Original article

Tc‑Hynic‑TOC imaging in the diagnostic of

 99m

neuroendocrine tumors
ABSTRACT
The aim of this study was to assess the potential of 99mTc‑Hynic‑TOC imaging in the primary diagnosis and follow‑up of midgut neuroendocrine
tumors (NETs). In comparison to 111In‑octreotide, 99mTc‑Hynic‑TOC has a higher imaging quality and leads to a lower radiation absorption
in patients. 99mTc‑Hynic‑TOC was used for assessing primary diagnosis (n = 14) and during follow‑up (n = 17) in patients with NETs. The
scintigraphic findings were compared with computed tomography scans and follow‑up. In 31 patients, 34 somatostatin receptor scans using
99mTc-Hynic-TOC were performed. The primary diagnoses were midgut NET. The scintigraphy was true positive in 17 patients, true negative
in 9, false negative in 4, and false positive in 1. From these data, a sensitivity of 81%, specificity of 90%, positive predictive value of 94%, and
negative predictive value of 69% were calculated. In summary, 99mTc‑TOC represents a useful radiotracer in imaging SSTR‑expressing tumor
lesions with slightly higher sensitivity, higher imaging quality, and lower radiation exposure for patients compared to 111In‑octreotide. A 1‑day
double‑acquisition protocol should be used to reduce false‑positive findings of the gut.

Keywords: 99mTc‑Hynic‑TOC imaging, neuroendocrine tumor, octreotide, somatostatin receptor

INTRODUCTION were randomized in a therapeutic group (n = 116) which

had a dose of 7.4 GBq every 8 weeks (four intravenous (IV)
Gastroenteropancreatic neuroendocrine tumors (GEP‑NETs) infusion) plus long‑acting octreotide (LAR) and in a control
are a rare disease. As with all NETs, they derive from group which had only LAR intramuscular application.
ectodermal cells of the diffuse endocrine system. The The response rate was 18% in the 177Lu‑DOTATATE group
majority of these tumors are hormonally inactive and they are versus 3% in the control group (P < 0.001). In the planned
usually diagnosed at an advanced stage as comparatively large interim analysis, 14 deaths occurred in the 177Lu‑DOTATATE
tumor masses with distant metastases, as their clinical impact group and 26 in the control group (P = 0.004).[3] In the
is often less impressive as with other tumor entities of the IEO Milan trial (1997–2013), 793 patients were included
pancreas.[1] The cumulative 5‑year survival rate is over 50% for in the study. Different application protocols were used:
the nonmetastasized stages and drops to roughly one‑fourth 278 patients received 177Lu‑octreotate (34.4%), 358 patients
in the presence of liver metastases. The incidence in Western 90
Y‑octreotide (44.4%), and 157 patients a combination of
countries is estimated around 1/100,000 with the majority of 177
Lu‑octreotate plus 90Y‑octreotide (19.5%), respectively.
cases diagnosed between 50 and 80 years of age.[2]
Knut Liepe, Andreas Becker1
Overexpression of cell surface somatostatin receptor Departments of Nuclear Medicine and 1Internal Medicine
(SSRs) in well‑differentiated NETs can be exploited for Gastroenterology, Klinikum Frankfurt (Oder), 15236
imaging and therapy with radiolabeled somatostatin Frankfurt (Oder), Germany
analogs. A Phase III trial investigated the therapeutic effect
Address for correspondence: Dr. Knut Liepe,
of 177Lu‑DOTATATE administration in 229 patients with Department of Nuclear Medicine, Klinikum Frankfurt (Oder),
well‑differentiated, metastatic midgut NETs. The patients Müllroser Chaussee 7, 15236 Frankfurt (Oder), Germany.
E‑mail: knut.liepe@klinikumffo.de

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DOI:
10.4103/wjnm.WJNM_41_17 How to cite this article: Liepe K, Becker A. 99mTc-Hynic-TOC imaging in
the diagnostic of neuroendocrine tumors. World J Nucl Med 2018;17:151-6.

© 2018 World Journal of Nuclear Medicine | Published by Wolters Kluwer ‑ Medknow 151

 Liepe and Becker: Tc‑Hynic‑TOC imaging
99m

Nephrotoxicity is an important side effect of peptide Germany). For the whole‑body studies and single‑photon
receptor radionuclide therapy (PRRT). The data analysis emission computed tomography (SPECT), the camera was
showed acute nephrotoxicity in 279 patients (34.6%), and in equipped with a low‑energy high‑resolution parallel‑hole
197 patients (24.3%), the impairment of renal function was collimator, window setting 140 keV, width 10%. Whole‑body
persistent. 90Y treatment was associated with significantly scintigrams were obtained at 1 and 4 h after administration
higher rates of nephrotoxicity (43.9%) and persistent renal of the radiopharmaceutical with SPECT following the 4 h
impairment (33.6%) compared to 177Lu treatment (25.5% and whole‑body scan in each patient.
13.4%; P < 0.001).[4]
Imaging and data analysis
Essential for PRRT is a pretherapeutic imaging of the The observer of the scans was blinded and had no information
somatostatin receptor (SSTR, especially the SSTR2. about the primary diagnosis of results of other diagnostic
Since 1992, 111In‑[DTPA‑D‑Phe1]‑octreotide was used for modalities. All the patients were diagnosed by the same
SSTR scintigraphy, and the most data are available for reader. Any focal tracer uptake exceeding physiological
this radiopharmaceutical.[5,6] Unfortunately, the physical uptake was regarded as a pathologic finding. Linear, nonfocal
characteristics of 111In are not optimal for gamma camera slight increase uptake of the intestine was also stated
imaging. Optimal methods for diagnosis of GEP‑NETs are as a physiological uptake. Of 23 patients, 22 underwent
68
Ga‑DOTATATE positron emission tomography/computed a previous CT and another one patient had a magnetic
tomography (CT)[7,8] or 64Cu‑DOTATATE.[9] Unfortunately, resonance imaging (MRI) of the abdomen within 1 month
a 68Ge/68Ga generator for the labeling of 68Ga‑DOTATATE before 99mTc‑TOC scan. In addition, in 3 patients ultrasounds
or DOTATOC is very expensive and so the availability of of the abdomen and in 4 MRI of the brain were performed.
a 99mTc‑labeled SSTR analogs allows a wide use of SSTR The clinical follow‑up was at least 2 years after first 99mTc‑TOC
scintigraphy with good imaging quality.[8,10] scan.

In this study, the diagnostic accuracy of 99m

Tc‑Hynic‑TOC Whole‑body scans and SPECT images were classified
(Tectrotyd©) was investigated. as true positive (correlation between other diagnostic
modalities with sign of tumor, clinical findings, and follow‑up
PATIENTS AND METHODS which evidence the positive finding in 99mTc‑TOC), true
negative (no pathologic finding in 99mTc‑TOC and negative
Patients finding in diagnostic modalities and no sign of tumor in
Octreotide scintigraphy was used during normal clinical the follow‑up), false positive (sign of tumor in 99mTc‑TOC
routine. All patients gave their informed consent for scan, but negative findings in other diagnostic modalities;
somatostatin receptor scintigraphy. In 31 patients, 34 no sign of tumor in follow‑up), and false negative according
somatostatin receptor scans using 99mTc‑Hynic‑TOC were to histopathology (primary diagnosis) or other diagnostic
performed. The primary diagnosis was GEP‑NET in all modalities (CT, MRI) in follow‑up. From this data analysis,
patients. 99mTc‑Hynic‑octreotide scintigraphy was performed the sensitivity, specificity, negative predictive value (NPV),
in 13 cases for primary staging and in 18 cases during a and positive predictive value (PPV) of 99mTc‑TOC scan were
follow‑up imaging. calculated.[11]

Radiopharmaceuticals and imaging RESULTS

99m
Tc‑Hynic‑TOC was used as a commercial kit (Rotop, Rossendorf,
Germany). For labeling the sodium pertechnetate‑99mTc The primary tumor was detected correctly with 99mTc‑TOC in
solution for injection, it should be obtained up to hours 6 cases (small bowel in 2 cases, pancreas in 3 cases, and 1
before the start of labeling. The radioactivity ≤2.2 GBq was within the rectum). In 4 symptomatic patients with suspicion
injected at a maximum volume of 1 ml into the vial with of a NET, the findings were correctly negative, and in the 2‑year
Hynic‑[D‑Phe1, Tyr3‑Octreotide] (Tectrotyd©) (99mTc‑TOC). The follow‑up, the signs for tumor presence could be evaluated. In
solution should be placed in a water bath or within a heated 11 cases, the metastases were correctly visualized (liver tumor
block with a temperature of 80°C for 20 min, maintaining in 7, soft tissue of abdomen in 3 and one in lung). Four tumor
the vial in an upright position. Each patient received the sites of primary or recurrent tumors were detected by SPECT
radiopharmaceutical at an average activity of 728 ± 25 MBq IV. but were missed in the whole‑body scan.

Whole‑body imaging was performed using a double‑headed In summary, the scans were true positive in 17 patients
camera (Discovery NM630, GE Healthcare, Solingen, (6 in primary disease and 11 in recurrent disease), true
152 World Journal of Nuclear Medicine / Volume 17 / Issue 3 / July-September 2018
 Liepe and Becker: 99m
Tc‑Hynic‑TOC imaging

negative in 9 (4 in primary disease and 5 in recurrent disease), 99m

Tc‑labeled somatostatin analogs to improve availability
false negative in 4 (3 in primary disease and 1 in recurrent and imaging quality of SSTR scintigraphy as well as to
disease), and 1 false positive (in recurrent disease). From reduce the radiation burden of patients.[10,11] 99mTc‑[HYNIC,
these data, a sensitivity of 73%, specificity of 88%, PPV of Tyr(3)]octreotide (99mTc‑TOC) and 99mTc‑[HYNIC, Tyr(3), Thr(8)]
92%, and NPV of 54% were calculated. In subgroup analysis of octreotide (99mTc‑TATE) were two interesting candidates
patients with primary staging, the sensitivity was lower with designated to replace the indium‑labeled octreotide in SSTR
67% compared to a sensitivity of 92% for using of 99mTc‑TOC imaging. Cwikla et  al.[15] published data on the uptake of
in the follow‑up. both radiopharmaceuticals in 12 patients with proven NETs.
A slightly higher number of SSTR‑expressing lesions was
The patient with a false‑positive finding had a GEP‑NET documented, especially in lymph nodes using 99mTc‑TATE.
within the pancreas. After surgery in 2005, the chromogranin However, only 99mTc‑TOC is commercially available and most
A value was persistently elevated. With respect to the data are published about this 99mTc‑labeled SSTR analog. In
elevated chromogranin A levels, 99mTc‑TOC scans were 2000, Bangard et al.[16] compared 111In‑octreotide and 99mTc‑TOC
performed in 2015 and 2016. Both imagings showed the and found a superior capability of 99mTc‑TOC as well to visualize
same lung lesion in the right upper lung lobe. The previous extrahepatic lesions. The authors stated that 99mTc‑TOC
scan using 111In‑octreotide in 2006 had shown the same has a favorable clinical characteristic in the detection of
lesion. However, over the whole period, the CT was negative SSTR‑positive tumors due to specific and high receptor affinity,
in this area and the chromogranin A levels showed no further good biodistribution, faster renal excretion, lower radiation
rise [Figure 1]. exposure, high imaging quality, and on‑demand availability.

DISCUSSION In the present study, a 1‑day acquisition protocol was used

with a double acquisition at 1 and 4 h after administration of
Somatostatin (SSTR) scintigraphy using 111In‑octreotide is an 99m
Tc‑TOC. This differs from protocols of other groups where
established diagnostic modality in the imaging of different 1‑day single‑acquisition protocols resorted to imaging at 2[17]
SSTR‑expressing tumors. [10,12‑14] However, the physical or 4 h after injection.[11,18] However, the double acquisition
characteristics of 111In are not optimal and 111In‑octreotide is can reduce the risk of false findings in the gut by avoiding
relative expensive. Several researchers have tried to develop the misinterpretation of physiological uptake.

a b

c d

e f

Figure 1: patient with false‑positive finding in 99mTc‑TOC and also in 111In‑octreoscan; (a and b) 99mTc‑TOC scan in 2015 with positive lesion in the right
upper lung; (c and d) 99mTc‑TOC scan in 2016 with the same lesion; (e) 111In‑octreoscan in 2006 with same lesion as in the first 99mTc‑TOC; and (f) computed
tomography chest in 2016 with no pathologic finding as correlate to the positive lesion in 99mTc‑TOC

World Journal of Nuclear Medicine / Volume 17 / Issue 3 / July-September 2018 153

 Liepe and Becker: 99m
Tc‑Hynic‑TOC imaging

In different papers,[15‑19] the accuracy of 99mTc‑TOC in GEP‑NETs the uncinate process of the pancreas, mimicking malignancy
was documented, for example, Chrapko et al.[20] showed the in 20% of the investigated patients. However, this was a
usefulness of 99mTc‑TOC in 117 NET patients, especially in single report, and we did not observe any patients with
primary diagnosis and restaging after primary tumor surgery. false‑positive uptake of 99mTc‑TOC in this area.
Another group[17] investigated the usefulness of 99mTc‑TOC
scans in solitary pulmonary nodules (SPNs) (n = 84). Positive Artiko et  al. [19] published preliminary results from a
scintigraphic results were found in 37 of 40 (93%) patients multicenter trial that included 495 patients with different
with malignant SPNs including 34 of 35 (97%) patients with NETs. There were 334 true positive, 73 true negative, 6 false
primary lung carcinoma. Two remaining false‑negative cases positive, and 82 false‑negative results. The authors calculated
turned out to be metastatic lesions of malignant melanoma a sensitivity of 80%, specificity of 92%, PPV of 98%, NPV of
and leiomyosarcoma. Among 45 benign tumors, negative 47, and accuracy of 82%. Unfortunately, the paper included
results were obtained in 31 cases (69%) and positive results different NETs such as medullary thyroid carcinomas (48),
in 14. False‑positive findings were in 6 cases by inflammatory lung (50), mediastinal (12), ovarian (6), kidney (4), hypophysis
lesion, 3 by tuberculosis, 3 by hamartomas, and 2 by unknown (10), brain (5), breast (7), paraganglioma (12), parathyroid (1),
etiology. The authors calculated an accuracy of the method pheochromocytoma (7), NET of unknown origin (95),
of 80%. Another study[10] included 88 patients with GETNEPs. pancreatic (97), gastric (32), colorectal (21), small bowel (71),
They reported true‑positive findings in 56 patients, true carcinoid of appendix (10), and liver (7).
negative in 17, false negative in 14, and false positive in 1.
The false‑positive finding was caused by a colonic adenoma. Patients with SSTR‑positive lesions are potential candidates
The authors calculated a 99mTc‑TOC scan sensitivity of 80%, for therapy with radiolabeled PRRT. One monocentric
specificity of 95%, and accuracy of 83%. These data are retrospective study from Bad Berka [22] examined the
comparable with the results of our study with a sensitivity effectiveness of PRRT labeled with Lutetium‑177 and
of 73%, specificity of 88%, PPV of 92%, and NPV of 54%. In our Yttrium‑90. In a total of 450 patients, a high effectiveness of
study, we also found one false‑positive patient. However, PRRT for patients with low‑to‑intermediate neuroendocrine
the exact cause of the false‑positive signal in the patient’s neoplasms with minor adverse effects was shown, with a
lung could not be solved over a 10‑year period where the complete remission in 5.6% of patients, a partial response
finding was constant and thus was left without resection in 22.4%, and stable disease in 47.3%. One of the patients
and treatment. Physiologic uptake in the uncinate process in our study also had two cycles of Lutetium‑177‑DOTATOC
of the pancreas can also mimic a (false) positive finding in with a partial response [Figures 2 and 3]. A follow‑up using
SSTR scans. Yamaga et al.[21] presented  a focal uptake within 99m
Tc‑TOC was not performed.

Figure 2: Male patient; 64 years; neuroendocrine tumor of pancreas, after surgery of pancreas splenectomy two years ago; actual multiple liver metastases
and in the area of pancreas. Whole body imaging one and four hours after 736 MBq of 99mTc –TOC is shown. The tumor lesions showed a high target to
background ratio indicating a high SSTR receptor expression. In the follow-up this patient had two cycles of Lutetium DOTATOC therapy with partial response
and without severe side-effects

154 World Journal of Nuclear Medicine / Volume 17 / Issue 3 / July-September 2018

 Liepe and Becker: Tc‑Hynic‑TOC imaging
99m

Figure 3: The single‑photon emission computed tomography imaging using 736 MBq of 99mTc‑TOC in the same patients as in Figure 2

Unfortunately, only limited data on kinetics and dosimetry given his/her/their consent for his/her/their images and other
are available. Grimes et al.[23] observed the uptake in critically clinical information to be reported in the journal. The patients
normal organs for radiation exposure (kidney, liver, and spleen) understand that their names and initials will not be published
in 28 patients. The maximum uptake in the kidney occurred and due efforts will be made to conceal their identity, but
after 5–10 min, followed by the washout phase. In the liver, anonymity cannot be guaranteed.
maximum uptake occurred in <5 min, followed by a rapid
washout. Uptake in the spleen was slower. From these data, Financial support and sponsorship
an effective half‑life of 5.3 h and biological half‑life of 47.9 h in Nil.
tumor lesions were calculated with similar effective half‑life/
biological half‑life of 5.4 h/51.5 h for kidney, 5.4 h/51.0 h for Conflicts of interest
liver, 5.3 h/57.9 h for spleen, and 4.6 h/19.7 h for thyroid, There are no conflicts of interest.
respectively. The relative absorbed doses of 0.021 ± 0.007
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