PET and PET/CT with 68Gallium-Labeled Somatostatin Analogues in Non GEP-NETs Tumors

Somatostatin (SST) is a 28-amino-acid cyclic neuropeptide mainly secreted by neurons and endocrine cells. A major interest for SST receptors (SSTR) as target for in vivo diagnostic and therapeutic purposes was born since a series of stable synthetic SST-analouges PET became available, being the native somatostatin non feasible for clinical use due to the very low metabolic stability. The rationale for the employment of SST-analogues to image cancer is both based on the expression of SSTR by tumor and on the high affinity of these compounds for SSTR. The primary indication of SST-analogues imaging is for neuroendocrine tumors (NETs), which usually express a high density of SSTR, so they can be effectively targeted and visualized with radiolabeled SST-analogues in vivo. Particularly, SST-analogues imaging has been widely employed in gastroenteropancreatic (GEP) NETs. Nevertheless, a variety of tumors other than NETs expresses SSTR thus SST-analogues imaging can also be used in these tumors, particularly if treatment with radiolabeled therapeutic SST-analouges PET is being considered. The aim of this paper is to provide a concise overview of the role of positron emission tomography/computed tomography (PET/CT) with 68Ga-radiolabeled SST-analouges PET in tumors other than GEP-NETs.

Finally, there was no observed toxicity, immediate or delayed, during the followup (1 year), for 68 Ga-DOTATATE demonstrating that this radiopharmaceutical is safe and both organ-specific and effective dose exposures are acceptable [23].
The primary indication of radiolabeled SST-analogues imaging is for neuroendocrine tumors (NETs), a heterogeneous group of neoplasms that arise from endocrine cells within glands (adrenal medulla, pituitary, and parathyroid) or from endocrine islets in thyroid, pancreas, or respiratory/gastrointestinal tract, which usually express a high density of SSTR. However radiolabeled SST-analogues can also be used in the imaging of inflammatory granulomatous and autoimmune conditions as well as non NETs although they cannot be considered as the first-choice functional imaging modality in the management of these patients, except for the determination of SSTR status [27][28][29][30]. Table 1 summarizes the different SSTR subtypes expressed by each tumor considered.
The aim of this paper is to provide a concise overview of the role of positron emission tomography/computed tomography (PET/CT) with 68 Ga-labeled SST-analogues in tumors other than GEP-NETs (Tables 2 and 3).

Sympathoadrenal System Tumors
The use of 68 Ga-labeled SST-analogues PET and PET/CT paraganglioma ( Figure 1) and phaeochromocytoma ( Figure 2) remains small, consisting mainly of case reports and small series.
Fanti et al. [31] evaluated the role of 68 Ga-DOTANOC in 14 patients with NET including 3 cases of paragangliomas. All paragangliomas were detected with 68 Ga-DOTANOC and were strongly positive. Mittal et al. [32] retrospectively evaluated 145 patients including phaeochromocytoma ( = 2) and paraganglioma ( = 3) with 68 Ga-DOTATATE PET/CT. PET/CT was positive in only 1 patient affected by paraganglioma. Several authors have reported the higher diagnostic performances of 68 Ga-DOTATATE PET/CT compared to 123 I-MIBG scintigraphy in phaeochromocytoma and paraganglioma [33][34][35]. Kroiss et al. [36] reported a higher sensitivity for lesion detection of 68 Ga-DOTATOC PET/CT in metastatic phaeochromocytoma patients ( = 6) compared to 123 I-MIBG scan (92% and 63%, resp.). More recently, Maurice et al. [37] reported similar results in 15 patients with phaeochromocytoma ( = 9) or paragangliomas ( = 6) evaluated with 68 Ga-DOTATATE PET/CT and 123 I-MIBG single photon emission computed tomography (SPECT). Utilizing 123 I-MIBG scintigraphy as gold standard, 68 Ga-DOTATATE had a sensitivity of 80% and a positive predictive value of 62%. The greatest discordance was in head and neck lesions, with the lesions in 4 patients being picked up by 68 Ga-DOTATATE and missed by 123 I-MIBG. On a per-lesion analysis, 68 Ga-DOTATATE was superior to 123 I-MIBG in detecting lesions in all anatomical locations (particularly bone lesions). Very recently, Sharma et al. [38] studied 26 patients with known or suspected head and neck paragangliomas by 68 Ga-DOTANOC PET/CT and compared PET/CT findings to 123 I-MIBG scintigraphy and CT/MRI results. 68 Ga-DOTANOC PET/CT was positive in all patients and it was able to detect more lesions ( = 78) compared to 123 I-MIBG alone or combined with CT/MRI ( = 30 and = 53, resp.). 68 Ga-DOTANOC PET/CT has also been compared to CT for the evaluation of bone metastases in patients with NET including patients with paraganglioma ( = 5), being more accurate than CT for the early identification of bone lesions [31].
Hofman et al. [39] compared 68 Ga-DOTATATE PET/CT to 111 In-octreotide imaging (SPECT or SPECT/CT) in a series of oncological patients including phaeochromocytoma ( = 4) in order to identify the management impact of incremental diagnostic information obtained from PET/CT compared with conventional staging. 68 Ga-DOTATATE PET/CT provided additional diagnostic information in a large proportion of patients with consequent high management impact. This impact included directing patients to curative surgery by identifying the primary site and directing patients with multiple metastases to systemic therapy.
In conclusion, in case of negative 123 I-MIBG scan in patients with a high pretest probability of phaeochromocytoma or paraganglioma, 68 Ga-labeled SST-analogues PET or PET/CT should be considered as the next investigation. Additionally, 68 Ga-labeled SST-analogues PET/CT should be considered in the staging of patients in whom metastatic spread, particularly to the bone, is suspected. 68 Ga-SST-analogues PET and PET/CT have been evaluated in all types of lung tumor (Figures 3 and 4). Hofmann et al. [15] compared the diagnostic values of 111 In-octreotide scintigraphy and 68 Ga-DOTATOC PET to morphologic imaging in 8 patients with metastatic carcinoid tumors including 2 bronchial carcinoids. 68 Ga-DOTATOC PET was superior to 111 In-octreotide scintigraphy in the identification of tumor lesions (overall sensitivity of 100% versus 85%). Similarly, Koukouraki et al. [40] used 68 Ga-DOTATOC PET to evaluate 15 cases of carcinoid tumors, including 2 cases of pulmonary carcinoids, reporting an overall sensitivity of 92%. Gabriel et al. [41] used 68 Ga-DOTATOC PET to evaluate 84 patients with NET, including 5 patients with bronchial carcinoids, and reported results higher than those obtained with radiolabeled SST-analogues SPECT or CT. Ambrosini et al. [42] compared 68 Ga-DOTANOC PET/CT to CT scan in 11 patients with bronchial carcinoids. There were no false-positive findings at PET/CT, and 68 Ga-DOTANOC PET/CT detected more lesions than CT (37 versus 21). On a clinical basis, The Scientific World Journal    The Scientific World Journal   Paraganglioma ( = 1); pulmonary carcinoid ( = 2); thymic carcinoid ( = 1); MTC ( = 1)      68 Ga-SST-analogues PET/CT has also been compared to CT and bone scintigraphy for the evaluation of bone metastases in patients with lung NET being more accurate than CT and bone scintigraphy for the early identification of bone lesions [48,49]. Finally, 68 Ga-DOTATATE PET/CT has also been evaluated to predict progression-free survival and clinical outcome after peptide radioreceptor therapy (PRRT) in a series of patients with well-differentiated NET including 4 cases with lung NET. Results showed that patients with a decline in tumor-to-spleen SUV ratio (SUV T/S ) after finishing the first cycle of PRRT had a significant longer time to progression than patients without favorable SUV T/S changes, suggesting that this parameter has a potential role in the early prediction of outcome in patients with well-differentiated NET [50].

Lung Tumors
Dimitrakopoulou-Strauss et al. [51] compared SSTR expression assessed by 68 Ga-DOTATOC PET to tumor viability assessed by [ 18 F]FDG-PET in 9 patients with NSCLC. Moderately enhanced 68 Ga-DOTATOC uptake was noted in 7/9 primary tumors (mean SUV max = 2.018 The Scientific World Journal 9   Recently, we evaluated the performances of PET/CT with 68 Ga-labeled SST-analogues in 24 patients with progressive extensive SCLC, to select patients for subsequent PRRT and compared 68 Ga-labeled SST-analogues PET/CT results to contrast-enhanced CT findings. PET/CT was positive in 83% of patients and concordant to CT findings for all the sites of disease in 37.5% of cases [52].
In conclusion, the degree of uptake and different uptake patterns on [ 18 F]FDG and 68 Ga-SST-analogues PET or PET/CT may be helpful in differentiating between typical and atypical carcinoids. 68 Ga-SST-analogues PET/CT may be useful also to stage disease in lung cancer and to select patients for the best treatment option, including PRRT.

Brain Neuroepithelial Tissue Tumors
The overexpression of SSTR has been reported in most high grade gliomas and it may be an interesting target for PRRT. 68 Ga-DOTATOC PET showed SSTR expression (unpublished data from Innsbruck Medical University) in the majority of patients with brain tumors (89%) including glioma ( = 3), medulloblastoma ( = 2), anaplastic astrocytoma ( = 1), and glioblastoma ( = 13) with a different degree of radiotracer uptake (faint = 37%, medium = 21%, and intense = 31%) [53]. Mittal et al. [32] retrospectively evaluated 145 patients including neuroblastoma ( = 8) with 68 Ga-DOTATATE PET/CT with different purposes (initial staging, = 6; disease recurrence detection and response evaluation, = 1 each). In all the patients evaluated PET/CT was positive and in 5/6 cases in which 68 Ga-DOTATATE PET/CT was performed as initial stage it was able to detect metastatic site of disease. Kroiss et al. [36] compared 68 Ga-DOTATOC PET/CT to 123 I-MIBG scan in a series of patients including neuroblastoma ( = 5) reporting the superiority of PET/CT compared to scintigraphy (sensitivity of 97% and 91%, resp.). 68 Ga-radiolabeled SST-analogues PET/CT has been also used to select patients for PRRT (neuroblastoma, = 8; glioma, = 3) [54,55] and to evaluate treatment response combined with other imaging modalities [54].

Meningioma
Several authors have investigated the role of 68 Ga-labeled SST-analogues PET/CT in patients with intracranial meningioma. Virtually, all patients with meningioma present 68 Galabeled SST-analogues uptake ( Figure 5). Afshar-Oromieh et al. [56] compared diagnostic accuracy of 68 Ga-DOTATOC PET/CT to brain contrast-enhanced MRI in a large series of meningioma patients before radiotherapy. In the 134 patients investigated by both modalities, 190 meningiomas were detected by 68 Ga-DOTATOC PET/CT and 171 by contrastenhanced MRI. With the knowledge of the PET/CT data, MRI scans were reinvestigated, leading to the detection of 4 of the 19 incidental meningiomas, resulting in an overall detection rate of 92% of the meningioma lesions that have been found by PET/CT. Milker-Zabel et al. [57] compared the planning target volume outlined on CT and contrastenhanced MRI to the planning target volume outlined on 68 Ga-DOTATOC PET. Patients were treated according to the planning target volume defined with CT, MRI, and PET. The planning target volume defined with CT, MRI, and PET was somewhat larger than the volume detectable in MRI/CT (median 57.2 cc and 49.6 cc, resp.). In all patients 68 Ga-DOTATOC PET delivered additional information concerning tumor extension and the planning target volume was significantly modified based on 68 Ga-DOTATOC PET data in 73% of the cases. Similarly, Gehler et al. [58] defined the gross tumor volume by MRI, CT, and 68 Ga-DOTATOC PET/CT in 26 patients with meningioma. Initial gross tumor volume definition was only based on radiological data and was secondarily integrated with 68 Ga-DOTATOC PET/CT information. 68 Ga-DOTATOC PET/CT provided additional information concerning tumor extension in 65% of patients (especially for skull base manifestations and recurrent disease after surgery) and modified the planning target volume in more than half of patients. Nyuyki et al. [59] investigated the potential value of 68 Ga-DOTATOC PET/CT in the definition of the gross tumor volume in 42 meningioma patients before radiotherapy. 68 Ga-DOTATOC PET/CT findings were compared to CT and MRI. Results showed that 68 Ga-DOTATOC PET/CT enabled delineation of SSTR-positive meningiomas and provided additional information compared to both CT and MRI regarding the planning of stereotactic radiotherapy (particularly for the detection of osseous infiltration). Additionally, in a subgroup of patients with multiple meningiomas, 68 Ga-DOTATOC PET/CT was able to identify more lesions compared to CT or MRI (19 versus 10, resp.). Similarly, Graf et al. [60] retrospectively compared 68 Ga-DOTATOC PET/CT to MRI and CT in the delineation of infracranial extension of skull base meningiomas in 16 patients subsequently treated with fractionated stereotactic radiotherapy. The mean infracranial volume delineable in PET was somewhat larger than the volume detectable in MRI/CT (10.1 ± 10.6 cm 3 and 8.4 ± 7.9 cm 3 , resp.). However, authors have concluded that 68 Ga-DOTATOC PET/CT may be useful for planning fractionated stereotactic radiation when used in addition to conventional imaging modalities often inconclusive in the skull base region. Henze et al. [61,62] characterized meningioma with dynamic 68 Ga-DOTATOC PET in order to evaluate kinetic parameters reporting a good correlation with MRI and CT findings and a significant difference of radiotracer uptake between meningioma and reference tissue (mean SUV = 10.5 and 1.3, resp.) suggesting a possible role of 68 Ga-DOTATOC PET/CT in monitoring meningioma SSTR expression after radiotherapy. Recently, Hänscheid et al. [63] evaluated the predictive role of 68 Ga-labeled SST-analogues PET to assess tumor radionuclide uptake in PRRT of meningioma. Results showed a strong correlation between SUV max and PRRT radionuclide tumor retention in the voxels with the highest uptake suggesting a potential role of 68  SST-analogues PET to estimate the PRRT achievable dose. Therefore 68 Ga-labeled SST-analogues PET/CT may provide additional information in patients with uncertain or equivocal results using MRI or could help to confirm a diagnosis of meningioma based on MRI or may help to confirm MRIbased diagnosis of meningioma in cases of biopsy limitations. Finally, 68 Ga-labeled SST-analogues PET or PET/CT may be useful to delineate the target volume for fractionated stereotactic radiotherapy.

Medullary Thyroid Cancer
Although studies investigating larger and more homogeneous patient populations are needed to better elucidate the potential diagnostic role of new PET tracers for the assessment of recurrent medullary thyroid carcinoma (MTC), the preliminary published data seem to suggest that the diagnostic role of 68 Ga-SST-analogues appears to be controversial ( Figure 6). In fact, well-differentiated tumors show a variable and often low SSTR subtype cell expression. Of course, the evidence of a high uptake of 68 Ga-labeled SST-analogues could be used to accurately define the tumor biology "map" and therefore may be potentially helpful in selecting the most appropriate therapeutic option. Conry et al.

Differentiated Thyroid Carcinoma
Although papillary, follicular, and anaplastic thyroid cancers and also Hürthle-cell carcinomas do not belong to the group of traditional NET, 68 Ga-SST-analogues PET and PET/CT may be positive in many patients ( Figure 7  In a per-lesion analysis, all lesions shown by contrast enhanced CT scan, which was considered the gold standard, were detected in 20% and 43% of cases using 68 Ga-SST-analogues and [ 18 F]FDG, respectively; in the remaining cases we observed at least one measurable CT lesion without either 68 Ga-SST-analogues or [ 18 F]FDG uptake. In this series of thymic neoplasms at restaging a predominant [ 18 F]FDG positivity was observed compared to 68 Ga-SST-analogues at PET/CT suggesting a relative loss of SSTR expression during thymic malignancies progression and a subsequent increasing of biological aggressiveness [73] ( Figure 8).

Merkel Cell Carcinoma
Merkel cell tumors are aggressive neoplasms that often metastasize and, despite therapy, the disease-related death rate is high. Ultrastructurally and immunocytochemically, The Scientific World Journal  the majority of these tumors have neuroendocrine characteristics. Establishing the extent of the disease may ensure an optimal choice of treatment for these tumors; however, due to the rarity of these tumors, few cases have been evaluated by 68 Ga-labeled SST-analogues PET/CT. Nevertheless, available data showed the usefulness of 68 Ga-labeled SST-analogues PET/CT to stage and restage patients with Merkel cell carcinoma, and also to identify patients suitable for PRRT and to evaluate treatment response [48,67,[74][75][76][77].

Breast Cancer
In breast cancer differentiated tumors express more SSTR2 than undifferentiated ones, and estrogens positively affect SSTR2 expression; additionally, the research of new factors that could allow a more accurate prognosis of the existing disease and that could improve traditional treatment strategies remains critical [29]. However no sufficient data are available about the role of 68 Ga-SST-analogues PET or PET/CT in this clinical setting (Figure 9). Elgeti et al. [78] retrospectively analyzed 68 Ga-DOTATOC PET/CT performed for staging purpose in 33 women with NET. In 6/33 patients 68 Ga-DOTATOC PET/CT revealed the presence of a breast lesion classified as suspected in 4/6 cases. In 2 cases the suspected breast lesion was diagnosed as NET metastases while in the remaining 2 cases it was diagnosed as primary breast cancer resulting in a change of therapeutic management. Primary breast cancer presented a lower 68 Ga-DOTATOC uptake compared to concomitant abdominal NET lesions. In this small series of patients 68 Ga-DOTATOC PET/CT not only improved NET staging but also increased the chance to detect 14 The Scientific World Journal

Colorectal Cancer
Some data suggest that SSTR2 gene expression in colorectal cancer might be related to a more favorable outcome [79]. However no sufficient data are available about the role of 68 Ga-SST-analogues PET/CT in this clinical setting [80,81]. Desai et al. [81] reported the usefulness of molecular imaging using different PET radiotracers in order to understand NET biology and subsequently to determine the best treatment option. In this case a different tumor pattern of [ 18 F]FDG and 68 Ga-DOTATATE uptake was shown by PET examinations within the liver, resulting in synchronous colorectal cancer and pancreatic NET liver metastases.

Melanoma
Few cases have been reported in the literature about the role of 68 Ga-labeled SST-analogues PET/CT in melanoma patients [48,82]. Brogsitter

Prostate Cancer
Few cases have been reported in the literature about the role of 68 Ga-labeled SST-analogues PET/CT in prostate cancer patients [31,41,48,49,[83][84][85]. Luboldt et al. [84] assessed SSTR expression in 20 patients with advanced prostate cancer to potentially guide SSTR-mediated therapies. On a side-by-side analysis only 30% of bone scintigraphy-positive metastases were seen with 68 Ga-DOTATOC PET/CT. The authors concluded by suggesting further studies with different SST-analogues with a higher affinity for SSTR1 and SSTR4 (expressed by prostate cancer), not adequately addressed with DOTATOC. The only case reported in the literature using 68 Ga-DOTATATE showed intense radiotracer uptake in bone metastases, confirming bone scan results and suggesting a potential role of 68 Ga-DOTATATE PET/CT to guide SSTRmediated therapies also in this clinical setting [85].
In this clinical setting 68 Ga-DOTATATE PET/CT may represent the first step functional imaging to identify the site of disease but further studies are needed to confirm these preliminary results.

Lymphoma
The use of 68 Ga-labeled SST-analogues PET/CT in lymphoma is limited to sporadic cases [31,80] (Figure 10).

Conclusion and General Remarks
The use of 68 Ga-labeled SST-analogues PET/CT in phaeochromocytoma and paraganglioma remains small, consisting mainly of case reports and small series. The diagnostic accuracy of 68 Ga-SST-analogues PET/CT is superior to 131 I-MIBG; thus, in the case of negative 123 I-MIBG scan in patients with a high pretest probability of phaeochromocytoma or paraganglioma, 68 Ga-labeled SST-analogues PET/ CT should be considered. Additionally, 68 Ga-labeled SSTanalogues PET/CT should be considered in the staging of patients in whom metastatic spread, particularly to the bone, is suspected.
Although limited experience exists in NCSCL and SCLC, 68 Ga-SST-analogues PET or PET/CT has been evaluated in all types of lung tumor. Particularly, the degree of uptake and the different uptake patterns on [ 18 F]FDG and 68 Ga-SSTanalogues PET or PET/CT may be helpful to differentiate typical from atypical carcinoids. 68 Ga-SST-analogues PET/CT may be useful also to stage lung cancer (especially for the early identification of bone lesions) and to select patients for the best treatment option, including PRRT.
Some interesting studies on radiolabeled SST-analogues PET/CT in patients with brain neuroepithelial tumors (either for staging, treatment selection, or response evaluation) are reported in the literature. 68 Ga-labeled SST-analogues PET/CT has been widely used in patients with intracranial meningioma. 68 Ga-labeled SST-analogues PET/CT provides additional information in patients with uncertain or equivocal results at MRI and helps to confirm a diagnosis of meningioma based on MRI or to confirm MRI-based diagnosis of meningioma in cases of biopsy limitations. Finally, 68 Ga-labeled SST-analogues PET or PET/CT may be useful to delineate the target volume for fractionated stereotactic radiotherapy. Although studies investigating larger and more homogeneous patient populations are needed to better elucidate the potential diagnostic role of radiolabeled SST-analogues for the assessment of recurrent MTC, the preliminary published data suggest a controversial role of 68 Ga-SST-analogues since well-differentiated tumors show a variable and often low SSTR subtype cell expression. 68 Ga-SST-analogues PET and PET/CT were positive in many patients with DTC providing, especially in negative radioiodine cases, new therapeutic options as PRRT. However, further studies comparing 68 Ga-SST-analogues to radioiodine scintigraphy and [ 18 F]FDG-PET/CT in DTC are needed.
Limited disappointing experience exists regarding the role of 68 Ga-SST-analogues PET/CT in patients with thymic malignancies. In thymic neoplasms a predominant [ 18 F]FDG positivity has been observed compared to 68 Ga-SST-analogues at PET/CT suggesting a relative loss of SSTR expression during thymic malignancy progression and subsequent increasing of biological aggressiveness.
Few but significant data are available about the role of 68 Ga-labeled SST-analogues PET/CT in Merkel cell carcinoma. 68 Ga-labeled SST-analogues PET/CT is useful to stage and restage patients, and also to select treatment for PRRT and to assess treatment response.
Although only few cases have been reported in the literature about the use of 68 Ga-labeled SST-analogues PET/CT in tumor-induced osteomalacia, 68 Ga-DOTATATE PET/CT may represent the first step functional imaging to identify mesenchymal tumors; however further studies are needed to confirm the promising preliminary results.
No sufficient data are available about the role of 68 Ga-SST-analogues PET or PET/CT in melanoma and breast, colorectal, and prostate cancers. The use of 68 Ga-labeled SSTanalogues PET/CT in lymphoma is limited to sporadic cases with unfavorable results.
In conclusion, although these preliminary experiences suggest a possible role of 68 Ga-SST-analogues PET or PET/ CT in many non GEP-NETs tumors, further studies are needed to confirm these promising results.

Conflict of Interests
All the authors declare that they have no conflict of interests.