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US Hybrid Imaging Compared with Conventional Diagnostic Thyroid Imaging with Scintigraphy and Ultrasound
Ultrasound in Med. & Biol., Vol. 45, No. 5, pp. 1243 1252, 2019 Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Printed in the USA. All rights reserved. 0301-5629/$ - see front matter
https://doi.org/10.1016/j.ultrasmedbio.2019.01.003
Original Contribution TECHNETIUM-99M SPECT/US HYBRID IMAGING COMPARED WITH CONVENTIONAL DIAGNOSTIC THYROID IMAGING WITH SCINTIGRAPHY AND ULTRASOUND AGEDPM T ARTIN
FREESMEYER, THOMAS WINKENS, CHRISTIAN KÜHNEL, THOMAS OPFERMANN, and PHILIPP SEIFERTTAGEDEN Clinic of Nuclear Medicine, Jena University Hospital, Jena, Germany (Received 25 June 2018; revised 3 January 2019; in final from 4 January 2019)
Abstract—Side-by-side evaluation of thyroid ultrasound (US) and 99mTcO4 scintigraphy can lead to uncertainties in the correct topographic assignment of thyroid nodules. The aim of this study was to evaluate 99mTcO4 singlephoton emission computed tomography/ultrasound (SPECT/US) fusion imaging. Seventy-nine patients were prospectively investigated. If conventional diagnostics of the thyroid gland (B-mode-US, scintigraphy) produced unclear findings, SPECT was performed and transferred to a US device for real-time sensor-navigated 3-D fusion US investigation. The data sets were manually matched according to their contours. Finally, SPECT/US versus conventional diagnostics was rated using an ordinal 4-point scale (SPECT/US >> conventional diagnostics, SPECT/US > conventional diagnostics, SPECT/US = conventional diagnostics, SPECT/US < conventional diagnostics). SPECT/US was superior (>>, >) in 84% and equivalent (=) in 16% of the cases, respectively. No statistically significant differences were observed for uni-, bi- and multinodular goiters (p 0.3). In 67%, the respective problem that arose after conventional diagnostics was clarified by SPECT/US. SPECT/US was feasible and was helpful for the clarification of uncertain functionality assessments of thyroid nodules. (E-mail: martin. [email protected]) © 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Single-photon emission computed tomography/ultrasound, Fusion imaging, Hybrid imaging, Thyroid, Ultrasound.
examinations. One aim of scintigraphy is to image thyroid metabolism to detect and localize abnormal thyroid tissue, that is, hyper- and hypofunctional areas. US, on the other hand, is used to detect the exact size of the thyroid gland, characterize the echogenicity of thyroid tissue and detect thyroid nodules with particular regard to morphologic criteria of malignancy (Cordes et al. 2016; Haugen et al. 2016; Musholt et al. 2015). A correlative analysis of both imaging modalities supports differential diagnosis and differential indications for further clinical measures. However, the side-by-side analysis of both imaging modalities demands considerable spatial imagination capabilities on the part of the practitioner, because thyroid scintigraphy is a planar summation image of a ventral view (coronal summation image), whereas sonography is a sectional imaging modality in the axial or sagittal plane. However, the presence of several closely adjacent nodules or a peripheral nodule position leads to ambiguities in the assignment of scintigraphic and sonographic findings, even for experienced practitioners.
INTRODUCTION Hybrid imaging of different modalities has proven very successful in the past in overcoming the limitations of individual imaging methodologies. For instance, positron emission tomography/computed tomography (PET/CT) and singlephoton emission computed tomography/computed tomography (SPECT/CT) have become an integral part of clinical care (Beyer et al. 2000; Hasegawa et al. 2002; Seo et al. 2008; Townsend 2008; Townsend et al. 2004). Over the past 10 y, ultrasound (US), which is widely available in clinical settings, has been tested for hybrid imaging applications (Bucki et al. 2007; Ewertsen et al. 2006, Galdames et al. 2011; Kuru et al. 2015; Peria et al. 1995). Sodium [99mTc]pertechnetate (99mTcO4) scintigraphy together with high-resolution US is a diagnostic combination that is regularly used to analyze two different imaging modalities, side-by-side, in thyroid Address correspondence to: Martin Freesmeyer, Clinic of Nuclear Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. E-mail: [email protected]
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The limitation that scintigraphy recorded from a ventral position represents a summation image can be circumvented with a 3-D acquisition of the 99mTcO4 activity distribution using rotating gamma cameras. As a result, overlapping and peripheral findings can be better demarcated than with planar scintigraphy alone (Darr et al. 2013). Because SPECT does not require an additional injection of a radiopharmacon, it would be, in principle, a sensible additional diagnostic procedure in combination with planar scintigraphy. However, it is rarely used in clinical practice (Ahn 2016; Bailey and Willowson 2013; Darr et al. 2013; Lee et al. 2016; Meller and Becker 2002; Ritt et al. 2011). Additional concepts exist that are aimed at imaging thyroid metabolism in three dimensions, without data overlap problems, for example, using a hand-held gamma probe (free hand single-photon emission computed tomography [fhSPECT]) and detection system (real-time handheld emission spot allocator [rthESA]) (Freesmeyer et al. 2014a, 2014b). According to a recently reported proof-of-concept, hybrid imaging with fhSPECT/US and 3-D 99mTcO4 scintigraphy is feasible—after overcoming technical obstacles—and might be well suited for application in routine clinical practice (Freesmeyer et al. 2014b). Thus, it is also likely that the use of a regular gamma camera for recording SPECT (camSPECT) can improve the congruence of the assignment of thyroid nodules with thyroid metabolism. The aim of this study was to evaluate the technical applicability and feasibility of a new hybrid imaging approach for thyroid diagnostics. A second goal was to ascertain whether single-photon emission computed tomography/ultrasound (SPECT/US) can provide additional information or clarify uncertainties of the conventional diagnostics and thus has potential to improve the diagnostic accuracy in the field of thyroid nodule characterization. Special attention was paid to the technical implementation, the integration into the clinical routine and the improved assignment of anatomy and metabolism in comparison to the conventional US and scintigraphy images. The influence of SPECT/US on therapeutic consequences has not been investigated in the present study.
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Investigators Single-photon emission computed tomography/ ultrasound was carried out by three investigators familiar with this method. M.F. has 19 y of professional experience in thyroid imaging. T.W. and P.S. each have 4 y of professional experience in thyroid imaging. Conventional thyroid diagnostics All patients included in the study were referred to a German university hospital for thyroid examination. A medical indication for thyroid scintigraphy was given according to German guidelines (Dietlein et al. 2013). All patients were initially assessed with conventional diagnostics comprising a laboratory analysis of thyroid parameters, high-resolution B-mode US (GE LOGIQ 9 or GE LOGIQ E9, GE Healthcare, Milwaukee, WI, USA) and planar thyroid scintigraphy (20 min after injection of 60 75 MBq [1.6 2.0 mCi] 99mTcO4, 4-min scan time) (Dietlein et al. 2013). After immediate evaluation of the findings, one of the above-mentioned investigators decided whether SPECT should be performed based on the following inclusion and exclusion criteria. Inclusion criteria Complete conventional thyroid diagnostics including laboratory thyroid parameters, thyroid US and thyroid scintigraphy Unclear findings in the conventional diagnosis (unclear functionality of one/several nodules and/or unclear assignment of a distinct scintigraphic finding to several nodules) Written consent Age >18 y US examination of sufficient quality Exclusion criteria
METHODS
99mTcO4 uptake <0.5% Regular use of thyroid medication Iodide exposure in the past 3 mo Thyroid-stimulating hormone values below lower limit of normal range Inadequate US conditions (short neck, pronounced obesity, lack of reclinability) Sonographically detected thyroid cysts >2 cm
Patients/ethics In this prospective study, patients were enrolled between February 2015 and July 2017. All patients gave their informed consent in writing. This analysis was part of a study for which approval from the responsible local ethics committee had been obtained (Reference No. 4286-12/14). All examinations were carried out in compliance with the Declaration of Helsinki.
Single-photon emission computed tomography The decision on inclusion was followed by thyroid SPECT (Siemens Symbia S, Erlangen, Germany) with a 128 £ 128 matrix and acquisition of 32 angles at 180˚ rotation. The recording time for each angle was 20 s. Subsequently, data were reconstructed iteratively (Flash3D) using a Gaussian filter (5.0). Total times for
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data acquisition and post-processing were 13 and 5 min, respectively. Data conversion Data obtained with SPECT needed to be converted as the LOGIQ E9 US instrument cannot process and display raw SPECT data. The SPECT data set was imported into PMOD software (Version 3.409, PMOD Technologies Ltd., Zurich, Switzerland) for converting the imaging matrix to 512 £ 512 £ 128. In addition, the Digital Imaging and Communications in Medicine (DICOM) modality was changed from nuclear medicine to PT (positron emission tomography [PET]). After data conversion and transfer into the US instrument, the data set could be easily displayed. Single-photon emission computed tomography/ ultrasound Single-photon emission computed tomography/ ultrasound hybrid imaging is based on sensor-navigated US. This requires the proprietary VNAV software package (GE Healthcare), a magnetic field transmitter connected to the US instrument and magnetic sensors attached to the US probe (Fig. 1). These sensors are detected within the magnetic field generated by the transmitter, allowing determination of the position of the US transducer and thereby the exact spatial location of the US image within the magnetic field. To link the SPECT images with the US images, the converted SPECT data set was transferred to the US instrument (LOGIQ E9, GE Healthcare) via the DICOM interface and opened with the VNAV software. Technical details of the fusion technique have been described previously with respect to PET/US fusion in patients
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with malignant melanoma (Freesmeyer et al. 2015a) and are also provided in Figure 1. Next, alignment and coregistration with the US images were manually and subjectively performed with respect to the contours of the thyroid gland and its nodules (as seen on SPECT and US, respectively). For this, representative structures of the thyroid gland were selected (axial plane; simultaneous imaging of the right and the left thyroid lobe including the isthmus), and the SPECT data set was manually aligned in the same orientation. Because the patient is transferred onto another examination table between the SPECT and US examinations, it is almost impossible to achieve exactly the same positioning of the neck. Therefore, the recording congruency of both data sets was checked in a sagittal plane and, if required, manually adjusted, such that the contours of the metabolic activity and the margins of the thyroid gland in the US image matched. The resulting 3-D linkage was saved; this enables real-time movement of the SPECT data set in congruence with the movements of the US transducer. The superimposed, linked image data sets were displayed on the regular screen of the US instrument, in split-screen mode (Fig. 1). In addition, the software allows free adjustment of the intensity weighting of the SPECT and US data sets in the fusion image, as well as “windowing” of the displayed SPECT data set. Image data can then be stored either as a static image or as a short video sequence (Supplementary Videos A-C, online only). To review whether metabolism (SPECT) and anatomy (US) are correctly aligned, the investigators constantly proved and re-assessed the correct alignment of SPECT and US of the thyroid gland’s contours in sagittal and transversal planes. If necessary, re-adjustment was performed. Subsequently, the nodule-based
Fig. 1. Performing single-photon emission computed tomography/ultrasound (SPECT/US). After transfer of the converted SPECT data set into the ultrasound instrument, sensor-navigated ultrasound examination is performed. Here, two magnetic sensors (A and B, orange arrow) that are mounted on the ultrasound transducer are detected within a magnetic field that is generated by a transmitter (B, green arrow). The orientation of the ultrasound image within this magnetic field can be determined based on the position of the transducer. After co-registration with the converted SPECT data set, both examinations are displayed in a semitransparent overlay in split-screen mode on the screen of the ultrasound instrument (A). If the ultrasound transducer is moved, the SPECT data set also moves concordantly, such that metabolism can be assigned to the sonographically detected nodules in real time.
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appraisal by means of the below-mentioned 4-point scale was carried out by the investigator. Data analysis/statistics To evaluate technical success, we assessed whether fusion of both data sets was achieved and whether technical limitations affected interpretation of the SPECT/ US data. Separately, the overall quality of the US examination was assessed (independent of the SPECT/US data, for example, because of the difficult anatomic conditions of the patient). Subsequently, the respective investigator subjectively assessed whether SPECT/US was more informative than the side-by-side findings of sonography and planar scintigraphy according to an ordinal 4-point scale: SPECT/US markedly superior to conventional diagnostics (SPECT/US >> conventional), SPECT/US superior to conventional diagnostics (SPECT/US > conventional), SPECT/US equivalent to conventional diagnostics (SPECT/US = conventional), SPECT/US inferior to conventional diagnostics (SPECT/US < conventional) (Table 1). In addition, we assessed whether SPECT/US could or could not improve the initial unclear assignment of anatomy and metabolism and thereby clarify the
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uncertainties that arose in conventional thyroid diagnostics (Table 2). These results were investigated for three groups (uninodular goiter, binodular goiter and multinodular goiter). Fisher’s exact test was used to examine differences between these three groups. RESULTS According to the inclusion and exclusion criteria, 79 patients were consecutively selected from the clinical routine. Patient data and findings are outlined in Table 3. Data conversion took approximately 3 min per patient, and data transfer, approximately 2 min. The duration of the subsequent SPECT/US examination from manual registration to completion of the examination was 5.5 § 2.5 min (range: 2 16 min, median: 5.2 min). All SPECT/US examinations were successfully executed without technical problems (n = 79/79, 100%). Both data sets could be viewed and analyzed in fusion image mode. The US conditions were classified in 33 patients (42%) as very good, in 30 patients (38%) as good, in 14 patients (18%) as moderate and in 2 patients (3%) as poor.
Table 1. Defining features of the comparison of SPECT/US and conventional diagnostics Category
Defining feature
SPECT/US >> conventional
The nodules are not assessable with certainty (e.g., Fig. 4, nodule II) or cannot be interpreted unequivocally (e.g., Fig. 2, nodule I) using conventional diagnostics. On the contrary, SPECT/US is unambiguously appraisable. The investigator is quite certain about the nodule’s functionality using conventional diagnostics, but SPECT/US reveals surprising findings (e.g., Fig. 4, nodule III). The nodule’s function is evaluated differently after SPECT/US assessment. Using conventional diagnostics, the investigator has a suspicion (but is not absolutely certain) regarding genuine nodule functionality, which can be unambiguously confirmed via SPECT/US assessment (e.g., Fig. 3, nodule I). SPECT/US confirms the findings of an already quite certain nodule assessment using conventional diagnostic. SPECT/US does not improve or change the initial nodule assessment obtained via conventional diagnostics. Conventional diagnostics reveal findings that are not depicted using SPECT/US.
SPECT/US > conventional SPECT/US = conventional
SPECT/US < conventional
SPECT = single-photon emission computed tomography; US = ultrasound.
Table 2. SPECT/US compared with conventional diagnostics Category
All cases (n = 79)
Uninodal goiter (n = 11)
Binodal goiter (n = 11)
SPECT/US >> conventional SPECT/US > conventional SPECT/US = conventional SPECT/US < conventional Clarification of problems in conventional diagnostics through SPECT/US
13 (16.5%) 53 (67.1%) 13 (16.5%) 0 (0.0%) 53 (67.1%)
1 (9.1%) 9 (81.8%) 1 (9.1%) 0 (0.0%) 8 (72.3%)
0 (0.0%) 8 (72.3%) 3 (27.3%) 0 (0.0%) 6 (54.5%)
Multinodal goiter (n = 57) 12 (21.1%) 36 (63.2%) 9 (15.8%) 0 (0.0%) 39 (68.4%)
p Value (Fisher’s exact test) 0.300 0.480 0.614 N/A 0.738
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Table 3. Patient and investigation data Parameter
Results n (%)
Mean § SD, range
Numbers of patients Total 79 (100) Males 19 (24) Females 60 (76) Age (y) 54.6 § 13.5, 23 75 Laboratory TSH (mU/L, normal = 0.25 4.04) 1.32 § 0.87, 0.25 5.8 Ultrasound Thyroid volume (mL) 28 § 18, 6 100 Nodule volume (mL) 2.1 § 4.2, 0.72 27.12 Maximum nodule 1.7 § 0.9, 0.5 5.4 diameter (cm) Scintigraphy Injected activity (MBq) 69.3 § 3.5. 60 76.6 Technetium-99m 1.47 § 0.75, 0.52 4.79 thyroidal uptake (%) TSH = thyroid-stimulating hormone; MBq = Megabecquerel.
The patients recruited according to the inclusion criteria were divided into the three categories: uninodular goiter n = 11, binodular goiter n = 11 and multinodular goiter n = 57. Patient examples are provided in Figures 2 4. Overall, SPECT/US was markedly superior to conventional diagnostics in 13 cases (16%) (SPECT/US >> conventional). In the majority of patients (n = 53, 67%), SPECT/US was superior to conventional diagnostics (SPECT/US > conventional). In 13 patients (16%), SPECT/US was equivalent to conventional diagnostics (SPECT/US = conventional). In no case was conventional diagnostics rated better than SPECT/US. There were no significant differences for these results regarding uninodular, binodular and multinodular goiters, respectively (all p values 0.3, Table 2). In 53 of 79 patients (67%), problems that arose after conventional thyroid diagnostics were resolved with SPECT/US. This was particularly common in the group with uninodular thyroid glands (8/11, 72%) (Table 2); however, there were no significant differences between the uninodular, binodular and multinodular goiter groups (p = 0.738). DISCUSSION In this study, SPECT/US carried out in addition to conventional thyroid diagnostics was proven to be helpful and practicable in cases of unclear findings. All SPECT/US examinations were technically successful. Conventional diagnostics comprising sonography and planar 99mTcO4 scintigraphy is limited, especially when several adjoining nodules are found in close proximity or in a peripheral position. This leads to uncertainties regarding the correct topographic assignment of
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sonographic and functional findings, even for experienced practitioners. Some of these diagnostic limitations can be overcome by a 3-D acquisition of 99mTcO4 SPECT. Although this provides more accurate results than planar scintigraphy (Darr et al. 2013; Zaidi 1996), not all ambiguities can be resolved because of the inherently limited spatial resolution (distance of the detectors from the thyroid gland, in particular, because of the shoulder distance in lateral views). However, the advantage of this method is that it can be performed in addition to planar scintigraphy without further radiation exposure. Notwithstanding, this method is not commonly used in routine clinical practice. The application of 99mTcO4-SPECT(/CT) is mentioned in the literature only sporadically (Ahmadzadehfar et al. 2012; Ferrando et al. 2016; Schmidt et al. 2016; Sergieva et al. 2014), whereas reports on the use of 123I SPECT are found more frequently. An advantage of this tracer includes higher uptake because of the organification of iodine. However, there are disadvantages such as the additional radiation exposure, higher costs and poorer availability (Ahmadzadehfar et al. 2012; Chen et al. 1988; Intenzo et al. 2012). Despite the above-mentioned possibilities of improved topographic representation of thyroid metabolism with SPECT, the correlation between nodules detected by sonography and their functional activity remains ambiguous in some patients. In the majority of cases, this limitation can be overcome by using SPECT/US, because the practitioner can view, in real time, the function of the thyroid nodule on the screen of the US instrument in a semitransparent superimposed fusion image (Fig. 1). This kind of representation is analogous to already widespread methods of hybrid-image data display, such as in positron emission tomography (PET)/CT and SPECT/CT. The use of SPECT/US results in instructive images that can better illustrate the findings and help improve the understanding and acceptance of functional imaging among nonspecialist and resident physicians. Also, in this regard, SPECT/US fits in well with already existing hybrid imaging concepts, such as SPECT/CT, PET/CT and PET/MRI. The results presented here indicate that in 84% of patients, SPECT/US was rated as superior to conventional diagnostics. The specific questions that were the reason for additional SPECT/US have been answered with this method in 67% of cases. The concept of a nuclear real-time US fusion in thyroid disease was introduced for the first time in 2014, but in conjunction with fhSPECT, in which a hand-held gamma probe with a dedicated optical tracking system is used (Freesmeyer et al. 2014b). Apart from thyroidrelated findings, initial experience with sensor-navigated
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Fig. 2. Sixty-five-year-old female patient referred for the exclusion of cold nodules. Thyroid volume = 21 mL (right: 17 mL, left: 4 mL). Thyroidstimulating hormone = 0.6 mU/L. No thyroid autoimmune antibodies. Nodule I, right, cranial (1.3 £ 2.0 £ 2.1 cm, 2.7 mL), partially cystic. Nodule II right, mid-third, lateral (1.2 £ 1.3 £ 1.6 cm. 1.3 mL), solid, in immediate proximity to nodule I. Thyroid scintigraphy 20 min after intravenous injection of 68.3 MBq 99mTcO4. Technetium-99m thyroidal uptake = (right) 1.45% and (left) 0.42%. Ambiguity: Scintigraphic hypofunctionality right cranial/lateral. Which of the nodules is hypofunctional? (A) The nodules cannot be unequivocally demarcated on planar scintigraphy. A concave area of reduced uptake can be seen in the right mid-third, laterally. (B) Schematic localization of nodules (coronal view) based on sonographic position. (C) Schematic nodule localization (axial view) based on sonographic position. (D1) Nodules I and II. Sagittal ultrasound view. Nodule I: orange arrow, nodule II: red arrow. (D2) single-photon emission computed tomography/ultrasound. Both the cystic portion of nodule I and the solid nodule II can be clearly classified as hypofunctional. See also Supplementary Video A.
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Fig. 3. Twenty-seven-year-old female patient with a thyroid nodule on the right. Thyroid volume = 17 mL (right: 14 mL, left: 3mL). Thyroid-stimulating hormone = 3.05 mU/L. No thyroid autoimmune antibodies. Nodule I right, caudal (1.8 £ 2.1 £ 2.5 cm; 4.7 mL). Thyroid scintigraphy 20 min after intravenous injection of 70.0 MBq 99mTcO4. Technetium-99m thyroidal uptake = (right) 0.65% and (left) 0.83%. Ambiguity: Almost symmetric representation of the thyroid gland in the scintigram. Without considering the ultrasound, normal findings. (A) Although the nodule can be indirectly intuited in the planar scintigram above an area of reduced relative uptake, it cannot be visually demarcated with certainty. (B) Schematic nodule localization (coronal view) based on sonographic position. (C) Schematic nodule localization (axial view) based on sonographic position. (D1) Nodule I: Sagittal ultrasound view. Nodule marked with orange arrow. (D2) Single-photon emission computed tomography/ultrasound. Compared with the surrounding thyroid tissue, the nodule is clearly hypometabolic and, therefore, scintigraphically cold. See also Supplementary Video B.
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Fig. 4. Fifty-year-old male patient referred for the exclusion of cold nodules. Thyroid volume = 15.5ml (right: 7.5 mL, left: 8 mL). Thyroid-stimulating hormone = 1.38mU/L. No thyroid autoimmune antibodies. Nodule I left, caudal, dorsal (0.9 £ 1.1 £ 1.4 cm, 0.69 mL). Nodule II right, mid-third, dorsal (0.6 £ 0.5 £ 0.7 cm, 0.11 mL). Nodule III right, caudal, dorsal (0.8 £ 0.8 £ 1.0 cm, 0.32 mL). Thyroid scintigraphy 20 min after intravenous injection of 70.5 MBq 99mTcO4. Technetium-99m thyroidal uptake = (right) 0.38% and (left) 0.41%. Ambiguity: Scintigraphic findings almost normal. Unreliable evidence for hypo- or hyperfunctional areas. (A) The nodules cannot be demarcated with certainty using planar scintigraphy. (B) Schematic nodule position (coronal view) based on sonographic position. (C) Schematic nodule position (axial view) based on the sonographic position. (D1) Top: Axial US view. Nodule I is marked with an orange arrow. Bottom: Single-photon emission computed tomography/ultrasound. Nodule I exhibits more intense thyroid metabolism than the surrounding thyroid tissue and is therefore hypermetabolic. (D2) Top: Sagittal ultrasound view. Nodule II is marked with a red arrow. The blue arrow indicates nodule III. Bottom: Single-photon emission computed tomography/ultrasound. Nodule III (blue arrow) exhibits a higher uptake than the surrounding thyroid tissue and is therefore also hypermetabolic. See also Supplementary Video C.
hybrid imaging has so far been reported only for the localization of sentinel lymph nodes and parathyroid adenomas (Bluemel et al. 2013; Bluemel et al. 2015). In contrast, the patient data presented here were recorded with a commercially available, widely used dual-head gamma camera (camSPECT). The acquisition of a SPECT data set of the thyroid gland is therefore available at any regular nuclear medicine unit. Apart
from the above-mentioned application areas, fusion concepts have been reported, in the past, for kidney and myocardial examinations. Although these enable subsequent (offline) fusion of both data sets on a workstation, in contrast to the method presented here, the fusion image cannot be viewed in real time (Bucki et al. 2007; Freesmeyer et al. 2012; Galdames et al. 2011; Guehne et al. 2016).
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Limitations of this study Performing SPECT/US requires additional technical and personnel resources. Special software for data conversion and an US instrument, with options for sensor navigation and image fusion, are needed. However, all these components are commercially available. The personnel time required per patient (in addition to conventional diagnostics) is approximately 30 min (radiographer: 18 min for SPECT + reconstruction, expert in medical physics: 5 min for data conversion and transfer, physician: 5 min for SPECT/US examination). However, this additional time requirement can, in principle, be integrated into the clinical workflow. The results presented here are based on expert assessments and not on a double-blind review. Thus, conclusions regarding diagnostic accuracy and interobserver variability cannot be drawn. This methodology was deemed appropriate for two reasons: First, the approach of fusion US with 99mTcO SPECT using a conventional gamma camera has not been described with respect to thyroid diagnostics before. Therefore, this study comprising 79 patients represents introduction of a new diagnostic tool and testing of its feasibility. Second, the appraisal of SPECT/US and its superiority to conventional diagnostic thyroid imaging was indeed performed during the SPECT/US exam and not by a second reading afterward. This represents the clinical routine of regular US exams (e.g., of the thyroid, the abdomen) in which the appraisal/report is conducted during the US exam and not by reviewing the complete exam (i.e., as a video sequence) afterward. To investigate these inter-observer variabilities, follow-up projects are planned. Furthermore, subjective assessment of inclusion and exclusion criteria regarding conventional thyroid diagnostics (i.e., unclear findings in conventional diagnosis and inadequate US condition) may have induced human variations and even errors. Because no gold standard has yet been established for verification of the correct spatial assignment of functionality to sonographically detected nodules, no quantitative analysis, including determination of sensitivity and specificity, could be carried out. Even after surgical removal of the thyroid gland and histologic processing, it is not possible to unequivocally confirm the correctness of a previous assignment of nodules by scintigraphy/sonography. This is because there no histologic or immunohistochemical parameter for functionality has been established. Thus, an exact assignment of several nodules within the resected tissue is not unequivocally possible. The potential for improving the spatial assignment through fusion of 124I PET with sonography has been determined casuistically, analogous to the SPECT/ US reported here (Darr et al. 2013; Drescher et al. 2013; Freesmeyer et al. 2014c; Freesmeyer et al. 2015a,
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2015b; Guehne et al. 2013). However, this method is associated with increased radiation exposure and requires a PET(/CT) scanner. In contrast, SPECT can be performed in any standard nuclear medicine facility. In the data presented, there is a selection bias with respect to the functionality of nodules, as only 10 hyperfunctional findings were recorded (data not shown). On the one hand, this is due to the clinical significance of hypofunctional nodules, suggesting malignancy, which require special attention (Cordes et al. 2016; Musholt and Musholt 2015). On the other hand, the detection and assignment of hypofunctional areas pose a particular challenge in planar scintigraphy, whereas hyperfunctional findings are much easier to detect and assess. Guidelines recommending thyroid scintigraphy differ between locations. In Germany, this functional study is widely used; however, there are countries in which thyroid scintigraphy is less frequently recommended although recent data advocate the use of scintigraphy in the assessment of thyroid nodules regarding malignancy (Schenke et al. 2019). The registration of the SPECT data set on the US instrument was carried out by experienced investigators at the beginning of the fusion examination. The orientation of the alignment was based on the contour of the thyroid gland. Cases with several hypofunctional and/or peripheral nodules increased the time of the SPECT/US examination, but alignment was ultimately possible in all cases. The investigators in this study constantly ensured correct alignment and re-adjusted, if necessary. Nevertheless, incorrect or inaccurate registration, leading to misidentification of anatomy and metabolism and, thus, to wrong conclusions regarding a nodule’s functionality, cannot be ruled out with certainty in SPECT/ US assessment. This strongly depends on the talent and the experience of the investigator. There might be interand intra-observer variability with respect to the registration process, which could not be determined by the present study design and needs to be investigated using more distinct rating protocols in the future. One option to improve congruency is the inclusion of a CT data set. First casuistic experiences with sensornavigated PET/US fusion have reported that low-dose CT data acquired in a previous PET/CT scan can be an important aid in adjusting and aligning (different) image data sets (Drescher and Freesmeyer 2014; Drescher et al. 2013; Freesmeyer et al. 2014d). By analogy, it is conceivable that the use of CT morphologic landmarks of a SPECT/CT scanner could provide an advantage over the method presented here. However, a SPECT/CT scanner is not always available (as in our clinic) and makes additional radiation exposure unavoidable. The complementary use of CT data needs to be the subject of further investigation.
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Although SPECT/US fusion imaging is performed in real time, data acquisition is carried out sequentially: first the SPECT data, then the US data with superimposed SPECT data. Because of different reclining angles of the head in each examination, a change in neck position is unavoidable. This must be taken into account when registering SPECT and US data. Moreover, in addition to the initial alignment and registration of both data sets, re-adjustment during the examination was necessary. This is because SPECT acquisition is contactless, but US requires slight pressure on the soft tissues of the neck, such that tissue deformation and tissue shifting lead to a lack of congruence (offset) of both data sets up to 1.5 cm (data not shown). However, this could be improved significantly in all cases with manual adjustment. Both drawbacks, the limited reproducibility of patient positioning and the slight tissue deformation by the US transducer, might be circumvented with a new methodological approach. In such an approach, the nuclear medical functional image and the US morphology are simultaneously recorded and superimposed. In this regard, a proof-of-concept study of a “real-time handheld emission spot allocator” (rthESA) has already been published. However, significant technical development is still required (Freesmeyer et al. 2014a). In contrast, the method presented in our study is based on commercially available and approved medical devices. CONCLUSIONS We report that in a large group of patients, SPECT/ US proved to be an applicable examination method that was always technically successful. Furthermore, it was found, based on expert assessments, that additional SPECT/US adds value and diagnostic gain in cases of unclear findings from conventional thyroid scintigraphy. Although a number of technical and personnel requirements need to be met to integrate this concept into the clinical routine, SPECT/US yields a more accurate assignment of function and morphology without additional radiation exposure and within a reasonable amount of time. Future studies should address the detailed nodule-by-nodule comparison of conventional diagnostics and SPECT/US, as well as blinded analyses and inter-observer variability. Also, its therapeutic relevance should be assessed. In addition, further fusion US concepts, taking into consideration rthESA and PET, should be investigated. Acknowledgments—GE Healthcare (Milwaukee, WI, USA) is gratefully acknowledged for providing hardware (LOGIQ E9) for this study. We thank ChristianHollenbach for assistance in data analysis. This study was funded exclusively with intramural grants from the Jena University Hospital.
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SUPPLEMENTARY DATA Supplementary data related to this article can be found at doi:10.1016/j.ultrasmedbio.2019.01.003. REFERENCES Ahmadzadehfar H, Habibi E, Huertos Lopez F, Ezziddin S, Biersack HJ, Sabet A. The utility of 99mTc pertechnetate SPECT/CT in the diagnosis of intrathoracic masses. J Nucl Med 2012;53(Suppl. 1):2044. Ahn BC. Retrosternal goiter visualized on 99mTc pertechnetate SPECT/CT, but not on planar scintigraphy. Clin Nucl Med 2016;41:e169–e170. Bailey DL, Willowson KP. An evidence-based review of quantitative SPECT imaging and potential clinical applications. J Nucl Med 2013;54:83–89. Beyer T, Townsend DW, Brun T, Kinahan PE, Charron M, Roddy R, Jerin J, Young J, Byars L, Nutt R. A combined PET/CT scanner for clinical oncology. J Nucl Med 2000;41:1369–1379. Bluemel C, Schnelzer A, Okur A, Ehlerding A, Paepke S, Scheidhauer K, Kiechle M. Freehand SPECT for image-guided sentinel lymph node biopsy in breast cancer. Eur J Nucl Med Mol Imaging 2013;40:1656–1661. Bluemel C, Kirchner P, Kajdi GW, Werner RA, Herrmann K. Localization of parathyroid adenoma with real-time ultrasound: Freehand SPECT fusion. Clin Nucl Med 2015;41:e141–e142. Bucki M, Chassat F, Galdames F, Asahi T, Pizarro D, Lobo G. Real-Time SPECT and 2D ultrasound image registration. In: Ayache N, Ourselin S, Maeder A, (eds). Medical Image Computing and Computer-Assisted Intervention—MICCAI. Berlin/Heidelberg: Springer; 2007. Lecture Notes Computer Sci 2007;4792:219 227. Chen JJ, LaFrance ND, Rippin R, Allo MD, Wagner HN, Jr. Iodine-123 SPECT of the thyroid in multinodular goiter. J Nucl Med 1988;29:110–113. Cordes M, Nagel H, Horstrup K, Sasiadek M, Kuwert T. Ultrasound characteristics of thyroid nodules diagnosed as follicular neoplasms by fine-needle aspiration cytology: A prospective study with histological correlation. Nuklearmedizin 2016;55:93–98. Darr AM, Opfermann T, Niksch T, Driesch D, Marlowe RJ, Freesmeyer M. Low-activity 124I-PET/low-dose CT versus 99mTc-pertechnetate planar scintigraphy or 99mTc-pertechnetate singlephoton emission computed tomography of the thyroid: A pilot comparison. Clin Nucl Med 2013;38:770–777. Dietlein M., Eschner W., Lassmann M., Verburg F.A., Luster M. DGNHandlungsempfehlung (S1-Leitlinie) Schilddru¨senszintigraphie (Version 4). AWMF Registernummer 031-011, 2013. Drescher R, Freesmeyer M. PET/US fusion as a problem-solving tool in oncology imaging: Differentiation of hernia repair mesh plugs from malignancy suspected on PET/CT. Clin Nucl Med 2014;39: e75–e77. Drescher R, Muller A, Lesser T, Freesmeyer M. PET/ultrasound fusion for differentiation of Vox implant silicone particles from recurrent cancer. Nuklearmedizin 2013;52:N29–N30. Ewertsen C, Grossjohann HS, Nielsen MB. Image fusion involving ultrasound. Ultraschall Med 2006;27:128–129. Ferrando R, Yerovi F, Munoz D, Zamora A, RamÃrez M, Bayardo K. SPECT/CT imaging in large multinodular goiters and poorly defined nodular thyroid disease. J Nucl Med 2016;57(Suppl. 2): 1279. Freesmeyer M, Wiegand S, Darr A, Steenbeck J, Schleussner E, Opfermann T. Offline fusion of 3-dimensional ultrasound and 99mTcO4-SPECT in focal thyroid adenoma: First experiences. Nuklearmedizin 2012;51:A95. Freesmeyer M, Winkens T, Kuhnel C. Real-time handheld emission spot allocator (rthESA) for simultaneous fusion imaging with ultrasound. Nuklearmedizin 2014a;53:265–271. Freesmeyer M, Opfermann T, Winkens T. Hybrid integration of realtime US and freehand SPECT: Proof of concept in patients with thyroid diseases. Radiology 2014b;271:856–861.
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Freesmeyer M, Dralle H, Winkens T. Diagnosis of small medullary thyroid carcinoma via PET/ultrasound (US) fusion. Jpn J Clin Oncol 2014c;44:300–301. Freesmeyer M, Drescher R, Winkens T. Unexpected Diagnosis of peripheral schwannoma on F-18-fluoroethylcholine PET/CT for localization of prostate cancer recurrence and biopsy under realtime PET/ultrasound fusion guidance. Clin Nucl Med 2014d;39:385–386. Freesmeyer M, Elsner P, Goetze S, Kaatz M, Winkens T. Positron emission tomography/ultrasound fusion technique in patients with malignant melanoma. J Med Imaging Radiat Oncol 2015a;59:320– 325. Freesmeyer M, Winkens T, Darr A. Diagnosis of small papillary thyroid cancer via sensor-navigated 124iodine PET/ultrasound (124IPET/US) fusion. J Clin Endocrin Metab 2015b;100:13–14. Galdames FJ, Perez CA, Estevez PA, Held CM, Jaillet F, Lobo G, Donoso G, Coll C. Registration of renal SPECT and 2.5D US images. Comput Med Imaging Graphics 2011;35:302–314. Guehne F, Winkens T, Mothes H, Freesmeyer M. Differential diagnosis of thyroid nodules via real-time PET/ultrasound (US) fusion in a case of co-existing medullary thyroid cancer and adenoma. J Clin Endocrinol Metab 2013;98:4250–4251. Guehne F, Mothes H, Freesmeyer M. Allocation of parathyroid adenoma and suspicious thyroid nodule by real-time 99mTc-MIBI SPECT/US fusion imaging. Endocrine 2016;54:560–561. Hasegawa BH, Wong KH, Iwata K, Barber WC, Hwang AB, Sakdinawat AE, Ramaswamy M, Price DC, Hawkins RA. Dual-modality imaging of cancer with SPECT/CT. Technol Cancer Res Treat 2002;1:449–458. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26:1–133. Intenzo CM, Dam HQ, Manzone TA, Kim SM. Imaging of the thyroid in benign and malignant disease. Semin Nucl Med 2012;42:49–61. Kuru TH, Futterer JJ, Schiffmann J, Porres D, Salomon G, Rastinehad AR. Transrectal ultrasound (US), contrast-enhanced us, real-time elastography, histoscanning, magnetic resonance imaging (MRI), and MRI-US fusion biopsy in the diagnosis of prostate cancer. Eur Urol Focus 2015;1:117–126.
Volume 45, Number 5, 2019 Lee H, Kim JH, Kang YK, Moon JH, So Y, Lee WW. Quantitative single-photon emission computed tomography/computed tomography for technetium pertechnetate thyroid uptake measurement. Medicine 2016;95:e4170. Meller J, Becker W. The continuing importance of thyroid scintigraphy in the era of high-resolution ultrasound. Eur J Nucl Med Mol Imaging 2002;29(Suppl. 2):S425–S438. Musholt TJ, Musholt PB. Molecular genetic markers for thyroid FNAB: Established assays and future perspective. Nuklearmedizin 2015;54:94–100. Musholt TJ, Clerici T, Dralle H, Frilling A, Goretzki PE, Hermann MM, Kussmann J, Lorenz K, Nies C, Schabram J, Schabram P, Scheuba C, Simon D, Steinmu¨ller T, Trupka AW, Wahl RA, Zielke A, Bockisch A, Karges W, Luster M, Schmid KW. Operative Therapie benigner Schilddru¨senerkrankungen. Federfu¨hrende Fachgesellschaft: Deutsche Gesellschaft fu¨r Allgemein- und Viszeralchirurgie. AWMF S2K-Leitlinie. Registernummer 088-007 2015. Peria O, Chevalier L, Francois-Joubert A, Caravel J, Dalsoglio S, Lavallee S. Using a 3D Position Sensor for Registration of SPECT and US images of the kidney. Comput Vision Virtual Reality Robot Med 1995;905:23–29. Ritt P, Vija H, Hornegger J, Kuwert T. Absolute quantification in SPECT. Eur J Nucl Med Mol Imaging 2011;38(Suppl. 1):S69–S77. Schenke S, Seifert P, Zimny M, Winkens T, Binse I, Goerges R. Risk stratification of thyroid nodules using Thyroid Imaging Reporting and Data System (TIRADS): The omission of thyroid scintigraphy increases the rate of falsely suspected lesions. J Nucl Med 2019;. doi: 10.2967/jnumed.118.211912. Published online before print. Schmidt D, Simmerl M, Kuwert T. Is there incremental value of SPECT/CT over planar imaging in the assessment of nodular goiter by Tc-99m-pertechnetate scintigraphy?. J Nucl Med 2016;57 (Suppl. 2):1699. Seo Y, Mari C, Hasegawa BH. Technological development and advances in single-photon emission computed tomography/computed tomography. Semin Nucl Med 2008;38:177–198. Sergieva S, Dimcheva M, Robev B. SPECT-CT in diagnosis of thyroid nodularity and retrosternal goiter. J Nucl Med 2014;55(Suppl. 1):1940. Townsend DW. Dual-modality imaging: Combining anatomy and function. J Nucl Med 2008;49:938–955. Townsend DW, Carney JP, Yap JT, Hall NC. PET/CT today and tomorrow. J Nucl Med 2004;45(Suppl. 1):4S–14S. Zaidi H. Comparative methods for quantifying thyroid volume using planar imaging and SPECT. J Nucl Med 1996;37:1421–1426.
https://doi.org/10.1016/j.ultrasmedbio.2019.01.003
Original Contribution TECHNETIUM-99M SPECT/US HYBRID IMAGING COMPARED WITH CONVENTIONAL DIAGNOSTIC THYROID IMAGING WITH SCINTIGRAPHY AND ULTRASOUND AGEDPM T ARTIN
FREESMEYER, THOMAS WINKENS, CHRISTIAN KÜHNEL, THOMAS OPFERMANN, and PHILIPP SEIFERTTAGEDEN Clinic of Nuclear Medicine, Jena University Hospital, Jena, Germany (Received 25 June 2018; revised 3 January 2019; in final from 4 January 2019)
Abstract—Side-by-side evaluation of thyroid ultrasound (US) and 99mTcO4 scintigraphy can lead to uncertainties in the correct topographic assignment of thyroid nodules. The aim of this study was to evaluate 99mTcO4 singlephoton emission computed tomography/ultrasound (SPECT/US) fusion imaging. Seventy-nine patients were prospectively investigated. If conventional diagnostics of the thyroid gland (B-mode-US, scintigraphy) produced unclear findings, SPECT was performed and transferred to a US device for real-time sensor-navigated 3-D fusion US investigation. The data sets were manually matched according to their contours. Finally, SPECT/US versus conventional diagnostics was rated using an ordinal 4-point scale (SPECT/US >> conventional diagnostics, SPECT/US > conventional diagnostics, SPECT/US = conventional diagnostics, SPECT/US < conventional diagnostics). SPECT/US was superior (>>, >) in 84% and equivalent (=) in 16% of the cases, respectively. No statistically significant differences were observed for uni-, bi- and multinodular goiters (p 0.3). In 67%, the respective problem that arose after conventional diagnostics was clarified by SPECT/US. SPECT/US was feasible and was helpful for the clarification of uncertain functionality assessments of thyroid nodules. (E-mail: martin. [email protected]) © 2019 World Federation for Ultrasound in Medicine & Biology. All rights reserved. Key Words: Single-photon emission computed tomography/ultrasound, Fusion imaging, Hybrid imaging, Thyroid, Ultrasound.
examinations. One aim of scintigraphy is to image thyroid metabolism to detect and localize abnormal thyroid tissue, that is, hyper- and hypofunctional areas. US, on the other hand, is used to detect the exact size of the thyroid gland, characterize the echogenicity of thyroid tissue and detect thyroid nodules with particular regard to morphologic criteria of malignancy (Cordes et al. 2016; Haugen et al. 2016; Musholt et al. 2015). A correlative analysis of both imaging modalities supports differential diagnosis and differential indications for further clinical measures. However, the side-by-side analysis of both imaging modalities demands considerable spatial imagination capabilities on the part of the practitioner, because thyroid scintigraphy is a planar summation image of a ventral view (coronal summation image), whereas sonography is a sectional imaging modality in the axial or sagittal plane. However, the presence of several closely adjacent nodules or a peripheral nodule position leads to ambiguities in the assignment of scintigraphic and sonographic findings, even for experienced practitioners.
INTRODUCTION Hybrid imaging of different modalities has proven very successful in the past in overcoming the limitations of individual imaging methodologies. For instance, positron emission tomography/computed tomography (PET/CT) and singlephoton emission computed tomography/computed tomography (SPECT/CT) have become an integral part of clinical care (Beyer et al. 2000; Hasegawa et al. 2002; Seo et al. 2008; Townsend 2008; Townsend et al. 2004). Over the past 10 y, ultrasound (US), which is widely available in clinical settings, has been tested for hybrid imaging applications (Bucki et al. 2007; Ewertsen et al. 2006, Galdames et al. 2011; Kuru et al. 2015; Peria et al. 1995). Sodium [99mTc]pertechnetate (99mTcO4) scintigraphy together with high-resolution US is a diagnostic combination that is regularly used to analyze two different imaging modalities, side-by-side, in thyroid Address correspondence to: Martin Freesmeyer, Clinic of Nuclear Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. E-mail: [email protected]
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The limitation that scintigraphy recorded from a ventral position represents a summation image can be circumvented with a 3-D acquisition of the 99mTcO4 activity distribution using rotating gamma cameras. As a result, overlapping and peripheral findings can be better demarcated than with planar scintigraphy alone (Darr et al. 2013). Because SPECT does not require an additional injection of a radiopharmacon, it would be, in principle, a sensible additional diagnostic procedure in combination with planar scintigraphy. However, it is rarely used in clinical practice (Ahn 2016; Bailey and Willowson 2013; Darr et al. 2013; Lee et al. 2016; Meller and Becker 2002; Ritt et al. 2011). Additional concepts exist that are aimed at imaging thyroid metabolism in three dimensions, without data overlap problems, for example, using a hand-held gamma probe (free hand single-photon emission computed tomography [fhSPECT]) and detection system (real-time handheld emission spot allocator [rthESA]) (Freesmeyer et al. 2014a, 2014b). According to a recently reported proof-of-concept, hybrid imaging with fhSPECT/US and 3-D 99mTcO4 scintigraphy is feasible—after overcoming technical obstacles—and might be well suited for application in routine clinical practice (Freesmeyer et al. 2014b). Thus, it is also likely that the use of a regular gamma camera for recording SPECT (camSPECT) can improve the congruence of the assignment of thyroid nodules with thyroid metabolism. The aim of this study was to evaluate the technical applicability and feasibility of a new hybrid imaging approach for thyroid diagnostics. A second goal was to ascertain whether single-photon emission computed tomography/ultrasound (SPECT/US) can provide additional information or clarify uncertainties of the conventional diagnostics and thus has potential to improve the diagnostic accuracy in the field of thyroid nodule characterization. Special attention was paid to the technical implementation, the integration into the clinical routine and the improved assignment of anatomy and metabolism in comparison to the conventional US and scintigraphy images. The influence of SPECT/US on therapeutic consequences has not been investigated in the present study.
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Investigators Single-photon emission computed tomography/ ultrasound was carried out by three investigators familiar with this method. M.F. has 19 y of professional experience in thyroid imaging. T.W. and P.S. each have 4 y of professional experience in thyroid imaging. Conventional thyroid diagnostics All patients included in the study were referred to a German university hospital for thyroid examination. A medical indication for thyroid scintigraphy was given according to German guidelines (Dietlein et al. 2013). All patients were initially assessed with conventional diagnostics comprising a laboratory analysis of thyroid parameters, high-resolution B-mode US (GE LOGIQ 9 or GE LOGIQ E9, GE Healthcare, Milwaukee, WI, USA) and planar thyroid scintigraphy (20 min after injection of 60 75 MBq [1.6 2.0 mCi] 99mTcO4, 4-min scan time) (Dietlein et al. 2013). After immediate evaluation of the findings, one of the above-mentioned investigators decided whether SPECT should be performed based on the following inclusion and exclusion criteria. Inclusion criteria Complete conventional thyroid diagnostics including laboratory thyroid parameters, thyroid US and thyroid scintigraphy Unclear findings in the conventional diagnosis (unclear functionality of one/several nodules and/or unclear assignment of a distinct scintigraphic finding to several nodules) Written consent Age >18 y US examination of sufficient quality Exclusion criteria
METHODS
99mTcO4 uptake <0.5% Regular use of thyroid medication Iodide exposure in the past 3 mo Thyroid-stimulating hormone values below lower limit of normal range Inadequate US conditions (short neck, pronounced obesity, lack of reclinability) Sonographically detected thyroid cysts >2 cm
Patients/ethics In this prospective study, patients were enrolled between February 2015 and July 2017. All patients gave their informed consent in writing. This analysis was part of a study for which approval from the responsible local ethics committee had been obtained (Reference No. 4286-12/14). All examinations were carried out in compliance with the Declaration of Helsinki.
Single-photon emission computed tomography The decision on inclusion was followed by thyroid SPECT (Siemens Symbia S, Erlangen, Germany) with a 128 £ 128 matrix and acquisition of 32 angles at 180˚ rotation. The recording time for each angle was 20 s. Subsequently, data were reconstructed iteratively (Flash3D) using a Gaussian filter (5.0). Total times for
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Tc SPECT/US for thyroid diagnostics M. FREESMEYER et al.
data acquisition and post-processing were 13 and 5 min, respectively. Data conversion Data obtained with SPECT needed to be converted as the LOGIQ E9 US instrument cannot process and display raw SPECT data. The SPECT data set was imported into PMOD software (Version 3.409, PMOD Technologies Ltd., Zurich, Switzerland) for converting the imaging matrix to 512 £ 512 £ 128. In addition, the Digital Imaging and Communications in Medicine (DICOM) modality was changed from nuclear medicine to PT (positron emission tomography [PET]). After data conversion and transfer into the US instrument, the data set could be easily displayed. Single-photon emission computed tomography/ ultrasound Single-photon emission computed tomography/ ultrasound hybrid imaging is based on sensor-navigated US. This requires the proprietary VNAV software package (GE Healthcare), a magnetic field transmitter connected to the US instrument and magnetic sensors attached to the US probe (Fig. 1). These sensors are detected within the magnetic field generated by the transmitter, allowing determination of the position of the US transducer and thereby the exact spatial location of the US image within the magnetic field. To link the SPECT images with the US images, the converted SPECT data set was transferred to the US instrument (LOGIQ E9, GE Healthcare) via the DICOM interface and opened with the VNAV software. Technical details of the fusion technique have been described previously with respect to PET/US fusion in patients
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with malignant melanoma (Freesmeyer et al. 2015a) and are also provided in Figure 1. Next, alignment and coregistration with the US images were manually and subjectively performed with respect to the contours of the thyroid gland and its nodules (as seen on SPECT and US, respectively). For this, representative structures of the thyroid gland were selected (axial plane; simultaneous imaging of the right and the left thyroid lobe including the isthmus), and the SPECT data set was manually aligned in the same orientation. Because the patient is transferred onto another examination table between the SPECT and US examinations, it is almost impossible to achieve exactly the same positioning of the neck. Therefore, the recording congruency of both data sets was checked in a sagittal plane and, if required, manually adjusted, such that the contours of the metabolic activity and the margins of the thyroid gland in the US image matched. The resulting 3-D linkage was saved; this enables real-time movement of the SPECT data set in congruence with the movements of the US transducer. The superimposed, linked image data sets were displayed on the regular screen of the US instrument, in split-screen mode (Fig. 1). In addition, the software allows free adjustment of the intensity weighting of the SPECT and US data sets in the fusion image, as well as “windowing” of the displayed SPECT data set. Image data can then be stored either as a static image or as a short video sequence (Supplementary Videos A-C, online only). To review whether metabolism (SPECT) and anatomy (US) are correctly aligned, the investigators constantly proved and re-assessed the correct alignment of SPECT and US of the thyroid gland’s contours in sagittal and transversal planes. If necessary, re-adjustment was performed. Subsequently, the nodule-based
Fig. 1. Performing single-photon emission computed tomography/ultrasound (SPECT/US). After transfer of the converted SPECT data set into the ultrasound instrument, sensor-navigated ultrasound examination is performed. Here, two magnetic sensors (A and B, orange arrow) that are mounted on the ultrasound transducer are detected within a magnetic field that is generated by a transmitter (B, green arrow). The orientation of the ultrasound image within this magnetic field can be determined based on the position of the transducer. After co-registration with the converted SPECT data set, both examinations are displayed in a semitransparent overlay in split-screen mode on the screen of the ultrasound instrument (A). If the ultrasound transducer is moved, the SPECT data set also moves concordantly, such that metabolism can be assigned to the sonographically detected nodules in real time.
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appraisal by means of the below-mentioned 4-point scale was carried out by the investigator. Data analysis/statistics To evaluate technical success, we assessed whether fusion of both data sets was achieved and whether technical limitations affected interpretation of the SPECT/ US data. Separately, the overall quality of the US examination was assessed (independent of the SPECT/US data, for example, because of the difficult anatomic conditions of the patient). Subsequently, the respective investigator subjectively assessed whether SPECT/US was more informative than the side-by-side findings of sonography and planar scintigraphy according to an ordinal 4-point scale: SPECT/US markedly superior to conventional diagnostics (SPECT/US >> conventional), SPECT/US superior to conventional diagnostics (SPECT/US > conventional), SPECT/US equivalent to conventional diagnostics (SPECT/US = conventional), SPECT/US inferior to conventional diagnostics (SPECT/US < conventional) (Table 1). In addition, we assessed whether SPECT/US could or could not improve the initial unclear assignment of anatomy and metabolism and thereby clarify the
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uncertainties that arose in conventional thyroid diagnostics (Table 2). These results were investigated for three groups (uninodular goiter, binodular goiter and multinodular goiter). Fisher’s exact test was used to examine differences between these three groups. RESULTS According to the inclusion and exclusion criteria, 79 patients were consecutively selected from the clinical routine. Patient data and findings are outlined in Table 3. Data conversion took approximately 3 min per patient, and data transfer, approximately 2 min. The duration of the subsequent SPECT/US examination from manual registration to completion of the examination was 5.5 § 2.5 min (range: 2 16 min, median: 5.2 min). All SPECT/US examinations were successfully executed without technical problems (n = 79/79, 100%). Both data sets could be viewed and analyzed in fusion image mode. The US conditions were classified in 33 patients (42%) as very good, in 30 patients (38%) as good, in 14 patients (18%) as moderate and in 2 patients (3%) as poor.
Table 1. Defining features of the comparison of SPECT/US and conventional diagnostics Category
Defining feature
SPECT/US >> conventional
The nodules are not assessable with certainty (e.g., Fig. 4, nodule II) or cannot be interpreted unequivocally (e.g., Fig. 2, nodule I) using conventional diagnostics. On the contrary, SPECT/US is unambiguously appraisable. The investigator is quite certain about the nodule’s functionality using conventional diagnostics, but SPECT/US reveals surprising findings (e.g., Fig. 4, nodule III). The nodule’s function is evaluated differently after SPECT/US assessment. Using conventional diagnostics, the investigator has a suspicion (but is not absolutely certain) regarding genuine nodule functionality, which can be unambiguously confirmed via SPECT/US assessment (e.g., Fig. 3, nodule I). SPECT/US confirms the findings of an already quite certain nodule assessment using conventional diagnostic. SPECT/US does not improve or change the initial nodule assessment obtained via conventional diagnostics. Conventional diagnostics reveal findings that are not depicted using SPECT/US.
SPECT/US > conventional SPECT/US = conventional
SPECT/US < conventional
SPECT = single-photon emission computed tomography; US = ultrasound.
Table 2. SPECT/US compared with conventional diagnostics Category
All cases (n = 79)
Uninodal goiter (n = 11)
Binodal goiter (n = 11)
SPECT/US >> conventional SPECT/US > conventional SPECT/US = conventional SPECT/US < conventional Clarification of problems in conventional diagnostics through SPECT/US
13 (16.5%) 53 (67.1%) 13 (16.5%) 0 (0.0%) 53 (67.1%)
1 (9.1%) 9 (81.8%) 1 (9.1%) 0 (0.0%) 8 (72.3%)
0 (0.0%) 8 (72.3%) 3 (27.3%) 0 (0.0%) 6 (54.5%)
Multinodal goiter (n = 57) 12 (21.1%) 36 (63.2%) 9 (15.8%) 0 (0.0%) 39 (68.4%)
p Value (Fisher’s exact test) 0.300 0.480 0.614 N/A 0.738
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Table 3. Patient and investigation data Parameter
Results n (%)
Mean § SD, range
Numbers of patients Total 79 (100) Males 19 (24) Females 60 (76) Age (y) 54.6 § 13.5, 23 75 Laboratory TSH (mU/L, normal = 0.25 4.04) 1.32 § 0.87, 0.25 5.8 Ultrasound Thyroid volume (mL) 28 § 18, 6 100 Nodule volume (mL) 2.1 § 4.2, 0.72 27.12 Maximum nodule 1.7 § 0.9, 0.5 5.4 diameter (cm) Scintigraphy Injected activity (MBq) 69.3 § 3.5. 60 76.6 Technetium-99m 1.47 § 0.75, 0.52 4.79 thyroidal uptake (%) TSH = thyroid-stimulating hormone; MBq = Megabecquerel.
The patients recruited according to the inclusion criteria were divided into the three categories: uninodular goiter n = 11, binodular goiter n = 11 and multinodular goiter n = 57. Patient examples are provided in Figures 2 4. Overall, SPECT/US was markedly superior to conventional diagnostics in 13 cases (16%) (SPECT/US >> conventional). In the majority of patients (n = 53, 67%), SPECT/US was superior to conventional diagnostics (SPECT/US > conventional). In 13 patients (16%), SPECT/US was equivalent to conventional diagnostics (SPECT/US = conventional). In no case was conventional diagnostics rated better than SPECT/US. There were no significant differences for these results regarding uninodular, binodular and multinodular goiters, respectively (all p values 0.3, Table 2). In 53 of 79 patients (67%), problems that arose after conventional thyroid diagnostics were resolved with SPECT/US. This was particularly common in the group with uninodular thyroid glands (8/11, 72%) (Table 2); however, there were no significant differences between the uninodular, binodular and multinodular goiter groups (p = 0.738). DISCUSSION In this study, SPECT/US carried out in addition to conventional thyroid diagnostics was proven to be helpful and practicable in cases of unclear findings. All SPECT/US examinations were technically successful. Conventional diagnostics comprising sonography and planar 99mTcO4 scintigraphy is limited, especially when several adjoining nodules are found in close proximity or in a peripheral position. This leads to uncertainties regarding the correct topographic assignment of
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sonographic and functional findings, even for experienced practitioners. Some of these diagnostic limitations can be overcome by a 3-D acquisition of 99mTcO4 SPECT. Although this provides more accurate results than planar scintigraphy (Darr et al. 2013; Zaidi 1996), not all ambiguities can be resolved because of the inherently limited spatial resolution (distance of the detectors from the thyroid gland, in particular, because of the shoulder distance in lateral views). However, the advantage of this method is that it can be performed in addition to planar scintigraphy without further radiation exposure. Notwithstanding, this method is not commonly used in routine clinical practice. The application of 99mTcO4-SPECT(/CT) is mentioned in the literature only sporadically (Ahmadzadehfar et al. 2012; Ferrando et al. 2016; Schmidt et al. 2016; Sergieva et al. 2014), whereas reports on the use of 123I SPECT are found more frequently. An advantage of this tracer includes higher uptake because of the organification of iodine. However, there are disadvantages such as the additional radiation exposure, higher costs and poorer availability (Ahmadzadehfar et al. 2012; Chen et al. 1988; Intenzo et al. 2012). Despite the above-mentioned possibilities of improved topographic representation of thyroid metabolism with SPECT, the correlation between nodules detected by sonography and their functional activity remains ambiguous in some patients. In the majority of cases, this limitation can be overcome by using SPECT/US, because the practitioner can view, in real time, the function of the thyroid nodule on the screen of the US instrument in a semitransparent superimposed fusion image (Fig. 1). This kind of representation is analogous to already widespread methods of hybrid-image data display, such as in positron emission tomography (PET)/CT and SPECT/CT. The use of SPECT/US results in instructive images that can better illustrate the findings and help improve the understanding and acceptance of functional imaging among nonspecialist and resident physicians. Also, in this regard, SPECT/US fits in well with already existing hybrid imaging concepts, such as SPECT/CT, PET/CT and PET/MRI. The results presented here indicate that in 84% of patients, SPECT/US was rated as superior to conventional diagnostics. The specific questions that were the reason for additional SPECT/US have been answered with this method in 67% of cases. The concept of a nuclear real-time US fusion in thyroid disease was introduced for the first time in 2014, but in conjunction with fhSPECT, in which a hand-held gamma probe with a dedicated optical tracking system is used (Freesmeyer et al. 2014b). Apart from thyroidrelated findings, initial experience with sensor-navigated
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Fig. 2. Sixty-five-year-old female patient referred for the exclusion of cold nodules. Thyroid volume = 21 mL (right: 17 mL, left: 4 mL). Thyroidstimulating hormone = 0.6 mU/L. No thyroid autoimmune antibodies. Nodule I, right, cranial (1.3 £ 2.0 £ 2.1 cm, 2.7 mL), partially cystic. Nodule II right, mid-third, lateral (1.2 £ 1.3 £ 1.6 cm. 1.3 mL), solid, in immediate proximity to nodule I. Thyroid scintigraphy 20 min after intravenous injection of 68.3 MBq 99mTcO4. Technetium-99m thyroidal uptake = (right) 1.45% and (left) 0.42%. Ambiguity: Scintigraphic hypofunctionality right cranial/lateral. Which of the nodules is hypofunctional? (A) The nodules cannot be unequivocally demarcated on planar scintigraphy. A concave area of reduced uptake can be seen in the right mid-third, laterally. (B) Schematic localization of nodules (coronal view) based on sonographic position. (C) Schematic nodule localization (axial view) based on sonographic position. (D1) Nodules I and II. Sagittal ultrasound view. Nodule I: orange arrow, nodule II: red arrow. (D2) single-photon emission computed tomography/ultrasound. Both the cystic portion of nodule I and the solid nodule II can be clearly classified as hypofunctional. See also Supplementary Video A.
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Fig. 3. Twenty-seven-year-old female patient with a thyroid nodule on the right. Thyroid volume = 17 mL (right: 14 mL, left: 3mL). Thyroid-stimulating hormone = 3.05 mU/L. No thyroid autoimmune antibodies. Nodule I right, caudal (1.8 £ 2.1 £ 2.5 cm; 4.7 mL). Thyroid scintigraphy 20 min after intravenous injection of 70.0 MBq 99mTcO4. Technetium-99m thyroidal uptake = (right) 0.65% and (left) 0.83%. Ambiguity: Almost symmetric representation of the thyroid gland in the scintigram. Without considering the ultrasound, normal findings. (A) Although the nodule can be indirectly intuited in the planar scintigram above an area of reduced relative uptake, it cannot be visually demarcated with certainty. (B) Schematic nodule localization (coronal view) based on sonographic position. (C) Schematic nodule localization (axial view) based on sonographic position. (D1) Nodule I: Sagittal ultrasound view. Nodule marked with orange arrow. (D2) Single-photon emission computed tomography/ultrasound. Compared with the surrounding thyroid tissue, the nodule is clearly hypometabolic and, therefore, scintigraphically cold. See also Supplementary Video B.
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Tc SPECT/US for thyroid diagnostics M. FREESMEYER et al.
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Fig. 4. Fifty-year-old male patient referred for the exclusion of cold nodules. Thyroid volume = 15.5ml (right: 7.5 mL, left: 8 mL). Thyroid-stimulating hormone = 1.38mU/L. No thyroid autoimmune antibodies. Nodule I left, caudal, dorsal (0.9 £ 1.1 £ 1.4 cm, 0.69 mL). Nodule II right, mid-third, dorsal (0.6 £ 0.5 £ 0.7 cm, 0.11 mL). Nodule III right, caudal, dorsal (0.8 £ 0.8 £ 1.0 cm, 0.32 mL). Thyroid scintigraphy 20 min after intravenous injection of 70.5 MBq 99mTcO4. Technetium-99m thyroidal uptake = (right) 0.38% and (left) 0.41%. Ambiguity: Scintigraphic findings almost normal. Unreliable evidence for hypo- or hyperfunctional areas. (A) The nodules cannot be demarcated with certainty using planar scintigraphy. (B) Schematic nodule position (coronal view) based on sonographic position. (C) Schematic nodule position (axial view) based on the sonographic position. (D1) Top: Axial US view. Nodule I is marked with an orange arrow. Bottom: Single-photon emission computed tomography/ultrasound. Nodule I exhibits more intense thyroid metabolism than the surrounding thyroid tissue and is therefore hypermetabolic. (D2) Top: Sagittal ultrasound view. Nodule II is marked with a red arrow. The blue arrow indicates nodule III. Bottom: Single-photon emission computed tomography/ultrasound. Nodule III (blue arrow) exhibits a higher uptake than the surrounding thyroid tissue and is therefore also hypermetabolic. See also Supplementary Video C.
hybrid imaging has so far been reported only for the localization of sentinel lymph nodes and parathyroid adenomas (Bluemel et al. 2013; Bluemel et al. 2015). In contrast, the patient data presented here were recorded with a commercially available, widely used dual-head gamma camera (camSPECT). The acquisition of a SPECT data set of the thyroid gland is therefore available at any regular nuclear medicine unit. Apart
from the above-mentioned application areas, fusion concepts have been reported, in the past, for kidney and myocardial examinations. Although these enable subsequent (offline) fusion of both data sets on a workstation, in contrast to the method presented here, the fusion image cannot be viewed in real time (Bucki et al. 2007; Freesmeyer et al. 2012; Galdames et al. 2011; Guehne et al. 2016).
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Limitations of this study Performing SPECT/US requires additional technical and personnel resources. Special software for data conversion and an US instrument, with options for sensor navigation and image fusion, are needed. However, all these components are commercially available. The personnel time required per patient (in addition to conventional diagnostics) is approximately 30 min (radiographer: 18 min for SPECT + reconstruction, expert in medical physics: 5 min for data conversion and transfer, physician: 5 min for SPECT/US examination). However, this additional time requirement can, in principle, be integrated into the clinical workflow. The results presented here are based on expert assessments and not on a double-blind review. Thus, conclusions regarding diagnostic accuracy and interobserver variability cannot be drawn. This methodology was deemed appropriate for two reasons: First, the approach of fusion US with 99mTcO SPECT using a conventional gamma camera has not been described with respect to thyroid diagnostics before. Therefore, this study comprising 79 patients represents introduction of a new diagnostic tool and testing of its feasibility. Second, the appraisal of SPECT/US and its superiority to conventional diagnostic thyroid imaging was indeed performed during the SPECT/US exam and not by a second reading afterward. This represents the clinical routine of regular US exams (e.g., of the thyroid, the abdomen) in which the appraisal/report is conducted during the US exam and not by reviewing the complete exam (i.e., as a video sequence) afterward. To investigate these inter-observer variabilities, follow-up projects are planned. Furthermore, subjective assessment of inclusion and exclusion criteria regarding conventional thyroid diagnostics (i.e., unclear findings in conventional diagnosis and inadequate US condition) may have induced human variations and even errors. Because no gold standard has yet been established for verification of the correct spatial assignment of functionality to sonographically detected nodules, no quantitative analysis, including determination of sensitivity and specificity, could be carried out. Even after surgical removal of the thyroid gland and histologic processing, it is not possible to unequivocally confirm the correctness of a previous assignment of nodules by scintigraphy/sonography. This is because there no histologic or immunohistochemical parameter for functionality has been established. Thus, an exact assignment of several nodules within the resected tissue is not unequivocally possible. The potential for improving the spatial assignment through fusion of 124I PET with sonography has been determined casuistically, analogous to the SPECT/ US reported here (Darr et al. 2013; Drescher et al. 2013; Freesmeyer et al. 2014c; Freesmeyer et al. 2015a,
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2015b; Guehne et al. 2013). However, this method is associated with increased radiation exposure and requires a PET(/CT) scanner. In contrast, SPECT can be performed in any standard nuclear medicine facility. In the data presented, there is a selection bias with respect to the functionality of nodules, as only 10 hyperfunctional findings were recorded (data not shown). On the one hand, this is due to the clinical significance of hypofunctional nodules, suggesting malignancy, which require special attention (Cordes et al. 2016; Musholt and Musholt 2015). On the other hand, the detection and assignment of hypofunctional areas pose a particular challenge in planar scintigraphy, whereas hyperfunctional findings are much easier to detect and assess. Guidelines recommending thyroid scintigraphy differ between locations. In Germany, this functional study is widely used; however, there are countries in which thyroid scintigraphy is less frequently recommended although recent data advocate the use of scintigraphy in the assessment of thyroid nodules regarding malignancy (Schenke et al. 2019). The registration of the SPECT data set on the US instrument was carried out by experienced investigators at the beginning of the fusion examination. The orientation of the alignment was based on the contour of the thyroid gland. Cases with several hypofunctional and/or peripheral nodules increased the time of the SPECT/US examination, but alignment was ultimately possible in all cases. The investigators in this study constantly ensured correct alignment and re-adjusted, if necessary. Nevertheless, incorrect or inaccurate registration, leading to misidentification of anatomy and metabolism and, thus, to wrong conclusions regarding a nodule’s functionality, cannot be ruled out with certainty in SPECT/ US assessment. This strongly depends on the talent and the experience of the investigator. There might be interand intra-observer variability with respect to the registration process, which could not be determined by the present study design and needs to be investigated using more distinct rating protocols in the future. One option to improve congruency is the inclusion of a CT data set. First casuistic experiences with sensornavigated PET/US fusion have reported that low-dose CT data acquired in a previous PET/CT scan can be an important aid in adjusting and aligning (different) image data sets (Drescher and Freesmeyer 2014; Drescher et al. 2013; Freesmeyer et al. 2014d). By analogy, it is conceivable that the use of CT morphologic landmarks of a SPECT/CT scanner could provide an advantage over the method presented here. However, a SPECT/CT scanner is not always available (as in our clinic) and makes additional radiation exposure unavoidable. The complementary use of CT data needs to be the subject of further investigation.
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Although SPECT/US fusion imaging is performed in real time, data acquisition is carried out sequentially: first the SPECT data, then the US data with superimposed SPECT data. Because of different reclining angles of the head in each examination, a change in neck position is unavoidable. This must be taken into account when registering SPECT and US data. Moreover, in addition to the initial alignment and registration of both data sets, re-adjustment during the examination was necessary. This is because SPECT acquisition is contactless, but US requires slight pressure on the soft tissues of the neck, such that tissue deformation and tissue shifting lead to a lack of congruence (offset) of both data sets up to 1.5 cm (data not shown). However, this could be improved significantly in all cases with manual adjustment. Both drawbacks, the limited reproducibility of patient positioning and the slight tissue deformation by the US transducer, might be circumvented with a new methodological approach. In such an approach, the nuclear medical functional image and the US morphology are simultaneously recorded and superimposed. In this regard, a proof-of-concept study of a “real-time handheld emission spot allocator” (rthESA) has already been published. However, significant technical development is still required (Freesmeyer et al. 2014a). In contrast, the method presented in our study is based on commercially available and approved medical devices. CONCLUSIONS We report that in a large group of patients, SPECT/ US proved to be an applicable examination method that was always technically successful. Furthermore, it was found, based on expert assessments, that additional SPECT/US adds value and diagnostic gain in cases of unclear findings from conventional thyroid scintigraphy. Although a number of technical and personnel requirements need to be met to integrate this concept into the clinical routine, SPECT/US yields a more accurate assignment of function and morphology without additional radiation exposure and within a reasonable amount of time. Future studies should address the detailed nodule-by-nodule comparison of conventional diagnostics and SPECT/US, as well as blinded analyses and inter-observer variability. Also, its therapeutic relevance should be assessed. In addition, further fusion US concepts, taking into consideration rthESA and PET, should be investigated. Acknowledgments—GE Healthcare (Milwaukee, WI, USA) is gratefully acknowledged for providing hardware (LOGIQ E9) for this study. We thank ChristianHollenbach for assistance in data analysis. This study was funded exclusively with intramural grants from the Jena University Hospital.
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