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68Ga-PSMA-HBED-CC Uptake in Cervical, Coeliac and Sacral Ganglia

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68Ga-PSMA-HBED-CC Uptake in Cervical, Coeliac and Sacral Ganglia Journal of Nuclear Medicine, published on January 25, 2018 as doi:10.2967/jnumed.117.204677 1 68Ga‐PSMA‐HBED‐CC uptake in cervical, coeliac and sacral ganglia as an important 2 pitfall in prostate cancer PET imaging 3 4 Christoph Rischpler1*, Teresa I. Beck2*, Shozo Okamoto1,3, Anna M. Schlitter4, Karina Knorr1, Markus 5 Schwaiger1, Jürgen Gschwend5, Tobias Maurer5, Philipp T. Meyer2, Matthias Eiber1 6 7 1Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany 8 2Department of Nuclear Medicine, Medical Center ‐ University of Freiburg, Germany 9 3Department of Nuclear Medicine, Hokkaido University Graduate School of 10 Medicine, Japan 11 4Institute of Pathology, Technical University Munich, Munich, Germany 12 5Department of Urology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany 13 14 *Both first authors contributed equally to this article. 15 16 Corresponding author: 17 Christoph Rischpler, MD 18 Email: [email protected] 19 Phone: +49 (0) 89 /4140‐6085 20 Klinikum Rechts der Isar, 21 Nuklearmedizinische Klinik und Poliklinik 22 Ismaninger Str. 22 23 81675 München 24 25 Word count (abstract): 348 26 Word count (whole manuscript): 3644 27 28 Short running title: PSMA‐ligand uptake in ganglia 1 29 ABSTRACT 30 31 The study aims to investigate the presence of physiological prostate‐specific membrane 32 antigen (PSMA)‐ligand uptake on positron‐emission‐tomography (PET) in cervical, coeliac and 33 sacral ganglia of the sympathetic trunk as a pitfall for lymph node metastases in prostate 34 cancer imaging. Methods: 407 patients who underwent “Glu‐NH‐CO‐NH‐Lys” radio‐labeled 35 with [68Ga]gallium N,N‐bis[2‐hydroxy‐5‐(carboxyethyl)benzyl]ethylenediamine‐N,N‐diacetic 36 acid (68Ga‐PSMA‐HBED‐CC) PET (combined with a diagnostic computed tomography (CT)) 37 were retrospectively analyzed. The number of PSMA PET‐positive cervical, coeliac and sacral 38 ganglia was determined and the configuration and maximum standardized uptake value 39 (SUVmax) of each ganglion was measured. In addition, the configuration and SUVmax of adjacent 40 lymph node metastases in the respective region (cervical, coeliac or sacral) were determined. 41 Results: PSMA‐ligand uptake above background was detected in 401 (98.5%) patients in any 42 peripheral ganglia, in 369 (92%) patients in cervical ganglia, in 363 (89%) patients in coeliac 43 ganglia, and in 183 (46%) patients in sacral ganglia. The PSMA‐ligand uptake was highest in 44 coeliac (mean SUVmax 2.9±0.8 vs. cervical (mean SUVmax 2.4±0.6) and sacral (mean SUVmax 45 1.7±0.5), both p<0.0001) ganglia. Intra‐individually there was a statistically significant, but weak 46 to moderate correlation between the PSMA‐ligand uptake in cervical vs. coeliac ganglia 47 (R=0.34, p<0.0001), cervical vs. sacral (R=0.52, p<0.0001) and coeliac vs. sacral (R=0.16, p<0.05). 48 The PSMA‐ligand uptake was significantly more intense in adjacent lymph node metastases 49 compared to the respective ganglia (cervical: 18.0±16.2 vs. 2.4±0.6, p<0.0001; coeliac: 13.5±12.3 50 vs. 2.9±0.8, p<0.0001; sacral: 13.4±11.6 vs. 1.7±0.5, p<0.0001). Furthermore, ganglia 51 predominantly exhibit a band‐shaped (71.2%), followed by a teardrop (26.8%) and only rarely a 52 nodular configuration (2.0%). Conversely, lymph node metastases are only rarely band‐shaped 2 53 (1.1%), but more often show teardrop (40.3%) or nodular appearance (58.6%) (p<0.00001). 54 Conclusion: PSMA‐ligand uptake in ganglia along the sympathetic trunk as assessed by 68Ga‐ 55 PSMA‐HBED‐CC PET represents an important pitfall in prostate cancer PET imaging. The 56 PSMA‐ligand uptake is higher in coeliac ganglia compared to cervical or sacral ganglia and the 57 level of PSMA‐ligand uptake seems to be patient‐related. For the differentiation between 58 lymph node metastases and sympathetic ganglia both intensity of PSMA‐ligand‐uptake as well 59 as exact localization and configuration of the respective lesion should be examined carefully. 60 3 61 INTRODUCTION 62 The prostate‐specific membrane antigen (PSMA) is a membrane‐bound enzyme, which is 63 highly expressed on prostate cancer cells and its metastases (1). It is also named glutamate 64 carboxypeptidase II based on its enzymatic function. PSMA‐targeted imaging using positron‐ 65 emission‐tomography (PET) radiotracers, such as “Glu‐NH‐CO‐NH‐Lys” radio‐labeled with 66 [68Ga]gallium N,N‐bis[2‐hydroxy‐5‐(carboxyethyl)benzyl]ethylenediamine‐N,N‐diacetic acid 67 (68Ga‐PSMA‐HBED‐CC), has therefore experienced an increasing demand during the last few 68 years (2). In some centers PSMA PET imaging is now regarded as the method of reference for 69 staging and re‐staging of patients with confirmed (high‐risk) prostate cancer or in case of 70 biochemical recurrence; furthermore, even at low PSA levels and for small lymph node 71 metastases, PSMA PET imaging offers a high sensitivity (2‐5). 72 However, high PSMA expression has also been described in malignant lesions not 73 related to the prostate (e.g. renal cell carcinoma, bronchial carcinoma, glioblastoma), in benign 74 tissues (e.g. renal tubules, duodenum, colon) and in benign lesions such as schwannomas, 75 osteophytes, thyroid adenomas or vertebral and subcutaneous hemangiomas (1,6‐14). The 76 ganglia of the sympathetic trunk are another tissue where an increased PSMA expression has 77 been reported (15,16). Histologic studies have found that the glutamate carboxypeptidase II is 78 highly expressed on non‐myelinating Schwann cells in ganglia of the sympathetic nervous 79 system. This potentially explains PSMA‐ligand uptake in various parts of the sympathetic 80 nervous system (17). As the sympathetic trunk runs along the vertebra, sympathetic ganglia 81 can easily be confused with lymph node metastases that are often found in close proximity 82 particularly to cervical, coeliac or sacral ganglia. Consequently, PSMA‐ligand uptake in such 83 ganglia is a potential source of misdiagnosis, which may even result directly in change of 84 therapy regimen and therefore represents an important pitfall. The aim of this retrospective 4 85 analysis was to give a detailed description of the incidence and imaging pattern in 68Ga‐PSMA‐ 86 HBED‐CC PET/computed tomography (CT) of cervical, coeliac and sacral ganglia in order to 87 facilitate the discrimination from prostate cancer related lymph node metastases. 88 89 MATERIALS AND METHODS 90 Patient Population, Radiotracer Synthesis and Imaging Protocol 91 407 patients from two centers (Technical University Munich and University of Freiburg) 92 who underwent 68Ga‐PSMA‐HBED‐CC PET/CT between October 2012 and August 2015 were 93 randomly selected and analyzed. Only studies with a diagnostic CT were chosen in order to 94 allow for detailed anatomical description of the configuration of ganglia and lymph node 95 metastases. 96 The retrospective study was approved by the Ethics Committee of the Technical 97 University Munich (permit 5665/13), and written informed consent was obtained from all 98 patients for the purpose of anonymized evaluation and publication of their data. All reported 99 investigations were conducted in accordance with the Helsinki Declaration and with national 100 regulations. 101 PET/CT scans were performed on a Siemens Biograph mCT (Siemens Healthcare, 102 Erlangen, Germany) or a 64‐slice GEMINI TF PET/CT (Philips Healthcare, USA). Radiotracer 103 synthesis was performed as previously described (3) and injected via an intravenous bolus 104 (167±28 MBq, range 120‐240 MBq). PET/CT acquisition was started 56±8 (range 32‐85) minutes 105 after tracer injection. The diagnostic CT scan was acquired after patients received oral contrast 106 and in portal venous phase. Subsequently, the PET scan was acquired in 3‐dimensional mode 107 with an acquisition time of 3‐4 minutes per bed position (Munich) or with 2 minutes per bed 108 position, whole‐body protocol with 50% overlap (Freiburg). Correction of emission data for 5 109 randoms, dead time, scatter and attenuation was performed. Iterative reconstruction of PET 110 data by an ordered‐subsets expectation maximization algorithm (4 iterations, 8 subsets) 111 followed by a post‐reconstruction smoothing gaussian filter (5 mm in full width at one‐half 112 maximum) was performed (Munich) or PET listmode‐data were reconstructed using a lines of 113 response‐based ordered‐subsets algorithm with time‐of‐flight information in a 2x2x2mm³ voxel 114 matrix (BLOB‐OS‐TF, 3 iterations, 33 subsets, relaxation parameter l=0.35, no additional 115 smoothing) (Freiburg). 116 117 Image Analysis 118 Images were analyzed by 2 experienced nuclear medicine physicians (4 and 12 years of 119 training). PET and CT images were analyzed side by side and the number, location (left/right, 120 cervical/coeliac/sacral), PSMA‐ligand uptake intensity (maximum standardized uptake value 121 (SUVmax) normalized to body weight and visual intensity ranging from 0 to 3 [faint / mild / 122 moderate / intense uptake]; Fig. 1) and configuration (band, teardrop or nodular shape; Fig. 2) 123 of PSMA‐positive sympathetic ganglia were assessed. Main criteria for ganglia were focal 124 PSMA‐ligand uptake that projected onto a structure with typical location for sympathetic 125 ganglia. In a second step, the same parameters for definite lymph node metastases in close 126 proximity to the respective ganglia were determined to investigate potential criteria for 127 differentiation. 128 129 Histology 130 From patients that had an extensive surgery of the pelvis, sacral ganglia were obtained 131 and stained for PSMA expression as previously described (18). 132 6 133 Statistics 134 Results are either demonstrated as frequencies (%) or as mean±standard deviation. P 135 values less than 0.05 were considered statistically significant.
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