent lesions because
of a high level of gastrin (n = 5), insulin (n = 1), or
chromogranin A (n = 1) after they underwent curative
surgery for histologically proven NETs. Conventional
imaging tests were negative. In group C, NETs had been
suspected based on laboratory data without definitive
localization of primary sites by conventional imaging
modalities. In this group, patients had been suspected of having
NET because of high levels of gastrin (n = 9),
adrenocorticotropic hormone (ACTH) (n = 8), insulin (n = 5),
5-hydroxyindoleacetic acid (n = 2), or chromogranin A
(n = 1). We checked all patients who had not taken a
longacting octreotide analogue within 1 month before their
DOTATOC-PET/CT scan. The ethics committee of our
institution approved the study, and written informed
consent was obtained from all patients.
PET/CT scanning was performed using a combined PET/
CT scanner (Discovery ST Elite; GE Healthcare,
Waukesha, WI, USA). This system integrates a PET scanner with
multidetector-row CT (16 detectors) and permits
acquisition of co-registered CT and PET images during a single
examination. For DOTATOC-PET/CT scanning,
approximately 130 MBq of 68Ga-DOTATOC was injected
intravenously, and whole-body PET/CT scanning was
performed approximately 60 min after injection. Just
before the PET/CT scanning, patients were requested to void
the bladder. Initially, starting at the level of the thigh, the
low-dose CT scans were acquired during shallow
breathing, and scanning included the area from the upper thigh to
the skull. Immediately after CT, a PET emission scan was
acquired with an acquisition time of 3 min per bed
position. For one patient in group A and two patients in group
C, diagnostic CT scans were also performed 30 and 90 s
after intravenous administration of 100 mL iopromide
(Iopamiron 300; Nihon Beyer, Osaka, Japan) with an
injection rate of 3 mL/s. The total acquisition time was
20–30 min. Unenhanced CT data were used for attenuation
correction, and images were reconstructed using a
commercial three-dimensional iterative reconstruction
algorithm called VUE Point Plus (matrix 128 9 128, interval
3.27 mm, 2 iterations, 14 subsets).
PET/CT images were interpreted visually by at least two
board-certified radiologists/nuclear medicine physicians
based on consensus. Focal moderate-to-intense uptake was
regarded as abnormal, but accumulations of DOTATOC in
some organs (e.g., pituitary gland, adrenal gland, accessory
spleen) that were considered physiological [
excluded. As a quantitative analysis, standardized uptake
values (SUVs) were calculated for each lesion if patients
had abnormal foci, but quantitative values were not used
for diagnostic criteria in this investigation. The findings
were compared with the final diagnoses obtained by
histopathological confirmation or clinical follow-up for at
least 6 months.
mets. metastasis, ACTH adrenocorticotropic hormone, 5-HIAA 5-hydroxyindoleacetic acid, Hx
histopathology, f/u follow-up
a Lesion diameter was measured on PET images when not clearly depicted by morphological modalities
b Prostatic cancer was suspected, but biopsy demonstrated benign prostatic hypertrophy
c A neuroendocrine tumor in the rectum was confirmed by endoscopic biopsy, but no uptake was observed
Patients’ profiles and PET/CT findings are summarized in
There were 14 patients who had been suspected of having a
primary NET because of pathologically proven liver
metastasis (n = 9), nodal metastasis (n = 3), or bone
metastasis (n = 2). In four of nine patients with metastatic
liver tumors, DOTATOC-PET/CT demonstrated positive
findings, such as a suspected primary tumor in the
duodenum (n = 2), jejunum (n = 1), and pancreatic tail (n = 1)
with the maximum SUV (SUVmax) ranging from 2.8 to
19.7. One case in which a duodenal submucosal tumor was
confirmed to be a primary NET is shown in Fig. 1.
DOTATOC-PET/CT showed no abnormal findings for the
remaining five patients. In three patients with nodal
metastasis, DOTATOC-PET/CT revealed abnormal uptake
in the duodenum (n = 1) and jejunum (n = 2). For two
patients with bone metastasis, DOTATOC-PET/CT was
negative in one patient but showed intense focal uptake in
the prostate, suggesting prostatic cancer. In the other
patient, the uptake was confirmed by biopsy to be due to
benign prostatic hypertrophy. The primary site remained
unknown. Thus, a final diagnosis of a
gastroenteropancreatic NET was obtained in 7 of 14 patients (50 %)
histopathologically (n = 3) and clinically (n = 4).
Seven patients in group B underwent surgery for a NET.
They had undergone DOTATOC-PET/CT. Except for one
patient with a high insulin level, DOTATOC-PET/CT
depicted 10 lesions in six patients (seven nodal metastases in
five patients, three liver metastases in one patient). The
SUVmax of these lesions ranged from 7.9 to 70.1. Two
patients had histopathological confirmation after surgery,
whereas the remaining four patients were under follow-up
with no surgical treatment. Thus, DOTATOC-PET/CT
provided additional information in six of seven patients
(86 %). A representative case of nodal metastasis is shown
in Fig. 2.
A total of 25 patients who had been suspected of having
NETs underwent DOTATOC-PET/CT. One patient with
suspected ACTH-producing tumors underwent
DOTATOC-PET/CT, which identified a pancreatic NET with
SUVmax of 68.5 (Fig. 3), followed by surgical
confirmation. For the remaining 24 patients, DOTATOC-PET/CT
did not provide any clinically relevant additional
information. The detection rate was significantly lower than in
other groups (Fisher’s exact test, p \ 0.01).
the patient’s serum gastrin level increased, but recurrence had not
been identified on CT. Focal intense DOTATOC uptake corresponds
to a subcentimeter node (arrows), which was confirmed as a nodal
metastasis during surgery
We demonstrated the clinical usefulness of
68Ga-DOTATOC-PET/CT when a primary or metastatic lesion had
been suspected, according to three situations. Additional
information would be expected especially when hormone
levels are high after surgery for histologically proven
NETs, as is often the case with FDG-PET/CT being
performed for restaging FDG-avid tumors. Its clinical value
was limited, however, when hormone levels were high in
patients without a history of NETs. According to
], the diagnostic performance of
DOTATOC-PET/CT has been excellent, but it is thought to be
influenced by clinical scenarios in which DOTATOC-PET/
CT scans are performed.
Articles have been published that are limited to cases in
which NETs had been confirmed histopathologically
without identifying a primary tumor (corresponding to our
group A) [
]. Prasad et al.  reported that
DOTANOCPET/CT identified the primary tumor in 35 of 59 patients
(59 %) with documented NETs but an unknown primary.
In their report, the primary sites were mainly in the
pancreas (n = 16), followed by the small intestine (n = 14).
Naswa et al. [
] demonstrated that DOTANOC-PET/CT
found 12 of 20 primary tumors (60 %) in NET patients
with unknown primary tumors. The primary sites were
mainly in the midgut (four in the duodenum, four in the
ileum, one in the colon). In our series, DOTATOC-PET/CT
revealed primary sites in half of the patients, which is
similar to the data from previous reports. Regarding
detected primary sites, our findings were consistent with the
results by Naswa et al. Pancreatic lesions were well
evaluated by contrast-enhanced CT and magnetic
resonance imaging at our institution. Therefore, it was a small
number of cases in which the primary sites were located in
the pancreas in this investigation.
One male patient had a bone metastasis from a NET,
which was confirmed histopathologically. Prostatic cancer
was suspected as the primary tumor because of intense
uptake in the prostate gland on DOTATOC-PET/CT.
Histopathological evaluation of biopsy tissue, however, did
not confirm a prostatic cancer. It may be because of a
sampling error, but DOTATOC accumulation in the
prostate was extensive, and eight specimens were acquired,
covering almost the entire prostate. This case was therefore
regarded as giving false-positive results. It is known that
somatostatin receptors are expressed not only in normal
prostate glands, but also in the presence of prostatic cancer
or prostatic hypertrophy [
]. It is thought that
accumulation in the prostate would be a pitfall when
interpreting DOTATOC-PET/CT images.
DOTATOC-PET/CT was useful when hormone levels
were high after surgery was undertaken for NETs. This
situation is similar to that of cases in which FDG-PET was
conducted because of suspected recurrence or metastasis
after surgery with a high level of tumor markers. As the
pretest probability is high and other imaging modalities
(e.g., conventional CT or FDG-PET/CT) are negative, it is
pancreatic tail (arrow), suggesting a pancreatic NET that had not been
identified by unenhanced CT. Surgery was performed, supplying
pathological confirmation of NET G2
reasonable that DOTATOC-PET/CT would be expected to
yield relevant information. As demonstrated in Fig. 2, a
subcentimeter node can be detected by CT, but it is difficult
to distinguish it from a benign inflammatory node. In
addition, NET tumors usually grow slowly. The high
accumulation of DOTATOC in a subcentimeter node is helpful
for detecting a local recurrence or metastasis after NET
On the other hand, without a history of NET,
DOTATOC-PET/CT might not provide helpful information
simply because hormone levels are high. Some reasons can be
considered. First, primary sites may be too small to be
detected by morphologic imaging modalities. If lesions are
extremely small, uptake tends to be underestimated
because of a partial volume effect with PET. Also, when the
primary site is in the upper abdomen or alimentary tract,
the uptake could be easily influenced by respiratory motion
and peristalsis. Second, it is not guaranteed that there is a
primary site because hyperfunctioning can cause high
hormone levels (e.g., nesidioblastosis in suspected with an
insulinoma or G-cell hyperplasia with a suspected
gastrinoma). In addition, it has been reported that somatostatin
receptor subtypes 2 and 5 are not well expressed in many
]. Thus, DOTATOC-PET/CT may have
failed to depict the primary tumor.
One patient had been suspected of having an
ACTHproducing tumor. Before DOTATOC-PET/CT scanning,
the patient had undergone unenhanced CT, but enhanced
CT performed after DOTATOC-PET/CT revealed a tumor
in the pancreatic tail. Therefore, DOTATOC-PET/CT may
be useful in such patients with high hormone levels if
enhanced CT cannot be performed for some reason, including
There are some limitations in this investigation. First,
the sample size is small. Also, histopathological
confirmation was not obtained in all cases, so there may have
been some false-positive cases despite the fact that
DOTATOC-PET/CT provided additional information. It is
not ethically acceptable to acquire histopathologic
confirmation of every lesion. Because this study was
retrospective, the imaging modalities before DOTATOC-PET/CT
became available were varied. For this reason, there may
be selection bias in our population. The scan times ranged
from 57 to 82 min (average 65 min) after injection of
68GaDOTATOC. Based on the procedure guidelines, these scan
times are considered normal after tracer administration
], but the most optimal scanning time remains unknown.
A different scanning time may alter the results.
Our data indicate that DOTATOC-PET/CT provided
additional useful information, especially when recurrence or
metastases were suspected because of high hormone levels
after surgery for a primary NET. It did not yield any
relevant information, however, in cases in which only the
hormone levels were high.
Acknowledgments We are grateful for support from a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan (25461816).
Conflict of interest There are no potential conflicts of interest
relevant to this article.
1. Tagliabue L , Del Sole A . Appropriate use of positron emission tomography with [(18)F]fluorodeoxyglucose for staging of oncology patients . Eur J Intern Med . 2014 ; 25 : 6 - 11 .
2. Rambaldi PF , Cuccurullo V , Briganti V , Mansi L . The present and future role of (111)In pentetreotide in the PET era . Q J Nucl Med Mol Imaging . 2005 ; 49 : 225 - 35 .
3. Ambrosini V , Fani M , Fanti S , Forrer F , Maecke HR . Radiopeptide imaging and therapy in Europe . J Nucl Med . 2011 ; 52 ( Suppl 2 ): 42S - 55S .
4. Gabriel M , Decristoforo C , Kendler D , Dobrozemsky G , Heute D , Uprimny C , et al. 68 Ga-DOTA- Tyr3 -octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT . J Nucl Med . 2007 ; 48 : 508 - 18 .
5. Poeppel TD , Binse I , Petersenn S , Lahner H , Schott M , Antoch G , et al. 68 Ga-DOTATOC versus 68 Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors . J Nucl Med . 2011 ; 52 : 1864 - 7 .
6. Yang J , Kan Y , Ge BH , Yuan L , Li C , Zhao W . Diagnostic role of Gallium-68 DOTATOC and Gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis . Acta Radiol . 2014 ; 55 : 389 - 98 .
7. Buchmann I , Henze M , Engelbrecht S , Eisenhut M , Runz A , Scha¨fer M, et al. Comparison of 68 Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours . Eur J Nucl Med Mol Imaging . 2007 ; 34 : 1617 - 26 .
8. Prasad V , Ambrosini V , Hommann M , Hoersch D , Fanti S , Baum RP . Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTA-NOC receptor PET/CT . Eur J Nucl Med Mol Imaging . 2010 ; 37 : 67 - 77 .
9. Naswa N , Sharma P , Kumar A , Soundararajan R , Kumar R , Malhotra A , et al. 68Ga-DOTANOC PET/CT in patients with carcinoma of unknown primary of neuroendocrine origin . Clin Nucl Med . 2012 ; 37 : 245 - 51 .
10. Kubota K , Okasaki M , Minamimoto R , Miyata Y , Morooka M , Nakajima K , et al. Lesion-based analysis of (18)F-FDG uptake and (111)In-Pentetreotide uptake by neuroendocrine tumors . Ann Nucl Med . 2014 ; 28 : 1004 - 10 .
11. Ito T , Sasano H , Tanaka M , Osamura RY , Sasaki I , Kimura W , et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan . J Gastroenterol . 2010 ; 45 : 234 - 43 .
12. Kroiss A , Putzer D , Decristoforo C , Uprimny C , Warwitz B , Nilica B , et al. 68 Ga-DOTA-TOC uptake in neuroendocrine tumour and healthy tissue: differentiation of physiological uptake and pathological processes in PET/CT . Eur J Nucl Med Mol Imaging . 2013 ; 40 : 514 - 23 .
13. Treglia G , Castaldi P , Rindi G , Giordano A , Rufini V. Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/ CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis . Endocrine . 2012 ; 42 : 80 - 7 .
14. Geijer H , Breimer LH . Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and metaanalysis . Eur J Nucl Med Mol Imaging . 2013 ; 40 : 1770 - 80 .
15. Reubi JC , Waser B , Schaer JC , Markwalder R . Somatostatin receptors in human prostate and prostate cancer . J Clin Endocrinol Metab . 1995 ; 80 : 2806 - 14 .
16. Hansson J , Bjartell A , Gadaleanu V , Dizeyi N , Abrahamsson PA . Expression of somatostatin receptor subtypes 2 and 4 in human benign prostatic hyperplasia and prostatic cancer . Prostate . 2002 ; 53 : 50 - 9 .
17. Portela-Gomes GM , Stridsberg M , Grimelius L , Rorstad O , Janson ET . Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomaspredominance of receptor subtype 4 . Endocr Pathol . 2007 ; 18 : 79 - 85 .
18. Virgolini I , Ambrosini V , Bomanji JB , Baum RP , Fanti S , Gabriel M , et al. Procedure guidelines for PET/CT tumour imaging with 68 Ga-DOTA-conjugated peptides: 68 Ga-DOTA-TOC, 68 GaDOTA-NOC, 68 Ga-DOTA-TATE . Eur J Nucl Med Mol Imaging . 2010 ; 37 : 2004 - 10 .