Evidence-Based PET for Endocrine Tumours and Disorders

Endocrine tumours have a wide range of clinical presentations and can be found anywhere from the neck to the pelvis. Diagnostic imaging is crucial to predict the exact tumour extent, foremost in metastatic disease. Anatomical imaging as computed tomography (CT) and magnetic resonance imaging (MRI) serves as the first-line modality in the locoregional staging of these tumours. Compared with anatomical imaging, PET shows both high sensitivity and specificity. Several meta-analyses have described the diagnostic performance of positron emission tomography (PET) and hybrid imaging (PET/CT) in endocrine tumours and disorders. 10.2 Adrenal Tumours and Paragangliomas


Paragangliomas
Rufini and co-authors compared the diagnostic performance of metaiodobenzylguanidine (MIBG scintigraphy) and PET with different radiopharmaceuticals in patients with paraganglioma (PGL). The authors concluded that the diagnostic performance of PET with different radiopharmaceuticals is clearly superior to that of MIBG scintigraphy in patients with PGL, mainly for familial, extra-adrenal and metastatic diseases [3].
A review article by Treglia and co-authors investigated the diagnostic performance of 18 F-DOPA PET in patients with paraganglioma (PGL). The pooled sensitivity of 18 F-DOPA PET and PET/CT in detecting PGL was 91% (95%CI: 87-94%) on a per-patient-based analysis and 79% (95%CI 76-81%) on a per-lesionbased analysis. The pooled specificity of 18 F-DOPA PET and PET/CT in detecting PGL was 95% (95%CI: 86-99%) on a per-patientbased analysis and 95% (95%CI: 84-99%) on a per-lesion-based analysis. The area under the receiver operating characteristic (ROC) curve was 0.95 on a per-patient-and 0.94 on a perlesion-based analysis. The authors described the possible risk of false-negative 18 F-DOPA PET results in metastatic PGL, besides the fact that succinate dehydrogenase subunit B (SDHB) gene mutations could influence the diagnostic performance of 18 F-DOPA PET or PET/CT [4].
Han and colleagues performed a systematic review and meta-analysis on the performance of 68 Ga-somatostatin analogues PET in the detection of PGL. The pooled detection rate was 93% (95%CI: 91-95%), which was significantly higher than that of 18 F-DOPA PET (80%; 95%CI: 69-88%), 18 F-FDG PET (74%; 95%CI: 46-91%) and MIBG scintigraphy (38%; 95%CI: 20-59%). A greater prevalence of head and neck PGL was associated with higher detection rates of 68 Ga-somatostatin analogues PET. The authors suggest the use of 68 Ga-somatostatin analogues PET as a first-line imaging modality for the primary staging or restaging of PGL with unknown genetic status [6].

Neuroblastoma
Bleeker and colleagues described the role of MIBG scintigraphy and 18 F-FDG PET for diagnosing neuroblastoma (NB). In one study, the sensitivity of 18 F-FDG PET/CT compared to MIBG scintigraphy was 100% and 92%, respectively. Specificity could not be calculated for both modalities. The diagnostic accuracy of 18 F-FDG PET/CT imaging in case of a negative 123 I-MIBG scintigraphy could not be calculated because of very limited data. It has to be mentioned that in about 10% of the patients with histologically proven NB the tumour does not accumulate 123 I-MIBG which underlines the importance of additional functional/anatomical imaging (e.g. 18 F-FDG PET/CT) [7].
A review article by Xia and co-authors demonstrated a summary sensitivity for MIBG scintigraphy and 18 F-FDG PET(/CT) of 79% and 89%, respectively. The summary specificity for MIBG scintigraphy and 18 F-FDG PET(/CT) was 84% and 71%, respectively. The authors concluded that 18 F-FDG PET(/CT) showed higher per-lesion accuracy than MIBG scintigraphy and might be the preferred modality for the staging of NB [8].

Merkel Cell Carcinoma
Treglia and co-authors investigated the diagnostic performance of 18 F-FDG PET and PET/CT in patients with Merkel cell carcinoma (MCC). The meta-analysis provided the following pooled results on a per-examination-based analysis: sensitivity was 90% (95%CI: 80-96%) and specificity was 98% (95%CI: 90-100%). The area under the summary ROC curve was 0.96. No significant statistical heterogeneity between the studies was found. The authors concluded that 18 F-FDG PET or PET/CT demonstrated high sensitivity and specificity, being accurate methods in the detection of MCC taking into account that literature in MCC remains limited [9].

Gastroenteropancreatic and Pulmonary Neuroendocrine Tumours
Singh and co-authors evaluated the diagnostic performance of 68 Ga-somatostatin analogues PET or PET/CT on neuroendocrine tumours (NETs). For the initial diagnosis of NETs, 68 Ga-somatostatin analogues PET or PET/CT had a pooled sensitivity of 91% (95%CI: 85-94%) and a pooled specificity of 94% (95%CI: 86-98%). In the setting of staging and restaging, the sensitivity of 68 Ga-somatostatin analogues PET or PET/CT for detecting primary and/or metastatic lesions ranged from 78.3 to 100%, whereas specificity ranged from 83 to 100%. Change in management occurred in 45% (95%CI: 36-55%) of the cases, with majority of the changes involving surgical planning and patient selection for peptide receptor radionuclide therapy [10]. This is in line with a systematic review by Barrio and colleagues who investigated the impact of 68 Ga-somatostatin analogues PET/CT in patients with NETs. A change of management occurred in 44% of cases after 68 Ga-somatostatin analogues PET/CT (range: 16-71%). In some studies, 68 Ga-somatostatin analogues PET/CT was performed after conventional scintigraphy ( 111 In-Octreotide). In this subgroup, additional information led to a change in management in 39% of cases (range: 16-71%). The authors concluded that the management was changed in more than one-third of patients undergoing 68 Ga-somatostatin analogues PET/CT even when performed after an 111 In-Octreotide scintigraphy [11].
The high diagnostic performance of 68 Ga-somatostatin analogues PET or PET/CT for thoracic and gastroenteropancreatic NETs was showed by the meta-analysis of Treglia et al. reporting a pooled sensitivity and specificity of 93% (95%CI: 91-95%) and 91% (95%CI: 82-97%), respectively. 68 Ga-somatostatin analogues PET/CT should be considered as first-line diagnostic imaging method for these tumours [13].
An updated meta-analysis on this regard reported a pooled sensitivity of 93% (95%CI: 91-94%) and a pooled specificity of 96% (95%CI: 95-98%) for 68 Ga-somatostatin analogues PET or PET/CT. The area under the summary ROC curve was 0.98, confirming the good diagnostic performance of 68 Ga-somatostatin analogues PET or PET/CT compared to diagnostic CT and conventional scintigraphy (e.g. 111 In-Octreotide) [14].
An evidence-based article compared 68 Ga-DOTATOC and 68 Ga-DOTATATE PET in NETs, reporting no statistically significant differences of diagnostic performance among these imaging methods on a per-patient-based analysis [15].

Congenital Hyperinsulinism
Paediatric patients with congenital hyperinsulinism (CHI) due to pancreatic disease can be evaluated by PET or PET/CT, in particular by using 18 F-DOPA. A systematic review and metaanalysis by Blomberg and co-authors aimed to quantify the diagnostic performance of pancreatic venous sampling (PVS), selective pancreatic arterial calcium stimulation with hepatic venous sampling (ASVS) and 18 F-DOPA PET in diagnosing and localizing focal form of CHI. 18 F-DOPA PET was superior in distinguishing focal from diffuse CHI compared to PVS and ASVS. Furthermore, it localized focal CHI in the pancreas more accurately than PVS and ASVS (pooled accuracy: 82% vs. 76% and 64%, respectively) [16].
Yang and colleagues performed a metaanalysis of published data on the diagnostic role of 18 F-DOPA PET in patients with CHI. The pooled sensitivity of 18 F-DOPA PET and PET/CT in detecting CHI was 88%. The pooled specificity of 18 F-DOPA PET and PET/CT in demonstrating CHI was 79%. The area under the ROC curve was 0.92. The authors concluded that 18 F-DOPA PET or PET/CT demonstrated high sensitivity and specificity in patients with CHI [17].
These findings are in line with another metaanalysis by Treglia and co-authors: the pooled sensitivity and specificity of 18 F-DOPA PET or PET/CT in differentiating between focal and diffuse CHI were 89% (95%CI: 81-95%) and 98% (95%CI: 89-100%), respectively. The area under the ROC curve was 0.95. The pooled accuracy of these functional imaging methods in localizing focal CHI was 80% (95%CI: 71-88%). Although possible sources of false-negative results for focal CHI should be kept in mind, the authors concluded that 18 F-DOPA PET or PET/CT are accurate methods for localizing focal CHI [18].

Thyroid Incidentalomas
Nayan and colleagues evaluated through a systematic review and meta-analysis the malignancy rates of thyroid incidentalomas identified in adults by 18  The authors stated that thyroid incidentalomas identified through 18 FDG PET require thorough investigation [19].
In this context, a review article by Qu and coauthors was focused on focal thyroid incidentalomas (FTI) identified on 18 F-FDG PET or PET/ CT. A meta-analysis was performed to investigate whether the maximum standardized uptake value (SUVmax) could discriminate between benign and malignant FTI and to explore the cutoff value of SUVmax for the diagnosis of malignancy. The results of this article indicated that there was no statistically significant difference in the size between benign and malignant FTI, while a significantly higher SUVmax was observed in the malignant group. The authors concluded that a higher SUVmax in FTI was associated with a higher risk of thyroid malignancy, especially at a threshold of 3.3 or more [20].
Treglia and co-authors described the prevalence and malignancy risk of FTI detected by 18 F-FDG PET or PET/CT. Pooled prevalence of FTI was 1.92% (95%CI: 1.87-1.99%). Considering FTI which underwent histopathology evaluation, the pooled risk of malignancy was 36.2% (95%CI: 33.8-38.6%), without significant differences among various geographic areas. The authors concluded that FTI are observed in about 2% of 18 F-FDG-PET or PET/CT and they should be further investigated due to a significant risk of malignancy [21].

Indeterminate Thyroid Nodules
A meta-analysis by Wang and colleagues evaluated the diagnostic accuracy of 18

Recurrence of Differentiated Thyroid Cancer
A meta-analysis by Haslerud and co-authors described the role of 18 [23]. A meta-analysis by Caetano and co-authors aimed to evaluate the accuracy of 18 F-FDG PET and PET/CT for detecting recurrence of DTC, not identified by 131 I whole-body scintigraphy (I-WBS). The combined sensitivity, specificity and accuracy for 18 F-FDG PET were 84%, 84% and 91%, respectively; for 18 F-FDG PET/CT, the combined sensitivity, specificity and accuracy were 93%, 81% and 93% respectively [24].
Another meta-analysis by Schütz and coauthors about the use of 18 F-FDG PET and PET/ CT for detecting recurrent DTC demonstrated that 18 F-FDG PET and PET/CT showed higher sensitivity (89.7% for PET and 94.3% for PET/ CT) compared with conventional imaging (65.4%) and comparable results for specificity [25].
Kim and colleagues investigated the diagnostic accuracy of 18 F-FDG PET/CT for the detection of recurrent and/or metastatic diseases in DTC patients with progressively and/or persistently elevated thyroglobulin antibodies (TgAb) levels and negative I-WBS through a systematic review and meta-analysis. The pooled sensitivity for 18 F-FDG PET or PET/CT was 84% (95%CI: 77-89%), the pooled specificity 78% (95%CI: 67-86%). The area under the ROC curve was 0.88 (95%CI: 0.85-0.90). The authors concluded that 18 F-FDG PET or PET/CT demonstrated moderate sensitivity and specificity for the detection of recurrent and/or metastatic diseases in DTC patients with progressively and/or persistently elevated TgAb levels and negative I-WBS [26].
A meta-analysis by Santhanam and co-authors investigated the accuracy of 18 F-FDG PET/CT in the detection of residual disease in patients with BRAF V600E mutated thyroid cancer. The authors demonstrated that presence of BRAF V600E mutation in DTC confers a higher likelihood of 18 F-FDG avidity and is associated with higher SUVmax values compared to BRAF V600Emutation negative status [27].
The role of 124 I-PET/CT in detecting lesions of DTC amenable to 131 I-therapy was recently described. The pooled sensitivity of 124 I-PET/CT in detecting DTC lesions amenable to 131 I-therapy was 94.2% (95%CI: 91.3-96.4%), and the pooled specificity was 49.0% (95%CI: 34.8-63.4%). The authors concluded that 124 I-PET/CT is a sensitive tool to diagnose radioiodine-avid DTC lesions, but also detects some new lesions that are not visualized on the post-treatment I-WBS [28].

Recurrence of Medullary Thyroid Cancer
Treglia and co-authors described the role of 18 [29].
Other PET radiotracers beyond 18 F-FDG were evaluated for detecting recurrent MTC. In a metaanalysis evaluating the DR of 18 F-DOPA PET or PET/CT for recurrent MTC, the DR of 18 F-DOPA PET and PET/CT on a per-patient-and a perlesion-based analysis was 66% and 71%, respectively. The DR significantly increased in patients with serum calcitonin ≥1000 ng/L (86%) and CTDT <24 months (86%). Therefore, 18 F-DOPA PET/CT may be a very useful functional imaging method in detecting recurrent MTC [31].
Another meta-analysis assessed the DR of 68 Ga-somatostatin analogues PET or PET/CT in patients with recurrent MTC. The DR on a perpatient-based analysis was 63.5% (95%CI: 49-77%). DR of 68 Ga-somatostatin analogues PET or PET/CT increased in patients with higher serum calcitonin levels (83% for calcitonin >500 ng/L). The authors concluded that the diagnostic performance of 68 Ga-somatostatin analogues PET or PET/CT in recurrent MTC was lower compared to that of the same imaging method in the majority of NETs [32].

Parathyroid Diseases
Different PET tracers may be used to detect hyperfunctioning parathyroid glands in patients with hyperparathyroidism (HPT), including 11 C-methionine ( 11 C-MET) and radiolabelled choline. 11 C-MET PET has an overall good sensitivity (69%) and positive predictive value (98%) in detecting hyperfunctioning parathyroid glands in patients with HPT and it may be considered a reliable second-line imaging method to enable minimally invasive parathyroidectomy [33].
Yuan and co-authors published a metaanalysis on the diagnostic value of 11 C-MET PET in detecting hyperfunctioning parathyroid glands in patients with HPT and negative 99m Tc-MIBI scan. Pooled sensitivity and specificity of 11 C-MET PET in patients with HPT with negative or inconclusive 99m Tc-MIBI scan were 86% and 86%, respectively. The authors concluded that 11 C-MET PET can be a useful functional imaging modality in patients with negative or inconclusive 99m Tc-MIBI scan [34].
Caldarella and co-authors investigated the diagnostic performance of 11 C-MET PET in patients with suspected parathyroid adenoma. Pooled sensitivity and DR values of 11 C-MET PET in patients with suspected parathyroid adenoma were 81% (95%CI: 74-86%) and 70% (95%CI: 62-77%), respectively, on a per-patientbased analysis. The authors also concluded that 11 C-MET PET could be helpful when conventional imaging techniques are negative or inconclusive in localizing parathyroid adenoma [35].