Original article
Comparison of 68Ga-DOTATATE PET-CT, 18F-FDG PET-CT and 99m Tc-(V)DMSA scintigraphy in the detection of recurrent or metastatic medullary thyroid carcinoma Zeynep G. Ozkana, Serkan Kuyumcua, Ayse Kubat Uzumb, Mehmet F. Gecera, Sevda Ozelc, Ferihan Aralb and Isik Adaleta Purpose We aimed to compare the efficacies of gallium-68 (68Ga) DOTATATE PET-computed tomography (CT), fluorine18 fluorodeoxyglucose (18F-FDG) PET-CT and technetium99m (99mTc)-(V)DMSA scintigraphy in the detection of residual/metastatic medullary thyroid carcinoma (MTC). Materials and method We retrospectively evaluated DOTATATE PET-CT, 18F-FDG PET-CT and (V)DMSA scintigraphy of 22 MTC patients, all taken within a 6-month period in each patient, because of high levels of calcitonin (Ct) and carcinoembryonic antigen (CEA). We investigated the relationships between the results of the imaging modalities and tumour marker levels and the sporadic versus hereditary nature of the disease, as well as the effect of imaging results on patient management. Results The ages of the patients at diagnosis were between 20 and 69 years. The median levels of Ct and CEA were 871.5 pg/ml and 11.2 ng/ml, respectively. In the patient-based analysis, we observed at least one focus of abnormal uptake in 15 of 22 DOTATATE PET-CT (68.2% sensitivity), eight of 18 18F-FDG PET-CT (44.4% sensitivity) and five of 15 (V)DMSA scans (33.3% sensitivity). These data showed a significant difference between DOTATATE PET-CT and (V)DMSA scintigraphy (P = 0.016), whereas the relationships between DOTATATE PET-CT and 18F-FDG PET-CT and between 18F-FDG PET-CT and (V)DMSA
Introduction Medullary thyroid carcinoma (MTC) is a rare disease that represents ∼ 10% of all thyroid malignant neoplasms [1]. One-fifth to one-fourth of these carcinomas are hereditary and belong to three syndromes: familial MTC, multiple endocrine neoplasia (MEN) type 2A and MEN type 2B [2]. As a result of its low incidence, broad clinical experience and definitive randomized clinical trials are limited [3]. All of the patients diagnosed with MTC should undergo total thyroidectomy and central lymph node (LN) dissection because LN involvement is the most common way of spreading [1–3]. After this first therapeutic approach, the American Thyroid Association (ATA) management guidelines for MTC recommend basal measurement of calcitonin (Ct) and carcinoembryonic antigen (CEA), which are two tumour markers that are 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
scintigraphy showed no significant differences (P > 0.05). In the lesion-based analysis, 134 lesions were detected with DOTATATE PET-CT, 76 lesions with 18F-FDG PET-CT and nine lesions with (V)DMSA scintigraphy. Conclusion DOTATATE PET-CT is an efficient imaging modality in MTC patients with increased Ct and CEA (especially > 1000 pg/ml and 50 ng/ml, respectively) for localizing recurrent or metastatic disease. 18F-FDG PET-CT can be performed if DOTATATE PET-CT is not available, but (V)DMSA scintigraphy is not recommended. Nucl Med Commun 36:242–250 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nuclear Medicine Communications 2015, 36:242–250 Keywords: calcitonin, carcinoembryonic antigen, 18F-FDG PET-CT, Ga DOTATATE PET-CT, medullary thyroid carcinoma, 99m Tc-(V)DMSA scintigraphy 68
Departments of aNuclear Medicine, bInternal Medicine, Endocrinology and Metabolism Division and cDepartment of Biostatistics and Medical Informatics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Correspondence to Zeynep Gozde Ozkan, MD, Nuclear Medicine Department, Istanbul Medical Faculty, Istanbul University, Istanbul 34390, Turkey Tel: + 90 212 414 2000/35085; fax: + 90 212 414 2056; e-mail: [email protected] Received 10 June 2014 Revised 1 October 2014 Accepted 2 October 2014
used during follow-up of the patients. Whereas undetectable Ct is correlated with long survival, high tumour marker levels require further workup for the detection of disease spread [3]. Unfortunately, no specific imaging modality can demonstrate disease burden definitively. In addition to radiological modalities, many radiopharmaceuticals have been used in nuclear medicine in MTC patients, such as technetium99m (99mTc)-labelled pentavalent dimercaptosuccinic acid ((V)DMSA), 99mTc-sestamethoxyisobutylisonitrile (MIBI), iodine-131/123 (131I/123I) metaiodobenzylguanidine (MIBG) and thallium-201 (201Tl). Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomographycomputed tomography (PET-CT) has also been used frequently in this patient group. MTC, a neuroendocrine tumour, contains somatostatin receptor type 2 (SSR2). Therefore, indium-111 (111In) DOI: 10.1097/MNM.0000000000000240
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Scintigraphy in medullary thyroid carcinoma Ozkan et al. 243
octreotide (Oct) can also be used in MTC patients. Oct scintigraphy has a wide range of sensitivity values (14–78.5%) [4–7]. In recent years, gallium-68 (68Ga)-labelled somatostatin analogues such as tetraazacyclododecane tetraacetic acid-octreotate (DOTATATE), which is a novel radiopharmaceutical that is produced in-house, has also been used in PET-CT cameras under the same conditions as Oct in MTC patients. Both because of the high affinity of DOTATATE for SSR2 and because of the advantages of PET over SPECT imaging, DOTATATE PET-CT overrides Oct scintigraphy in MTC patients. Many studies have compared the efficacies of different radiopharmaceuticals in MTC patients [4,7–15], but none has compared (V)DMSA scintigraphy, which is a conventional imaging agent for MTC, with 18F-FDG PETCT, which is now frequently used in MTC patients, or with DOTATATE PET-CT, which is one of the newest radiopharmaceuticals used in this patient group. In this article, we aimed to compare the efficacies of DOTATATE PET-CT, 18F-FDG PET-CT and (V) DMSA whole-body scintigraphy for the detection of residual or metastatic MTC. We evaluated the relationships between these modalities and tumour markers and investigated their effects on patient management.
Materials and methods Patients
This retrospective study included 22 MTC patients (11 female, 11 male) with high Ct, each of whom underwent DOTATATE PET-CT and most of whom underwent FDG PET-CT and (V)DMSA whole-body scans. In each patient, all scans were taken within a 6-month period between April 2011 and February 2013 to detect recurrences or metastases of MTC. Between these imagings, the patients were given no treatments. The study was approved by the local ethics committee. Informed consent was obtained from all patients before imaging. We evaluated whether they had hereditary MTC. For every patient, Ct and CEA levels at the time of scanning were noted. Preparation of radiopharmaceuticals DOTATATE labelling 68
Ga-DOTATATE was prepared in-house on a fully automated system (Eckert & Ziegler Eurotope, Berlin, Germany). Commercially available germanium-68 (68Ge)/68Ga generator (IGG100; Eckert & Ziegler Eurotope) was eluted with 0.1 mol/l hydrochloric acid. Effluent containing the 68Ga fraction was passed through a cationic exchange column (Strata-X-C-cartridge) to concentrate and purify the 68Ga from residual traces of 68 Ge coming from the generator. The 68Ga was then eluted with 0.02 mol/l hydrochloric acid and 98% acetone into the reaction vial. Next, 0.2 mol/l sodium acetate buffer solution and 40 μg DOTATATE (ABX, Rodeberg,
Germany), dissolved in 0.04 ml water, were added to the vial. The reaction was carried out at 95°C for 400 s. 68Ga-DOTATATE was then purified by adsorption on a tC-18 light cartridge. The purified 68 Ga-DOTATATE was eluted with an ethanol/water solution, formulated with PBS and passed through a 0.22 μm filter directly into a sterile vial. Radiochemical purity, as determined by high-performance liquid chromatography, exceeded 95% in all cases. 18
F-FDG
This radiopharmaceutical was obtained in synthesized form (Eczacıbası, Monrol, Istanbul, Turkey). (V)DMSA preparation
(V)DMSA was prepared by adding 0.2 ml 7% sodium bicarbonate to a standard DMSA vial (Eczacıbası, Monrol) using aseptic techniques. Thereafter, 40 mCi 99mTc-pertechnetate in 2 ml was injected into the vial and incubated at room temperature for 20 min. (V)DMSA was administered to the patients within 2 h of preparation. Image acquisitions DOTATATE and 18F-FDG PET-CT
Images were obtained on a dedicated PET-CT scanner (Biograph TruePoint PET-CT; Siemens Medical Solutions Inc. Molecular Imaging, Illinois, USA) 45–60 min after intravenous injection of 3–4 mCi of 68Ga DOTATATE and 60–90 min after intravenous injection of 0.2 mCi/kg 18F-FDG. CT acquisition was performed on a spiral four-slice CT with a slice thickness of 4 mm. After the transmission scan, 3D PET acquisition was performed for 3 min per bed position for six to eight bed positions. CT-based attenuation correction of the emission images was employed. PET images were reconstructed by the iterative method ordered-subset expectation maximization (two iterations; eight subsets) with a filter size of 5 mm. After completion of PET acquisitions, the reconstructed attenuation-corrected PET images, CT images and fused images of matching pairs of PET and CT were available for review in the axial, coronal and sagittal planes and in maximumintensity projections with three-dimensional cine mode. (V)DMSA scan
Two to three hours after the injection of 15–20 mCi of 99m Tc-(V)DMSA, images were acquired using a largefield-of-view gamma camera fitted with a low-energy collimator (Siemens ECAM; Siemens Medical Solutions Inc.). Symmetrical 20% energy windows were centred over a photopeak of 144 keV. Whole-body scanning (16 cm/min; 256 × 1024 matrix) was performed 2–3 h after injection. Afterwards, planar and SPECT images were acquired from the neck–chest region for 500 000 counts using a 256 × 256 word matrix for planar images and 64 frames, a 128 × 128 matrix, 360° rotation and 30 s/frame for SPECT images. Planar and SPECT images of the
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abdomen and pelvis were acquired if necessary. Thereafter, CT acquisitions of the appropriate regions were performed on the spiral four-slice CT (CT component of Biograph TruePoint PET-CT; Siemens Medical Solutions Inc.) with a slice thickness of 4 mm. The CT images and reconstructed SPECT images were evaluated after fusion images were rendered using Siemens SYNGO software (Siemens Medical Solutions Inc.). Image analysis
All of the scans were reviewed by an experienced nuclear medicine physician. Any focus of DOTATATE, 18 F-FDG and (V)DMSA uptake superior to the background in unexpected locations was accepted as abnormally increased tracer uptake. All detected lesions were documented as LN, bone or lung. The confirmation of imaging was based on histopathological and radiological findings and clinical follow-up. Ct was measured by immunoradiometric assay. Its normal range was less than 10 pg/ml for female patients and less than 15 pg/ml for male patients. CEA was measured with electrochemiluminescence immunoassay. Its normal range was less than 5 ng/ml. Statistical analysis
Statistical analyses were performed using SPSS software version 21 (IBM Corporation, Somers, NY, USA). The relationships of the hereditary nature of MTC with age, Ct and CEA were evaluated. Numeric values that were not distributed normally were evaluated with the Mann–Whitney U-test, whereas categorical values were evaluated with Fisher’s exact test (2 × 2) with Freeman–Halton extension for 2 × 3 contingency tables. The sensitivities of DOTATATE PET-CT, 18F-FDG PET-CT and (V)DMSA scintigraphy on a per-patient basis were calculated. All of the patients in the study were regarded as positive for MTC because Ct was high in all of them. The McNemar test was used to compare these values. A P value of less than 0.05 was considered statistically significant.
Results The ages of the patients at the initial diagnosis ranged between 20 and 69 years (mean: 42.9 ± 15; median: 45.5). The follow-up period was 2–19 years (median: 5). Ct was high in all patients (range: 57.9–7370 pg/ml; median: 871.5 pg/ml). The Ct levels were categorized into three groups: 0–500, 500–1000, and greater than 1000 pg/ml; there were eight, four and 10 patients in each group, respectively. The CEA levels were between 1.9 and 613.6 ng/ml (median: 11.2 ng/ml). The CEA levels were categorized into three groups: 0–5, 5–50 and greater than 50 ng/ml, with seven, 11 and four patients in each group, respectively. MTC was sporadic in 17 patients and hereditary in five patients (MEN 2A in four patients and
MEN 2B in one patient). In three patients, the disease was restricted to the cervical region (patients 4, 8 and 15), whereas in 13 patients the disease had spread more extensively. In patients 11, 18 and 20, there were metastatic LNs in the mediastinum, along with cervical involvement. Patient 12 had isolated mediastinal LNs, whereas patient 13 had metastatic LNs in the supraclavicular, axillary and abdominal regions, along with cervical and mediastinal spread of the disease. Patient 1 had only bone metastasis, but patients 2, 3, 9, 19, 21 and 22 had bone metastases along with cervical and/or mediastinal metastatic LNs. In patient 5, there were lung metastases along with cervical and mediastinal LNs and bone metastases. The patient characteristics are summarized in Table 1. All 22 patients received DOTATATE PET-CT, 18 patients 18F-FDG PET-CT and 15 patients (V)DMSA scintigraphy. In seven patients (patients 5, 6, 14, 15, 17, 18 and 19) (V)DMSA scintigraphy and in four patients (patients 4, 17, 19 and 20) 18F-FDG PET-CT could not be performed. Scan results, numbers of lesions and lesion types detected in each modality are summarized in Table 2. In the patient-based analysis, at least one focus of abnormal uptake was observed in 15 patients on DOTATATE PET-CT (68.2% sensitivity), in eight patients on 18F-FDG PET-CT (44.4% sensitivity) and in five patients on (V)DMSA scintigraphy (33.3% sensitivity). When the sensitivity values of these modalities were compared, there was a statistically significant difference between DOTATATE PET-CT and (V)DMSA scintigraphy (P = 0.016), whereas the relationships between DOTATATE PET-CT and 18F-FDG PET-CT and between 18F-FDG PET-CT and (V)DMSA scintigraphy showed no significant differences (P > 0.05). In lesion-based analysis, when each lesion was counted separately to find the detected number of lesions with each modality, we found that 134 lesions (79 LN, 54 bone, one lung) were detected with DOTATATE PETCT, compared with 76 (50 LN, 25 bone, one lung) with 18 F-FDG PET-CT and nine (all LN) with (V)DMSA scintigraphy (Table 3). The diameters of detected LNs with DOTATATE PET-CT were 0.8–3.7 cm, and those of 18F-FDG PET-CT and (V)DMSA scintigraphy were 0.6–2.5 and 1–2 cm, respectively. The lung metastasis was 2 cm in diameter, which could have been detected with DOTATATE and 18F-FDG PET-CTs. In addition, 13 lesions (six LN, seven lung) were detected with radiological modalities. Five LN and seven lung lesions smaller than 1 cm in diameter in two patients (patients 2 and 5) were detected with the CT component of PETCT. CT also enabled us to distinguish malignant processes from physiological/inflammatory processes such as brown fat (patient 10), ovulation (patient 2) and infection (patient 6). In patient 15, although both DOTATATE
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Scintigraphy in medullary thyroid carcinoma Ozkan et al. 245
Table 1
Patient characterictics
Patient number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sex
Age at diagnosis (years)
Follow-up since diagnosis (years)
Male Female Female Male Male Male Female Female Female Female Male Male Male Female Female Male Female Female Male Female Male Male
45 40 20 44 46 56 56 31 49 20 60 21 46 55 29 29 25 49 52 69 68 34
2 5 12 2 2 7 3 17 19 18 7 4 7 7 5 2 17 5 9 2 2 3
Hereditary or sporadic disease Sporadic Sporadic Hereditary (MEN Sporadic Sporadic Hereditary (MEN Sporadic Sporadic Sporadic Hereditary (MEN Sporadic Hereditary (MEN Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Hereditary (MEN
Calcitonin level (pg/ ml)
CEA level (ng/ ml) Type of metastases
99.4 5495 2539 884 1733 57.9 393 242 306 7370 1738 2062 4372 859 120.7 632 291 717.1 3744 235 1228 2579
2A)
2A)
2A) 2B)
2A)
5.0 23.8 5.5 1.9 9.5 3.7 2.5 10.7 2.8 194.8 83 31.9 24.9 11.6 3.1 5.5 12.6 2.5 76 16.7 48 613.6
Bone LN, bone LN, bone LN LN, bone, lung – – LN LN, bone – LN LN LN – LN – – LN LN, bone LN LN, bone LN, bone
CEA, carcinoembryonic antigen; LN, lymph node; MEN, multiple endocrine neoplasia.
Table 2
DOTATATE PET-CT,
Patient number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
18
F-FDG PET-CT and (V)DMSA scintigraphy results
DOTATE
DOTATATE lesion number
DOTATATE lesion type
+ + + + + − − + + − + + + − − − − + + + + +
1 5 20 1 14 0 0 1 2 0 7 1 18 0 0 0 0 5 16 3 31 9
Bone LN, bone LN, bone LN LN, bone, lung − − LN Bone − LN LN LN − − − − LN LN, bone LN LN, bone LN, bone
CT, computed tomography;
LN Bone Lung Total
F-FDG
F-FDG lesion number
18
F-FDG lesion type
− + +
0 8 6
− LN, bone LN, bone
+ − − − + − − − + − − −
18 0 0 0 1 0 0 0 7 0 0 0
LN, bone, lung − − − LN − − − LN − − −
+
5
LN
+ +
23 8
LN, bone LN, bone
(V)DMSA lesion number
(V)DMSA lesion type
− + + −
0 1 1 0
− LN LN −
− − − − + − −
0 0 0 0 3 0 0
− − − − LN − −
−
0
−
+ − +
1 0 3
LN − LN
F-FDG, fluorine-18 fluorodeoxyglucose; LN, lymph node; + , lesion detected; − , lesion not detected.
DOTATATE [n (%)] 79/85 (92.9) 54/54 (100) 1/8 (12.5) 134/147 (91.1)
18
F-FDG [n (%)]
50/85 (58.8) 25/54 (46.3) 1/8 (12.5) 76/147 (51.7)
18
F-FDG
18 Table 4 DOTATATE PET-CT, F-FDG PET-CT and (V)DMSA scintigraphy results in terms of hereditary/sporadic disease
(V)DMSA [n (%)] 9/85 (10.6) 0/54 (0) 0/8 (0) 9/147 (6.1)
DOTATATE [n (%)] Hereditary group Sporadic group Whole group
3/5 (60) 12/17 (70.6) 15/22 (68.2)
CT, computed tomography; CT, computed tomography;
(V)DMSA
18
Table 3 Lesion numbers detected in DOTATATE PET-CT, PET-CT and (V)DMSA scintigraphy Lesion number
18 18
18
F-FDG [n (%)] 2/5 (40) 6/13 (46.2) 8/18 (44.4)
(V)DMSA [n (%)] 2/4 (50) 3/11 (27.2) 5/15 (33.3)
18
F-FDG, fluorine-18 fluorodeoxyglucose.
18
F-FDG, fluorine-18 fluorodeoxyglucose.
and 18F-FDG PET-CT were negative, ultrasound (US) imaging revealed an LN, 5 mm in diameter, with metastasis, proven after the operation. Miliary liver
metastases detected in patient 8 with MR were not included in the total number of detected lesions. There was no radiopharmaceutical uptake in these lesions.
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18 Table 5 DOTATATE PET-CT, F-FDG PET-CT and (V)DMSA scintigraphy results in different calcitonin categories
Calcitonin (pg/ml) 0–500 500–1000 > 1000
DOTATATE [n (%)] 4/8 (50) 2/4 (50) 9/10 (90)
CT, computed tomography;
18
18
F-FDG [n (%)] 1/6 (16.7) 1/3 (33.3) 6/9 (66.7)
(V)DMSA [n (%)] 1/5 (20) 0/2 (0) 4/8 (50)
F-FDG, fluorine-18 fluorodeoxyglucose.
Unfortunately, in six patients (patients 6, 7, 10, 14, 16 and 17) neither scintigraphic nor radiological modalities could have shown metastatic sites. The scan results according to the presence of hereditary or sporadic disease were also reviewed (Table 4). The results of DOTATATE PET-CT (n = 22 patients), 18 F-FDG PET-CT (n = 18 patients) and (V)DMSA scintigraphy (n = 15 patients) in terms of different Ct and CEA categories are given in Tables 5 and 6, respectively. In four patients (18.2%), DOTATATE PET-CT changed patient management significantly. In patient 1, 18 F-FDG PET-CT and (V)DMSA scintigraphy were negative, whereas DOTATATE accumulated significantly in metastasis on the dorsal vertebra (Fig. 1). Although patient 4 did not receive 18F-FDG PET-CT, (V)DMSA scintigraphy was negative. DOTATATE PET-CT revealed LN metastasis. Both patients 1 and 4 underwent successful operations by which detected metastatic lesions were resected, resulting in diminished tumour marker levels. In patient 13, there was moderate 18F-FDG uptake in the conglomerated abdominal metastatic LNs, but DOTATATE uptake was very high. After the resection of these conglomerated LNs, the patient was given lutetium-177 (177Lu) DOTATATE treatment because of multiple DOTATATE-avid nonresected metastatic LNs in the cervical, mediastinal and axillary regions (Figs 2 and 3). During the follow-up of patient 3, who was a MEN 2A patient who had undergone surrenalectomy due to pheochromocytoma, clinical onset signalled the recurrence of pheochromocytoma. In 18F-FDG PET-CT, which was performed after the detection of a recurrent mass in the surrenalectomy region on MRI, there was moderate 18F-FDG uptake in this recurrent mass along with metastatic cervical and mediastinal LNs and bone lesions. In DOTATATE-PET-CT, although there was no pathologic uptake in the recurrent mass in the surrenalectomy region, even more metastatic LNs and bone lesions were detected. During the resection operation for the mass in the surrenalectomy region, miliary liver metastases were also detected, which were shown to be MTC metastases by histopathologic evaluation. In this patient, preoperative abdomen MRI was normal in terms of liver metastases. In addition, DOTATATE and
18 Table 6 DOTATATE PET-CT, F-FDG PET-CT and (V)DMSA scintigraphy results in different CEA categories
CEA (ng/ml)
DOTATATE [n (%)]
0–5 5–50 > 50
4/7 (57.1) 8/11 (72.7) 3/4 (75)
18
F-FDG [n (%)] 2/6 (33.3) 5/9 (55.6) 1/3 (33.3)
(V)DMSA [n (%)] 0/4 (0) 3/8 (37.5) 2/3 (66.7)
CEA, carcinoembryonic antigen; CT, computed tomography; 18F-FDG, fluorine-18 fluorodeoxyglucose.
18
F-FDG uptakes of the liver were within the physiological limits. After the operation, biochemical markers were normal in terms of clinical onset of pheochromocytoma. The patient who had high Ct received 177Lu DOTATATE treatment because of DOTATATE-avid lesions of LN and bone, which were identified as MTC metastases along with miliary liver metastases.
Discussion Two to three decades ago, (V)DMSA scintigraphy seemed to be very effective in localizing disease extent compared with other tumour imaging radiopharmaceuticals, such as 131 I-MIBG, 201Tl, 99mTc-tetrofosmin and 99mTc-MIBI. In the articles published in the 1980s and 1990s, the sensitivity values of (V)DMSA were higher (80–95%) than our sensitivity value, which is 33.3% [8–11]. A probable reason for their higher sensitivity values is larger lesion size. Currently, with routine imaging modalities such as US, many obvious lesions can be detected easily, and those patients never come to nuclear medicine departments. This may explain the lower sensitivity values of (V)DMSA in recent articles, including ours [5,6]. In the 2000s, new radiopharmaceuticals such as 111In Oct and 18F-FDG have been used for MTC patients. These have widely varying sensitivity values (69.9–78.5% for 111 In Oct and 41–93% for 18F-FDG) [2,4–7,16–21]. In our patient group, the sensitivity of 18F-FDG PET-CT was higher than that of (V)DMSA scintigraphy (44.4 vs. 33.3%), although there was no significant difference between them. Therefore, 18F-FDG PET-CT must be the preferred scanning method over (V)DMSA scintigraphy. Diehl et al. [5] reported sensitivity values of 25, 33 and 78% for 111In Oct, (V)DMSA and 18F-FDG PET, respectively. The same values were 14, 17 and 41%, respectively, in the article by de Groot et al. [6]. These authors also recommended 18F-FDG PET-CT in MTC patients. In recent years, new PET radiopharmaceuticals for SSR imaging have been used in MTC patients. In our study, the sensitivity of DOTATATE PET-CT was 68.2%. Although there was no significant difference between DOTATATE and 18F-FDG PET-CT, DOTATATE PET-CT was positive, whereas 18F-FDG PET-CT was negative in four patients (patients 1, 8, 11 and 12). Few articles have compared the patient-based sensitivities of 18F-FDG and 68Ga somatostatin-analogue PET-CT
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Fig. 1
68
Ga-DOTATATE is accumulated intensely (a) in the metastasis of a dorsal vertebra (b). Although the same metastasis can be seen in the CT component of 18F-FDG PET-CT (d), there is no significant 18F-FDG uptake in the lesion (c). CT, computed tomography.
[12–15,22]. Conry et al. [13] observed that 18F-FDG PET-CT had a higher sensitivity than DOTATATE PET-CT (77.8 vs. 72.2%), whereas Naswa et al. [14] reported a higher sensitivity for 68Ga-DOTANOC PETCT (DOTANOC is another somatostatin analogue) than for 18F-FDG PET-CT (75.6 vs. 63.4%). Conry et al. [13] and Naswa et al. [14] concluded their articles by emphasizing the complementary roles of 18F-FDG PETCT and 68Ga somatostatin-analogue PET-CT. It should be kept in mind that the different sensitivity values of different types of imaging modalities in these articles may also be due to changes in camera technology, differences in acquisition and reconstruction, tomographic versus planar imaging, attenuation correction, sample size and patient selection. When we compared the patient-based sensitivity values of DOTATATE PET-CT and (V)DMSA scintigraphy, we found a significant difference between them. In terms of lesion number and type, DOTATATE PET-CT was more efficient than (V)DMSA scintigraphy (Table 3). In (V)DMSA scans, there were very few LNs compared with DOTATATE PET-CT. In addition, none of the bone and lung metastases could be detected with (V) DMSA. To our knowledge, no other study has compared
DOTATATE PET-CT and (V)DMSA scintigraphy. There are also few articles that have compared lesionbased sensitivities between different scintigraphic modalities. Our lesion-based results showed that DOTATATE PET-CT was far superior to both 18F-FDG PET-CT and (V)DMSA scintigraphy (91.1 vs. 51.7 and 6.1%, respectively). In this sense, our results differed from those of Conry et al. [13] and Treglia et al. [15]. In our investigation, when each lesion was counted separately, 134 lesions were detected with DOTATATE PET-CT, 76 lesions with 18F-FDG PET-CT and nine lesions with (V)DMSA scintigraphy. DOTATATE PETCT detected 92.9% of the LNs, whereas 18F-FDG PETCT was poorer in this sense (58.8%). In contrast, (V) DMSA scintigraphy was very inefficient in detecting LNs (10.6%). Naswa et al. [14] reported significantly superior lesion-based sensitivity of DOTANOC PETCT over 18F-FDG PET-CT in terms of cervical nodal metastases, but Treglia et al. [15] found the same LN detection rate with 18F-FDG PET-CT and 68Ga somatostatin analogues (30%) . For local evaluation, US is the first-line imaging modality in the follow-up of MTC patients [3]. In experienced hands, this modality can delineate disease burden in the neck region quite well.
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Fig. 2
68
Ga-DOTATATE PET-CT (a) and 18F-FDG PET-CT (b) of the same patient. DOTATATE accumulates more intensely and in more lesions than does F-FDG. Mesenteric LNs accumulate DOTATATE more intensely than FDG (thick arrow). Paratracheal and supraclavicular LNs accumulate DOTATATE both more intensely and more in number (arrow). Some supraclavicular and all of the axillary LNs accumulate only DOTATATE (dashed arrow). 18
Fig. 3
Transaxial sections of the lesions in Fig. 2. There is more intense DOTATATE uptake in conglomerated mesenteric lymph nodes (a) compared with the 18 F-FDG image (b). There is more intense and more widespread DOTATATE uptake (c) than 18F-FDG uptake (d) in the paratracheal and supraclavicular lymph nodes. There is intense DOTATATE uptake in axillary lymph nodes (e), whereas there is no 18F-FDG uptake (f).
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In our study, in one patient, the only metastatic site, which was a subcentimetric LN, was revealed with US, whereas both DOTATATE and 18F-FDG PET-CT were negative. In our study, in terms of bone lesions, DOTATATE PET-CT was much more sensitive than 18F-FDG PETCT (100 vs. 46.3%). Naswa et al. [14] did not find a significant difference among these radiopharmaceuticals. Similar to our study, Treglia et al. [15] found that 68Ga somatostatin-analogue PET-CT showed more bone lesions compared with 18F-FDG PET-CT (50 vs. 25%). Conry et al. [13] also found discordant lesions between DOTATATE and 18F-FDG PET-CT. They also mentioned that, although bone lesions were detected with the CT component of PET-CT, they were accurately recognized by the use of DOTATATE and 18F-FDG. In our patient group, both DOTATATE and 18F-FDG PET-CT were very weak for detecting lung metastases (12.5% each). The only metastasis that was detected with DOTATATE and 18F-FDG PET was 2 cm in diameter. The other seven subcentimetric lesions were detected with the CT component of PET-CT imaging. In accordance with the literature, the CT component was especially useful in detecting micrometastases of the lung [7,13]. In two patients, all three modalities missed miliary liver metastases in our study. The MRI of one of these patients was also negative. Szakall et al. [2] detected small hepatic metastases with hepatic angiography in 35 patients. In 89% of the patients in the article of Esik et al. [23], multiple small hypervascular hepatic metastases were localized only with angiography. Although the authors advised hepatic angiography for restaging in MTC patients to avoid unnecessary extensive surgical LN dissection in the neck and mediastinum, ATA guidelines do not recommend hepatic angiography before reoperation [3,23]. Treglia et al. [15] determined that fluorine-18 fluoro dihydroxyphenylalalanine (DOPA) PET-CT was the most efficient modality (72%) for liver metastases compared with 68Ga somatostatin-analogue PET-CT (0%) and 18F-FDG PET-CT (28%) . According to the authors, 18 F-FDG seemed to be significantly more efficient than 68 Ga somatostatin analogues (P
Comparison of 68Ga-DOTATATE PET-CT, 18F-FDG PET-CT and 99m Tc-(V)DMSA scintigraphy in the detection of recurrent or metastatic medullary thyroid carcinoma Zeynep G. Ozkana, Serkan Kuyumcua, Ayse Kubat Uzumb, Mehmet F. Gecera, Sevda Ozelc, Ferihan Aralb and Isik Adaleta Purpose We aimed to compare the efficacies of gallium-68 (68Ga) DOTATATE PET-computed tomography (CT), fluorine18 fluorodeoxyglucose (18F-FDG) PET-CT and technetium99m (99mTc)-(V)DMSA scintigraphy in the detection of residual/metastatic medullary thyroid carcinoma (MTC). Materials and method We retrospectively evaluated DOTATATE PET-CT, 18F-FDG PET-CT and (V)DMSA scintigraphy of 22 MTC patients, all taken within a 6-month period in each patient, because of high levels of calcitonin (Ct) and carcinoembryonic antigen (CEA). We investigated the relationships between the results of the imaging modalities and tumour marker levels and the sporadic versus hereditary nature of the disease, as well as the effect of imaging results on patient management. Results The ages of the patients at diagnosis were between 20 and 69 years. The median levels of Ct and CEA were 871.5 pg/ml and 11.2 ng/ml, respectively. In the patient-based analysis, we observed at least one focus of abnormal uptake in 15 of 22 DOTATATE PET-CT (68.2% sensitivity), eight of 18 18F-FDG PET-CT (44.4% sensitivity) and five of 15 (V)DMSA scans (33.3% sensitivity). These data showed a significant difference between DOTATATE PET-CT and (V)DMSA scintigraphy (P = 0.016), whereas the relationships between DOTATATE PET-CT and 18F-FDG PET-CT and between 18F-FDG PET-CT and (V)DMSA
Introduction Medullary thyroid carcinoma (MTC) is a rare disease that represents ∼ 10% of all thyroid malignant neoplasms [1]. One-fifth to one-fourth of these carcinomas are hereditary and belong to three syndromes: familial MTC, multiple endocrine neoplasia (MEN) type 2A and MEN type 2B [2]. As a result of its low incidence, broad clinical experience and definitive randomized clinical trials are limited [3]. All of the patients diagnosed with MTC should undergo total thyroidectomy and central lymph node (LN) dissection because LN involvement is the most common way of spreading [1–3]. After this first therapeutic approach, the American Thyroid Association (ATA) management guidelines for MTC recommend basal measurement of calcitonin (Ct) and carcinoembryonic antigen (CEA), which are two tumour markers that are 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
scintigraphy showed no significant differences (P > 0.05). In the lesion-based analysis, 134 lesions were detected with DOTATATE PET-CT, 76 lesions with 18F-FDG PET-CT and nine lesions with (V)DMSA scintigraphy. Conclusion DOTATATE PET-CT is an efficient imaging modality in MTC patients with increased Ct and CEA (especially > 1000 pg/ml and 50 ng/ml, respectively) for localizing recurrent or metastatic disease. 18F-FDG PET-CT can be performed if DOTATATE PET-CT is not available, but (V)DMSA scintigraphy is not recommended. Nucl Med Commun 36:242–250 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nuclear Medicine Communications 2015, 36:242–250 Keywords: calcitonin, carcinoembryonic antigen, 18F-FDG PET-CT, Ga DOTATATE PET-CT, medullary thyroid carcinoma, 99m Tc-(V)DMSA scintigraphy 68
Departments of aNuclear Medicine, bInternal Medicine, Endocrinology and Metabolism Division and cDepartment of Biostatistics and Medical Informatics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Correspondence to Zeynep Gozde Ozkan, MD, Nuclear Medicine Department, Istanbul Medical Faculty, Istanbul University, Istanbul 34390, Turkey Tel: + 90 212 414 2000/35085; fax: + 90 212 414 2056; e-mail: [email protected] Received 10 June 2014 Revised 1 October 2014 Accepted 2 October 2014
used during follow-up of the patients. Whereas undetectable Ct is correlated with long survival, high tumour marker levels require further workup for the detection of disease spread [3]. Unfortunately, no specific imaging modality can demonstrate disease burden definitively. In addition to radiological modalities, many radiopharmaceuticals have been used in nuclear medicine in MTC patients, such as technetium99m (99mTc)-labelled pentavalent dimercaptosuccinic acid ((V)DMSA), 99mTc-sestamethoxyisobutylisonitrile (MIBI), iodine-131/123 (131I/123I) metaiodobenzylguanidine (MIBG) and thallium-201 (201Tl). Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomographycomputed tomography (PET-CT) has also been used frequently in this patient group. MTC, a neuroendocrine tumour, contains somatostatin receptor type 2 (SSR2). Therefore, indium-111 (111In) DOI: 10.1097/MNM.0000000000000240
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Scintigraphy in medullary thyroid carcinoma Ozkan et al. 243
octreotide (Oct) can also be used in MTC patients. Oct scintigraphy has a wide range of sensitivity values (14–78.5%) [4–7]. In recent years, gallium-68 (68Ga)-labelled somatostatin analogues such as tetraazacyclododecane tetraacetic acid-octreotate (DOTATATE), which is a novel radiopharmaceutical that is produced in-house, has also been used in PET-CT cameras under the same conditions as Oct in MTC patients. Both because of the high affinity of DOTATATE for SSR2 and because of the advantages of PET over SPECT imaging, DOTATATE PET-CT overrides Oct scintigraphy in MTC patients. Many studies have compared the efficacies of different radiopharmaceuticals in MTC patients [4,7–15], but none has compared (V)DMSA scintigraphy, which is a conventional imaging agent for MTC, with 18F-FDG PETCT, which is now frequently used in MTC patients, or with DOTATATE PET-CT, which is one of the newest radiopharmaceuticals used in this patient group. In this article, we aimed to compare the efficacies of DOTATATE PET-CT, 18F-FDG PET-CT and (V) DMSA whole-body scintigraphy for the detection of residual or metastatic MTC. We evaluated the relationships between these modalities and tumour markers and investigated their effects on patient management.
Materials and methods Patients
This retrospective study included 22 MTC patients (11 female, 11 male) with high Ct, each of whom underwent DOTATATE PET-CT and most of whom underwent FDG PET-CT and (V)DMSA whole-body scans. In each patient, all scans were taken within a 6-month period between April 2011 and February 2013 to detect recurrences or metastases of MTC. Between these imagings, the patients were given no treatments. The study was approved by the local ethics committee. Informed consent was obtained from all patients before imaging. We evaluated whether they had hereditary MTC. For every patient, Ct and CEA levels at the time of scanning were noted. Preparation of radiopharmaceuticals DOTATATE labelling 68
Ga-DOTATATE was prepared in-house on a fully automated system (Eckert & Ziegler Eurotope, Berlin, Germany). Commercially available germanium-68 (68Ge)/68Ga generator (IGG100; Eckert & Ziegler Eurotope) was eluted with 0.1 mol/l hydrochloric acid. Effluent containing the 68Ga fraction was passed through a cationic exchange column (Strata-X-C-cartridge) to concentrate and purify the 68Ga from residual traces of 68 Ge coming from the generator. The 68Ga was then eluted with 0.02 mol/l hydrochloric acid and 98% acetone into the reaction vial. Next, 0.2 mol/l sodium acetate buffer solution and 40 μg DOTATATE (ABX, Rodeberg,
Germany), dissolved in 0.04 ml water, were added to the vial. The reaction was carried out at 95°C for 400 s. 68Ga-DOTATATE was then purified by adsorption on a tC-18 light cartridge. The purified 68 Ga-DOTATATE was eluted with an ethanol/water solution, formulated with PBS and passed through a 0.22 μm filter directly into a sterile vial. Radiochemical purity, as determined by high-performance liquid chromatography, exceeded 95% in all cases. 18
F-FDG
This radiopharmaceutical was obtained in synthesized form (Eczacıbası, Monrol, Istanbul, Turkey). (V)DMSA preparation
(V)DMSA was prepared by adding 0.2 ml 7% sodium bicarbonate to a standard DMSA vial (Eczacıbası, Monrol) using aseptic techniques. Thereafter, 40 mCi 99mTc-pertechnetate in 2 ml was injected into the vial and incubated at room temperature for 20 min. (V)DMSA was administered to the patients within 2 h of preparation. Image acquisitions DOTATATE and 18F-FDG PET-CT
Images were obtained on a dedicated PET-CT scanner (Biograph TruePoint PET-CT; Siemens Medical Solutions Inc. Molecular Imaging, Illinois, USA) 45–60 min after intravenous injection of 3–4 mCi of 68Ga DOTATATE and 60–90 min after intravenous injection of 0.2 mCi/kg 18F-FDG. CT acquisition was performed on a spiral four-slice CT with a slice thickness of 4 mm. After the transmission scan, 3D PET acquisition was performed for 3 min per bed position for six to eight bed positions. CT-based attenuation correction of the emission images was employed. PET images were reconstructed by the iterative method ordered-subset expectation maximization (two iterations; eight subsets) with a filter size of 5 mm. After completion of PET acquisitions, the reconstructed attenuation-corrected PET images, CT images and fused images of matching pairs of PET and CT were available for review in the axial, coronal and sagittal planes and in maximumintensity projections with three-dimensional cine mode. (V)DMSA scan
Two to three hours after the injection of 15–20 mCi of 99m Tc-(V)DMSA, images were acquired using a largefield-of-view gamma camera fitted with a low-energy collimator (Siemens ECAM; Siemens Medical Solutions Inc.). Symmetrical 20% energy windows were centred over a photopeak of 144 keV. Whole-body scanning (16 cm/min; 256 × 1024 matrix) was performed 2–3 h after injection. Afterwards, planar and SPECT images were acquired from the neck–chest region for 500 000 counts using a 256 × 256 word matrix for planar images and 64 frames, a 128 × 128 matrix, 360° rotation and 30 s/frame for SPECT images. Planar and SPECT images of the
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abdomen and pelvis were acquired if necessary. Thereafter, CT acquisitions of the appropriate regions were performed on the spiral four-slice CT (CT component of Biograph TruePoint PET-CT; Siemens Medical Solutions Inc.) with a slice thickness of 4 mm. The CT images and reconstructed SPECT images were evaluated after fusion images were rendered using Siemens SYNGO software (Siemens Medical Solutions Inc.). Image analysis
All of the scans were reviewed by an experienced nuclear medicine physician. Any focus of DOTATATE, 18 F-FDG and (V)DMSA uptake superior to the background in unexpected locations was accepted as abnormally increased tracer uptake. All detected lesions were documented as LN, bone or lung. The confirmation of imaging was based on histopathological and radiological findings and clinical follow-up. Ct was measured by immunoradiometric assay. Its normal range was less than 10 pg/ml for female patients and less than 15 pg/ml for male patients. CEA was measured with electrochemiluminescence immunoassay. Its normal range was less than 5 ng/ml. Statistical analysis
Statistical analyses were performed using SPSS software version 21 (IBM Corporation, Somers, NY, USA). The relationships of the hereditary nature of MTC with age, Ct and CEA were evaluated. Numeric values that were not distributed normally were evaluated with the Mann–Whitney U-test, whereas categorical values were evaluated with Fisher’s exact test (2 × 2) with Freeman–Halton extension for 2 × 3 contingency tables. The sensitivities of DOTATATE PET-CT, 18F-FDG PET-CT and (V)DMSA scintigraphy on a per-patient basis were calculated. All of the patients in the study were regarded as positive for MTC because Ct was high in all of them. The McNemar test was used to compare these values. A P value of less than 0.05 was considered statistically significant.
Results The ages of the patients at the initial diagnosis ranged between 20 and 69 years (mean: 42.9 ± 15; median: 45.5). The follow-up period was 2–19 years (median: 5). Ct was high in all patients (range: 57.9–7370 pg/ml; median: 871.5 pg/ml). The Ct levels were categorized into three groups: 0–500, 500–1000, and greater than 1000 pg/ml; there were eight, four and 10 patients in each group, respectively. The CEA levels were between 1.9 and 613.6 ng/ml (median: 11.2 ng/ml). The CEA levels were categorized into three groups: 0–5, 5–50 and greater than 50 ng/ml, with seven, 11 and four patients in each group, respectively. MTC was sporadic in 17 patients and hereditary in five patients (MEN 2A in four patients and
MEN 2B in one patient). In three patients, the disease was restricted to the cervical region (patients 4, 8 and 15), whereas in 13 patients the disease had spread more extensively. In patients 11, 18 and 20, there were metastatic LNs in the mediastinum, along with cervical involvement. Patient 12 had isolated mediastinal LNs, whereas patient 13 had metastatic LNs in the supraclavicular, axillary and abdominal regions, along with cervical and mediastinal spread of the disease. Patient 1 had only bone metastasis, but patients 2, 3, 9, 19, 21 and 22 had bone metastases along with cervical and/or mediastinal metastatic LNs. In patient 5, there were lung metastases along with cervical and mediastinal LNs and bone metastases. The patient characteristics are summarized in Table 1. All 22 patients received DOTATATE PET-CT, 18 patients 18F-FDG PET-CT and 15 patients (V)DMSA scintigraphy. In seven patients (patients 5, 6, 14, 15, 17, 18 and 19) (V)DMSA scintigraphy and in four patients (patients 4, 17, 19 and 20) 18F-FDG PET-CT could not be performed. Scan results, numbers of lesions and lesion types detected in each modality are summarized in Table 2. In the patient-based analysis, at least one focus of abnormal uptake was observed in 15 patients on DOTATATE PET-CT (68.2% sensitivity), in eight patients on 18F-FDG PET-CT (44.4% sensitivity) and in five patients on (V)DMSA scintigraphy (33.3% sensitivity). When the sensitivity values of these modalities were compared, there was a statistically significant difference between DOTATATE PET-CT and (V)DMSA scintigraphy (P = 0.016), whereas the relationships between DOTATATE PET-CT and 18F-FDG PET-CT and between 18F-FDG PET-CT and (V)DMSA scintigraphy showed no significant differences (P > 0.05). In lesion-based analysis, when each lesion was counted separately to find the detected number of lesions with each modality, we found that 134 lesions (79 LN, 54 bone, one lung) were detected with DOTATATE PETCT, compared with 76 (50 LN, 25 bone, one lung) with 18 F-FDG PET-CT and nine (all LN) with (V)DMSA scintigraphy (Table 3). The diameters of detected LNs with DOTATATE PET-CT were 0.8–3.7 cm, and those of 18F-FDG PET-CT and (V)DMSA scintigraphy were 0.6–2.5 and 1–2 cm, respectively. The lung metastasis was 2 cm in diameter, which could have been detected with DOTATATE and 18F-FDG PET-CTs. In addition, 13 lesions (six LN, seven lung) were detected with radiological modalities. Five LN and seven lung lesions smaller than 1 cm in diameter in two patients (patients 2 and 5) were detected with the CT component of PETCT. CT also enabled us to distinguish malignant processes from physiological/inflammatory processes such as brown fat (patient 10), ovulation (patient 2) and infection (patient 6). In patient 15, although both DOTATATE
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Scintigraphy in medullary thyroid carcinoma Ozkan et al. 245
Table 1
Patient characterictics
Patient number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Sex
Age at diagnosis (years)
Follow-up since diagnosis (years)
Male Female Female Male Male Male Female Female Female Female Male Male Male Female Female Male Female Female Male Female Male Male
45 40 20 44 46 56 56 31 49 20 60 21 46 55 29 29 25 49 52 69 68 34
2 5 12 2 2 7 3 17 19 18 7 4 7 7 5 2 17 5 9 2 2 3
Hereditary or sporadic disease Sporadic Sporadic Hereditary (MEN Sporadic Sporadic Hereditary (MEN Sporadic Sporadic Sporadic Hereditary (MEN Sporadic Hereditary (MEN Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Hereditary (MEN
Calcitonin level (pg/ ml)
CEA level (ng/ ml) Type of metastases
99.4 5495 2539 884 1733 57.9 393 242 306 7370 1738 2062 4372 859 120.7 632 291 717.1 3744 235 1228 2579
2A)
2A)
2A) 2B)
2A)
5.0 23.8 5.5 1.9 9.5 3.7 2.5 10.7 2.8 194.8 83 31.9 24.9 11.6 3.1 5.5 12.6 2.5 76 16.7 48 613.6
Bone LN, bone LN, bone LN LN, bone, lung – – LN LN, bone – LN LN LN – LN – – LN LN, bone LN LN, bone LN, bone
CEA, carcinoembryonic antigen; LN, lymph node; MEN, multiple endocrine neoplasia.
Table 2
DOTATATE PET-CT,
Patient number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
18
F-FDG PET-CT and (V)DMSA scintigraphy results
DOTATE
DOTATATE lesion number
DOTATATE lesion type
+ + + + + − − + + − + + + − − − − + + + + +
1 5 20 1 14 0 0 1 2 0 7 1 18 0 0 0 0 5 16 3 31 9
Bone LN, bone LN, bone LN LN, bone, lung − − LN Bone − LN LN LN − − − − LN LN, bone LN LN, bone LN, bone
CT, computed tomography;
LN Bone Lung Total
F-FDG
F-FDG lesion number
18
F-FDG lesion type
− + +
0 8 6
− LN, bone LN, bone
+ − − − + − − − + − − −
18 0 0 0 1 0 0 0 7 0 0 0
LN, bone, lung − − − LN − − − LN − − −
+
5
LN
+ +
23 8
LN, bone LN, bone
(V)DMSA lesion number
(V)DMSA lesion type
− + + −
0 1 1 0
− LN LN −
− − − − + − −
0 0 0 0 3 0 0
− − − − LN − −
−
0
−
+ − +
1 0 3
LN − LN
F-FDG, fluorine-18 fluorodeoxyglucose; LN, lymph node; + , lesion detected; − , lesion not detected.
DOTATATE [n (%)] 79/85 (92.9) 54/54 (100) 1/8 (12.5) 134/147 (91.1)
18
F-FDG [n (%)]
50/85 (58.8) 25/54 (46.3) 1/8 (12.5) 76/147 (51.7)
18
F-FDG
18 Table 4 DOTATATE PET-CT, F-FDG PET-CT and (V)DMSA scintigraphy results in terms of hereditary/sporadic disease
(V)DMSA [n (%)] 9/85 (10.6) 0/54 (0) 0/8 (0) 9/147 (6.1)
DOTATATE [n (%)] Hereditary group Sporadic group Whole group
3/5 (60) 12/17 (70.6) 15/22 (68.2)
CT, computed tomography; CT, computed tomography;
(V)DMSA
18
Table 3 Lesion numbers detected in DOTATATE PET-CT, PET-CT and (V)DMSA scintigraphy Lesion number
18 18
18
F-FDG [n (%)] 2/5 (40) 6/13 (46.2) 8/18 (44.4)
(V)DMSA [n (%)] 2/4 (50) 3/11 (27.2) 5/15 (33.3)
18
F-FDG, fluorine-18 fluorodeoxyglucose.
18
F-FDG, fluorine-18 fluorodeoxyglucose.
and 18F-FDG PET-CT were negative, ultrasound (US) imaging revealed an LN, 5 mm in diameter, with metastasis, proven after the operation. Miliary liver
metastases detected in patient 8 with MR were not included in the total number of detected lesions. There was no radiopharmaceutical uptake in these lesions.
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18 Table 5 DOTATATE PET-CT, F-FDG PET-CT and (V)DMSA scintigraphy results in different calcitonin categories
Calcitonin (pg/ml) 0–500 500–1000 > 1000
DOTATATE [n (%)] 4/8 (50) 2/4 (50) 9/10 (90)
CT, computed tomography;
18
18
F-FDG [n (%)] 1/6 (16.7) 1/3 (33.3) 6/9 (66.7)
(V)DMSA [n (%)] 1/5 (20) 0/2 (0) 4/8 (50)
F-FDG, fluorine-18 fluorodeoxyglucose.
Unfortunately, in six patients (patients 6, 7, 10, 14, 16 and 17) neither scintigraphic nor radiological modalities could have shown metastatic sites. The scan results according to the presence of hereditary or sporadic disease were also reviewed (Table 4). The results of DOTATATE PET-CT (n = 22 patients), 18 F-FDG PET-CT (n = 18 patients) and (V)DMSA scintigraphy (n = 15 patients) in terms of different Ct and CEA categories are given in Tables 5 and 6, respectively. In four patients (18.2%), DOTATATE PET-CT changed patient management significantly. In patient 1, 18 F-FDG PET-CT and (V)DMSA scintigraphy were negative, whereas DOTATATE accumulated significantly in metastasis on the dorsal vertebra (Fig. 1). Although patient 4 did not receive 18F-FDG PET-CT, (V)DMSA scintigraphy was negative. DOTATATE PET-CT revealed LN metastasis. Both patients 1 and 4 underwent successful operations by which detected metastatic lesions were resected, resulting in diminished tumour marker levels. In patient 13, there was moderate 18F-FDG uptake in the conglomerated abdominal metastatic LNs, but DOTATATE uptake was very high. After the resection of these conglomerated LNs, the patient was given lutetium-177 (177Lu) DOTATATE treatment because of multiple DOTATATE-avid nonresected metastatic LNs in the cervical, mediastinal and axillary regions (Figs 2 and 3). During the follow-up of patient 3, who was a MEN 2A patient who had undergone surrenalectomy due to pheochromocytoma, clinical onset signalled the recurrence of pheochromocytoma. In 18F-FDG PET-CT, which was performed after the detection of a recurrent mass in the surrenalectomy region on MRI, there was moderate 18F-FDG uptake in this recurrent mass along with metastatic cervical and mediastinal LNs and bone lesions. In DOTATATE-PET-CT, although there was no pathologic uptake in the recurrent mass in the surrenalectomy region, even more metastatic LNs and bone lesions were detected. During the resection operation for the mass in the surrenalectomy region, miliary liver metastases were also detected, which were shown to be MTC metastases by histopathologic evaluation. In this patient, preoperative abdomen MRI was normal in terms of liver metastases. In addition, DOTATATE and
18 Table 6 DOTATATE PET-CT, F-FDG PET-CT and (V)DMSA scintigraphy results in different CEA categories
CEA (ng/ml)
DOTATATE [n (%)]
0–5 5–50 > 50
4/7 (57.1) 8/11 (72.7) 3/4 (75)
18
F-FDG [n (%)] 2/6 (33.3) 5/9 (55.6) 1/3 (33.3)
(V)DMSA [n (%)] 0/4 (0) 3/8 (37.5) 2/3 (66.7)
CEA, carcinoembryonic antigen; CT, computed tomography; 18F-FDG, fluorine-18 fluorodeoxyglucose.
18
F-FDG uptakes of the liver were within the physiological limits. After the operation, biochemical markers were normal in terms of clinical onset of pheochromocytoma. The patient who had high Ct received 177Lu DOTATATE treatment because of DOTATATE-avid lesions of LN and bone, which were identified as MTC metastases along with miliary liver metastases.
Discussion Two to three decades ago, (V)DMSA scintigraphy seemed to be very effective in localizing disease extent compared with other tumour imaging radiopharmaceuticals, such as 131 I-MIBG, 201Tl, 99mTc-tetrofosmin and 99mTc-MIBI. In the articles published in the 1980s and 1990s, the sensitivity values of (V)DMSA were higher (80–95%) than our sensitivity value, which is 33.3% [8–11]. A probable reason for their higher sensitivity values is larger lesion size. Currently, with routine imaging modalities such as US, many obvious lesions can be detected easily, and those patients never come to nuclear medicine departments. This may explain the lower sensitivity values of (V)DMSA in recent articles, including ours [5,6]. In the 2000s, new radiopharmaceuticals such as 111In Oct and 18F-FDG have been used for MTC patients. These have widely varying sensitivity values (69.9–78.5% for 111 In Oct and 41–93% for 18F-FDG) [2,4–7,16–21]. In our patient group, the sensitivity of 18F-FDG PET-CT was higher than that of (V)DMSA scintigraphy (44.4 vs. 33.3%), although there was no significant difference between them. Therefore, 18F-FDG PET-CT must be the preferred scanning method over (V)DMSA scintigraphy. Diehl et al. [5] reported sensitivity values of 25, 33 and 78% for 111In Oct, (V)DMSA and 18F-FDG PET, respectively. The same values were 14, 17 and 41%, respectively, in the article by de Groot et al. [6]. These authors also recommended 18F-FDG PET-CT in MTC patients. In recent years, new PET radiopharmaceuticals for SSR imaging have been used in MTC patients. In our study, the sensitivity of DOTATATE PET-CT was 68.2%. Although there was no significant difference between DOTATATE and 18F-FDG PET-CT, DOTATATE PET-CT was positive, whereas 18F-FDG PET-CT was negative in four patients (patients 1, 8, 11 and 12). Few articles have compared the patient-based sensitivities of 18F-FDG and 68Ga somatostatin-analogue PET-CT
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Fig. 1
68
Ga-DOTATATE is accumulated intensely (a) in the metastasis of a dorsal vertebra (b). Although the same metastasis can be seen in the CT component of 18F-FDG PET-CT (d), there is no significant 18F-FDG uptake in the lesion (c). CT, computed tomography.
[12–15,22]. Conry et al. [13] observed that 18F-FDG PET-CT had a higher sensitivity than DOTATATE PET-CT (77.8 vs. 72.2%), whereas Naswa et al. [14] reported a higher sensitivity for 68Ga-DOTANOC PETCT (DOTANOC is another somatostatin analogue) than for 18F-FDG PET-CT (75.6 vs. 63.4%). Conry et al. [13] and Naswa et al. [14] concluded their articles by emphasizing the complementary roles of 18F-FDG PETCT and 68Ga somatostatin-analogue PET-CT. It should be kept in mind that the different sensitivity values of different types of imaging modalities in these articles may also be due to changes in camera technology, differences in acquisition and reconstruction, tomographic versus planar imaging, attenuation correction, sample size and patient selection. When we compared the patient-based sensitivity values of DOTATATE PET-CT and (V)DMSA scintigraphy, we found a significant difference between them. In terms of lesion number and type, DOTATATE PET-CT was more efficient than (V)DMSA scintigraphy (Table 3). In (V)DMSA scans, there were very few LNs compared with DOTATATE PET-CT. In addition, none of the bone and lung metastases could be detected with (V) DMSA. To our knowledge, no other study has compared
DOTATATE PET-CT and (V)DMSA scintigraphy. There are also few articles that have compared lesionbased sensitivities between different scintigraphic modalities. Our lesion-based results showed that DOTATATE PET-CT was far superior to both 18F-FDG PET-CT and (V)DMSA scintigraphy (91.1 vs. 51.7 and 6.1%, respectively). In this sense, our results differed from those of Conry et al. [13] and Treglia et al. [15]. In our investigation, when each lesion was counted separately, 134 lesions were detected with DOTATATE PET-CT, 76 lesions with 18F-FDG PET-CT and nine lesions with (V)DMSA scintigraphy. DOTATATE PETCT detected 92.9% of the LNs, whereas 18F-FDG PETCT was poorer in this sense (58.8%). In contrast, (V) DMSA scintigraphy was very inefficient in detecting LNs (10.6%). Naswa et al. [14] reported significantly superior lesion-based sensitivity of DOTANOC PETCT over 18F-FDG PET-CT in terms of cervical nodal metastases, but Treglia et al. [15] found the same LN detection rate with 18F-FDG PET-CT and 68Ga somatostatin analogues (30%) . For local evaluation, US is the first-line imaging modality in the follow-up of MTC patients [3]. In experienced hands, this modality can delineate disease burden in the neck region quite well.
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Fig. 2
68
Ga-DOTATATE PET-CT (a) and 18F-FDG PET-CT (b) of the same patient. DOTATATE accumulates more intensely and in more lesions than does F-FDG. Mesenteric LNs accumulate DOTATATE more intensely than FDG (thick arrow). Paratracheal and supraclavicular LNs accumulate DOTATATE both more intensely and more in number (arrow). Some supraclavicular and all of the axillary LNs accumulate only DOTATATE (dashed arrow). 18
Fig. 3
Transaxial sections of the lesions in Fig. 2. There is more intense DOTATATE uptake in conglomerated mesenteric lymph nodes (a) compared with the 18 F-FDG image (b). There is more intense and more widespread DOTATATE uptake (c) than 18F-FDG uptake (d) in the paratracheal and supraclavicular lymph nodes. There is intense DOTATATE uptake in axillary lymph nodes (e), whereas there is no 18F-FDG uptake (f).
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Scintigraphy in medullary thyroid carcinoma Ozkan et al. 249
In our study, in one patient, the only metastatic site, which was a subcentimetric LN, was revealed with US, whereas both DOTATATE and 18F-FDG PET-CT were negative. In our study, in terms of bone lesions, DOTATATE PET-CT was much more sensitive than 18F-FDG PETCT (100 vs. 46.3%). Naswa et al. [14] did not find a significant difference among these radiopharmaceuticals. Similar to our study, Treglia et al. [15] found that 68Ga somatostatin-analogue PET-CT showed more bone lesions compared with 18F-FDG PET-CT (50 vs. 25%). Conry et al. [13] also found discordant lesions between DOTATATE and 18F-FDG PET-CT. They also mentioned that, although bone lesions were detected with the CT component of PET-CT, they were accurately recognized by the use of DOTATATE and 18F-FDG. In our patient group, both DOTATATE and 18F-FDG PET-CT were very weak for detecting lung metastases (12.5% each). The only metastasis that was detected with DOTATATE and 18F-FDG PET was 2 cm in diameter. The other seven subcentimetric lesions were detected with the CT component of PET-CT imaging. In accordance with the literature, the CT component was especially useful in detecting micrometastases of the lung [7,13]. In two patients, all three modalities missed miliary liver metastases in our study. The MRI of one of these patients was also negative. Szakall et al. [2] detected small hepatic metastases with hepatic angiography in 35 patients. In 89% of the patients in the article of Esik et al. [23], multiple small hypervascular hepatic metastases were localized only with angiography. Although the authors advised hepatic angiography for restaging in MTC patients to avoid unnecessary extensive surgical LN dissection in the neck and mediastinum, ATA guidelines do not recommend hepatic angiography before reoperation [3,23]. Treglia et al. [15] determined that fluorine-18 fluoro dihydroxyphenylalalanine (DOPA) PET-CT was the most efficient modality (72%) for liver metastases compared with 68Ga somatostatin-analogue PET-CT (0%) and 18F-FDG PET-CT (28%) . According to the authors, 18 F-FDG seemed to be significantly more efficient than 68 Ga somatostatin analogues (P
