REVIEW

PET/CT assessment of neuroendocrine tumors of the lungwith special emphasis on bronchial carcinoids

Filippo Lococo & Alfredo Cesario & Massimiliano Paci & Angelina Filice & Annibale Versari &Cristian Rapicetta & Tommaso Ricchetti & Giorgio Sgarbi & Marco Alifano &

Alberto Cavazza & Giorgio Treglia

Received: 4 April 2014 /Accepted: 13 May 2014# International Society of Oncology and BioMarkers (ISOBM) 2014

Abstract Pulmonary neuroendocrine tumors (pNETs) arisefrom bronchial mucosal cells known as enterochromaffin cellswhich are part of the diffuse neuroendocrine system. Thepathological spectrum of pNETs ranges from low-/intermedi-ate-grade neoplasms such as bronchial carcinoids (BCs), alsoknown as typical or atypical carcinoids, to high-grade neo-plasms as large-cell neuroendocrine carcinoma and small-celllung cancer. The tumor biology of pNETs still represents amatter of open debate. The distinct features among the differ-ent pNETs include not only their pathologic characteristics butalso their clinical behavior, epidemiology, treatment, andprognosis. In this sense, a correct pathological identificationin the preoperative setting is a key element for planning thebest strategy of care in pNETs and especially in BCs. Contro-versial results have been reported on the diagnostic accuracyof fluorine-18-fluorodeoxyglucose positron emission tomog-raphy or positron emission tomography/computed

tomography (F-18-FDG PET or PET/CT) in BCs. On theother hand, there is increasing evidence supporting the useof PET with somatostatin analogues (DOTA-TOC, DOTA-NOC, or DOTA-TATE) labeled with gallium-68 (Ga-68) inpNETs. Herein, we review the pertinent literature aiming tobetter define the current state of art of PET/CT in the detectionand histological differentiation of pNETs with special empha-sis on BCs.

Keywords Neuroendocrine tumors . Pulmonary tumors .

PET/CT . Functional imaging

Introduction

Pulmonary neuroendocrine tumors (pNETs) represent a spec-trum of neoplastic entities distinguished not only on the basisof pathologic characteristics but also regarding their clinicalbehavior, epidemiology, treatment, and prognosis. About thebronchial carcinoids (BCs), typical carcinoids (TCs) are indo-lent neoplasms with a good prognosis, whereas atypical car-cinoids (ACs) have a less indolent behavior with a certainpropensity for metastatic spread. Both these pNETs are opti-mally treated with complete surgical excision. Conversely,more aggressive pNETs, such as large-cell neuroendocrinecarcinoma and small-cell lung cancer (LCNEC and SCLC,respectively), often present with local invasion, regionallymph nodal metastases, and distant spread; as a result, theyshow a poor prognosis and usually may not be candidates forsurgical resection [1, 2].

Recent evidences [2, 3] suggest that even when surgery isindicated in well- or intermediate-differentiated pNETs, theextension of both pulmonary resection and lymph nodal dis-section are determined by the cyto/histology characteristics ofBCs. Unfortunately, TCs and ACs share structural

F. Lococo (*) :M. Paci : C. Rapicetta : T. Ricchetti :G. SgarbiUnit of Thoracic Surgery, IRCCS-Arcispedale Santa Maria Nuova,Reggio Emilia, Italye-mail: filippo_lococo@yahoo.it

A. CesarioIRCCS-San Raffaele della Pisana, Rome, Italy

A. Filice :A. VersariDepartment of Nuclear Medicine, Reggio Emilia, Italy

M. AlifanoDepartment of Thoracic Surgery, Descartes University HospitalCochin, Paris, France

A. CavazzaUnit of Pathology, IRCCS-Arcispedale Santa Maria Nuova, ReggioEmilia, Italy

G. TregliaDepartment of Nuclear Medicine, Oncology Institute of SouthernSwitzerland, Bellinzona, Switzerland

Tumor Biol.DOI 10.1007/s13277-014-2102-y

radiological findings and a clear differentiation between thesepNETs is not possible through radiological findings only [4,5].

In this context, the functional imaging evaluation by usingnuclear medicine techniques has improved in the last twodecades with the aim of helping the physicians in the chal-lenging management of pNETs [6]. In particular, positronemission tomography (PET) by using different tracers is par-ticularly useful in the work-up of pNETs being able to detectfunctional abnormalities which often precede the onset ofmorphological lesions on conventional radiological imaging,such as computed tomography (CT) [7]. Tracer uptake at PETimaging may be evaluated visually or by using semi-quantitative measures such as the maximal standardized up-take value (SUVmax). Finally, the development of hybridPET/CT tomographs has greatly contributed to a more accu-rate delineation of areas of increased tracer uptake, overcom-ing the limits of patients repositioning when the two imageswere acquired independently and fused afterwards [7].

In the last years, several PET tracers have been proposedfor the assessment of disease extent, restaging, and therapyresponse in pNETs [6]. However, in this review, we focus ourattention and deeply discuss on the potential role of PET orPET/CT using fluorine-18-fluorodeoxyglucose (F-18-FDG)and somatostatin analogues labeled with gallium-68 (Ga-68-DOTA-peptides) in pNETs with a particular attention on clin-ical and surgical implications in BCs.

Histopathological classification of pulmonary NETs

It is well known that pNETs arise from Kulchitzky cells thatare normally present in the bronchial mucosa and share thecommon morphologic features of neuroendocrine tumors in-cluding organoid nesting, palisading, rosettes, or a trabeculargrowth pattern. Travis and colleagues have proposed in 1991[8] a histological classification of pNETs (revised in 2004 [9])that includes TCs as low-grade tumors, ACs as intermediate-grade malignancies, and LCNEC and SCLC as high-grademalignancies (Table 1). Moreover, WHO recognized as adifferent entity the so-called diffuse idiopathic pulmonaryneuroendocrine cell hyperplasia (DIPNECH), a preinvasiveprecursor of carcinoid tumors [10].

The pathological distinction of pNETs is based on histo-logical features, particularly mitotic rate and presence of ne-crosis. BCs, both TCs and ACs, consist of small nests orinterconnecting trabeculae of uniform cells separated by aprominent vascular stroma and numerous thin-walled bloodvessels. Mitoses and necrosis are the histopathologic featuresthat distinguish TCs from ACs, in particular ACs have smallfoci of necrosis and 2–10 mitoses per 10 high-power fields(Table 1 and Fig. 1).

A correct pathological identification of pNETs during thepreoperative setting is a key element for planning the beststrategy of care, considering the different biological behaviorof the various histology subtypes. Nevertheless, a correctpreoperative pathological differentiation between TCs andACs (often based on cytology only) is generally hard toobtain. Similarly, the histological characterization betweenthe WHO histotypes during frozen-section intraoperative as-sessment is something extremely difficult. In this context, thepreoperative PET evaluation by using different tracers couldrepresent a sort of “noninvasive biopsy” trying to correlate asaccurately as possible the uptake pattern of pNETs with thehistological subtypes.

Role of F-18-FDG PET (PET/CT) scan

Since F-18-FDG is a glucose analogue, this tracer may be veryuseful in detecting malignant lesions which usually presenthigh glucose metabolism and consequently increased F-18-FDG uptake [7, 11]. Slow-growing pulmonary tumors usuallyexhibit a lower F-18-FDG uptake when compared to aggres-sive pulmonary malignancies [12]. As a result of that,LCNECs and SCLCs show higher F-18-FDG uptake com-pared to BCs [13, 14], while, to date, a significant increasedF-18-FDG uptake in DIPNECH cases has not been reported[10]. Whereas F-18-FDG PETand PET/CTare widely used inevaluating aggressive tumors such as high-grade pNETs, inparticular for staging, restaging, or treatment response assess-ment [7], many physicians consider F-18-FDG PET or PET/CT as tools of limited value for the evaluation of BCs, due tothe commonly slow growth of these tumors.

Several articles in the literature evaluated the detection rateof F-18-FDG PET or PET/CT in BCs reporting conflicting

Table 1 Grading and diagnostic criteria of pulmonary NETs based on the 2004 WHO classification

Typical carcinoid Atypical carcinoid Large-cell neuroendocrine carcinoma Small-cell lung cancer

Grade Low Intermediate High High

Mitosesa <2 2–10 >10 >10

Necrosis None Often (focal) Often (diffuse) Frequent (diffuse)

Morphology Well differentiated Moderate differentiated Poorly differentiated (large cells) Poorly differentiated (small cells)

a ×10 high-power fields

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results in this setting (detection rate ranged from 14 % tovalues >90 %) [15–25]. The main findings of these articlesare described in Table 2.

A recent prospective study on 32 patients with clinicalsuspicion of BC demonstrated that F-18-FDG PET/CT had asensitivity, specificity, and accuracy in detecting BCs of 78,11, and 59 %, respectively. Nevertheless, F-18-FDG PET/CTwas positive in all cases of AC and false-negative in eight

cases of TC (sensitivity was 62 and 100 % for TCs and ACs,respectively) [22].

Interestingly, the method of analysis of F-18-FDG uptakein the pulmonary nodule is pivotal for an adequate evaluationof the accuracy of PET or PET/CT in BCs. In fact, as recentlyremarked by Stefani et al. [23], the detection rate of F-18-FDGPET or PET/CT for BCs was generally investigated on thebasis of a visual assessment (usually considering as positive

Fig. 1 a Typical carcinoid (Hematoxylin-Eosin, ×100), consisting inwell-vascularized nests composed of bland epithelioid cells with largecytoplasm. No necrosis was present, andmitotic activity was negligible. b

Atypical carcinoid (Hematoxylin-Eosin, ×100), with an area of comedo-like necrosis. This tumor had three mitoses per 10 high-power fields

Table 2 F-18-FDG PET or PET/CT findings in bronchial carcinoids: data from the literature (case reports excluded)

First author(year)

No. ofpulmonaryNETs (BCs)

Histologyof BCs

Detection rate (%) of BCs[positivity criterion]

Mean SUVmaxin TCsa

MeanSUVmaxin ACsa

Detection rate (%) of TCs versus ACs[positivity criterion]

Erasmus(1998)

7 (7) 6 TCs, 1 AC 1/7 (14) [uptake>mediastinum] N.A. N.A. 1/6 (17) vs. 0/1 (0) [uptake>mediastinum]

Kruger (2006) 13 (13) 12 TCs, 1 AC 7/13 (54) [SUVmax >2.5] 3.0±1.5 8.5 6/12 (50) vs. 1/1 (100) [SUVmax>2.5]

Daniels(2007)

16 (16) 11 TCs, 5 ATs 12/16 (75) [uptake>mediastinum]

N.A. N.A. 8/11 (73) vs. 4/5 (80) [uptake>mediastinum]

Chong (2007) 37 (7) 2 TCs, 5 ACs 3/7 (43) [uptake>mediastinum] 3.3±0.1 4.3±2.0 0/2 (0) vs. 3/5 (60) [uptake>mediastinum]

Kayani (2009) 18 (13) 11 TCs, 2 ACs 9/13 (69) [uptake>mediastinum]

5.5±4.0 13.1±2.0 7/11 (64) vs. 2/2 (100) [uptake>mediastinum]

Jindal (2011) 20 (20) 13 TCs, 7 ACs 14/20 (70) [uptake>mediastinum]

2.1±0.9 5.3±2.0 7/13 (54) vs. 7/7 (100) [uptake>mediastinum]

Kuyumcu(2012)

10 (10)b 6 TCs, 4 ACs 8/10b (80) [SUVmax >2.5] 2.9±0.8 7.9±5.4 4/6 (67) vs. 4/4 (100) [SUVmax >2.5]

Stefani (2013) 25 (25) 24 TCs, 1 AC 13/25 (52) [SUVmax >2.5]24/25 (96) [SUVmax ≥1.5]

3.6±2.8 5.0 12/24 (50) vs. 1/1 (100) [SUVmax >2.5]23/24 (96) vs. 1/1 (100) [SUVmax ≥1.5]

Alpay (2013) 27 (27) 17 TCs, 8 ACs,2 OCs

23/25 (92) [SUVmax >2.5] 5.28 5.08 16/17 (94) vs. 7/8 (88) [SUVmax >2.5]

Moore (2013) 29 (29) 23 TCs, 6 ACs N.A. 2.7±1.6 8.1±4.1 N.A.

Venkitaraman(2014)

26 (26) 21 TCs, 5 ACs 18/26 (69) [uptake>mediastinum]

2.88 4.37 13/21 (62) vs. 5/5 (100) [uptake>mediastinum]

BCs bronchial carcinoids, ACs atypical carcinoids, TCs typical carcinoids, OCs oncocytic carcinoids, N.A. not availablea Data extrapolated by the tables of the pertinent articlesb Patients assessed before surgery

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an uptake superior to the mediastinal background) or aSUVmax cutoff (usually considering a cutoff of 2.5 asapplied in the first studies on the use of F-18-FDG PETin lung carcinoma). However, BCs, especially TCs, usu-ally show a lower metabolic activity compared to lungcarcinoma and an increased detection rate of F-18-FDGPET in BCs could be obtained by using SUVmax cutoffvalues lower than 1.5 and considering the normal lung,and not the mediastinum, as background region for thevisual assessment [23].

F-18-FDG uptake in pNETs was found to be related tosome biologic features. In particular, Kaira et al. clearly dem-onstrated that F-18-FDG uptake is determined by the presenceof glucose metabolism, hypoxia, and angiogenesis in pNETs[13]. A correlation between F-18-FDG uptake and the expres-sion of glucose transporters (Glut-1) in pNETs has been alsoreported [14].

About the hystological type, the detection rate ofF-18-FDG PET or PET/CT seems to be overall higherin ACs compared to TCs due to the more aggressivebehavior and high proliferation rate of ACs (Table 2).In this regard, a recent retrospective study [24] reportedthat ACs usually show a higher F-18-FDG uptake com-pared to TCs and a SUVmax≥6 had a predictive value>95 % for distinguishing ACs from TCs. The signifi-cant higher SUVmax in ACs compared to TCs at F-18-FDG PET was also evident in other studies [16, 19–21].Conversely, a recent article did not demonstrate a sig-nificant difference in SUVmax between TCs and ACs[25].

Whereas F-18-FDG uptake is usually related to the tumorsize for lung carcinomas [26], controversial results about thepossible correlation between F-18-FDG uptake, visually orsemi-quantitatively assessed, and tumor size in BCs werereported [15, 16, 18, 21, 23, 24].

Furthermore, a correlation between functional imag-ing staging by F-18-FDG PET or PET/CT and surgicalstaging could not be definitively assessed due to thelimited number of metastatic BCs included in the perti-nent articles [15–25].

Finally, SUVmax has been reported to be related tothe patients’ survival in poorly differentiated pNETs(LCNECs and SCLCs) [17, 26–28]. On the other hand,the prognostic value of F-18-FDG PET or PET/CT inBCs is far to be defined and studies on a large cohortof patients are warranted.

In conclusion, F-18-FDG PETor PET/CT seems to be sub-optimal in detecting BCs, whereas higher detection rate andSUVmax in ACs vs. TCs are often reported. Nevertheless,when a BC is strongly suspected by clinical or radiologicalfindings, even a low F-18-FDG uptake should not be consid-ered as a negative result and, in such cases, a surgical resectionor a biopsy could be performed.

Role of Ga-68-DOTA-peptides PET (PET/CT) scan

Neuroendocrine tumors including pNETs usually overexpresssomatostatin receptors (SSTRs) on their cell surface. SSTRsdensity is related to the degree of the tumor differentiation.Therefore, well-differentiated pNETs usually express a higherdensity of SSTRs compared to poorly differentiated pNETs[29].

In the last years, the recent development of novel tracers, inparticular somatostatin analogues labeled with gallium-68(Ga-68-DOTA-peptides), has allowed an accurate imagingof SSTRs by PET. In detail, Ga-68-DOTA-peptides bind toSSTRs overexpressed on neuroendocrine tumor cells. Thestructure of these radiopharmaceuticals includes the somato-statin analogue binding to SSTR (TOC, NOC, TATE), achelant (DOTA) and a positron-emitting isotope (Ga-68) [6,30]. The most relevant difference among these compoundsrelies in a variable affinity to SSTR subtypes: all can bindto subtypes 2, but only DOTA-NOC presents a goodaffinity for subtypes 2, 3, and 5. Despite the observeddifferences in receptor binding affinity between the dif-ferent somatostatin analogues used for PET, they seems toprovide similar diagnostic accuracy and clinical impact inpNETs [6]. The uptake of these tracers is not dependenton the cellular metabolism (as compared ,for example, toF-18-DOPA or F-18-FDG) and noninvasively providesinformation on SSTR expression with direct therapeuticalimplications. For example, metastatic pNETs with highSSTR expression could be suitable for peptideradioreceptor therapy [6, 30].

Finally, beyond the easier labeling and synthesis process[31], Ga-68-DOTA-peptides PET offer several advantagesover somatostatin receptor scintigraphy with Indium-111-pentetreotide for diagnosis and therapy planning of pNETs,including the higher affinity for SSTRs type 2, the superiorresolution derived by the use of PET technique, and the morerapid examination time [6, 32, 33].

Several articles in the literature have demonstrated theusefulness of Ga-68-DOTA-peptides PET or PET/CT in pa-tients with neuroendocrine tumors [34], but a limited numberof articles was focused on pNETs only [35] (Table 3). Inparticular, the rarity of BCs strongly limits the acquisition oflarge and robust evidences on the use of new diagnostic toolsin this setting. Moreover, the employment of Ga-68-DOTA-peptides, despite increasing, is still limited to specializedcenters [6].

Ambrosini et al. [36] evaluated 11 patients with BCs byusing Ga-68-DOTA-NOC PET/CT. This method detected ahigher number of lesions as compared to CT scan only (37versus 21, respectively) providing additional information in82 % (9 of 11) of patients, contributing to a better evaluationof the extent of the disease and changing the management inabout 30 % of cases.

Tumor Biol.

Kayani et al. [19] performed Ga-68-DOTA-TATE PET/CTin 18 patients with pNETs. All TCs were positive at Ga-68-DOTA-TATE PET/CT. ACs and high-grade pNETs had lessGa-68-DOTA-TATE avidity compared to TCs. Two cases ofDIPNECH did not show significant uptake of Ga-68-DOTA-TATE.

Jindal et al. [20, 37] evaluated 20 patients with BCs (13TCs and 7 ACs) by using Ga-68-DOTA-TOC PET/CT. The

overall detection rate of this method for BCs was 95 % (19 of20 cases were positive). All TCs showed significant uptake ofGa-68-DOTA-TOC. One AC lacked any significant traceruptake. TCs also showed significantly higher uptake of Ga-68-DOTA-TOC compared to ACs. In one patient, Ga-68-DOTA-TOC PET/CT facilitated the detection of additionallesions compared to conventional imaging. These findingswere confirmed by a further prospective study of the same

Table 3 Ga-68-DOTA-peptides PETor PET/CT findings in selected articles from the literature focused on pulmonary carcinoids (case reports excluded)

First author (year) Tracer No. ofpatients

Histology Detectionrate (%) of BCs

Mean SUVmaxin TCsa

Mean SUVmaxin ACsa

Detection rate (%) ofTCs versus ACs

Ambrosini (1998) DOTA-NOC 11 11 BCs 9/9 (100) N.A. N.A. N.A.

Kayani (2009) [19] DOTA-TATE 18 11 TCs, 2 ACs,5 other pNETs

13/13 (100) 40±30.7 4.9±0.28 11/11 (100) vs. 2/2 (100)

Jindal (2010, 2011) DOTA-TOC 20 13 TCs, 7 ACs 19/20 (95) 36.7±18.1 9.6±5.9 13/13 (100) vs. 6/7 (86)

Venkitaraman (2014) DOTA-TOC 32 21 TCs, 5 ACs,6 other tumors

25/26 (96) 21.5 15.4 21/21 (100) vs. 4/5 (80)

pNETs pulmonary neuroendocrine tumors, BCs bronchial carcinoids, ACa atypical carcinoids, TCa typical carcinoids, N.A. not availablea Data extrapolated by tables of the pertinent articles

Fig. 2 Increased uptake ofradiolabeled somatostatinanalogues (a, b; arrows) and low/absent uptake of F-18-FDG (c, d)in a case of typical carcinoid ofthe right lung (images fromIRCCS, Arcispedale Santa MariaNuova, Reggio Emilia, Italy)

Tumor Biol.

group [22] which reported an overall sensitivity, specificity,and accuracy of Ga-68-DOTA-TOC PET/CT in the diagnosisof BCs of 96, 100, and 97 %, respectively, confirming asignificant higher SUVmax in TCs compared to ACs.

About high-grade pNETs, a recent study of Sollini et al.[38] on 24 patients with extensive disease SCLC reported thatGa-68-DOTA-peptides PET/CT was positive in 83 % of pa-tients, demonstrating enhanced SSTR expression in 50 % ofcases. Based on these preliminary results, the authors suggesta potential role of somatostatin receptor PET/CT in selectingSCLC patients who are suitable for peptide radioreceptortherapy.

Overall, the detection rate of Ga-68-DOTA-peptides PETor PET/CT in BCs is very high and these techniques mayprovide additional information compared to conventional im-aging techniques. Since TCs have been reported to express theSSTRs more abundantly if compared with higher gradepNETs [29], it seems logical that TCs show higher uptake ofGa-68-DOTA-peptides [19]. Some false-negative findings ofGa-68-DOTA-peptides PETor PET/CT in pNETs may be dueto tumors with low expression of SSTRs (mainly cases ofintermediate and high-grade pNETs). Although inflammatorydiseases can yield false-positive results at somatostatin recep-tor imaging since SSTRs are overexpressed by the inflamma-tory cells [39–41], false-positive findings of Ga-68-DOTA-peptides PET in pNETs are rarely described [42]. Whereas therole of somatostatin receptor PETor PET/CT seems to be well

defined in low-grade pNETs (TCs), further studies should becarried out to assess the value of this functional imagingmethod in DIPNECH, and intermediate- and high-gradepNETs.

Dual tracer PET evaluation using Ga-68-DOTA-peptidesand F-18-FDG

The evaluation of solitary pulmonary nodule (SPN) is a seri-ous diagnostic challenge for which clinicians may use variousimaging modalities and algorithms to detect and predict thelikelihood of malignancy. SPNs (especially the round-shapenodules) are difficult to accurately diagnose based on limitedsensitivity of noninvasive imaging, technical limitations ofbiopsy (especially in small-size lesions), and the high frequen-cy of benign lesions detected during radiological evaluation.In this setting, functional imaging techniques could potentiallyhelp the physicians in such challenging process, carrying outuseful information for the diagnosis and histological differen-tiation of the SPNs. F-18-FDG PET or PET/CT may be veryuseful in distinguishing benign lesions from malignant onesbut when a BC is suspected, the low/absent metabolic activityof the lesion does not completely exclude such diagnosis. Onthe other hand, in case of increased F-18-FDG uptake, thesuspicious of BC enters in the differential diagnosis processwith other entities (including other lung tumors and

Fig. 3 Moderate uptake ofradiolabeled somatostatinanalogues (a, b; arrows) andincreased F-18-FDG uptake (c, d;arrows) in a case of atypicalcarcinoid of the left lung (imagesfrom IRCCS, Arcispedale SantaMaria Nuova, Reggio Emilia,Italy)

Tumor Biol.

inflammatory diseases). Differently, Ga-68-DOTA-peptidesare more specific tracers in the detection of pNETs. In partic-ular, a positivity at Ga-68-DOTA-peptides PET is highlypredictive for a definitive diagnosis of pNET (excluding rarefalse-positive findings). Nevertheless, the absence of Ga-68-DOTA-peptides uptake does not exclude the diagno-sis of pNET, especially in intermediate- and high-gradesubtypes. At the light of these considerations, the sci-entific community has started to investigate the oppor-tunity of using a combined Ga-68-DOTA-peptides andF-18-FDG PET/CT evaluation for suspected pNETs [43,44]. Actually, only few reports [18, 19, 21, 45–47] onsmall series in the literature assessed the use of Ga-68-DOTA-peptides in comparison to F-18-FDG for theevaluation of histological subtypes of pNETs.

Kumar et al. [46] evaluated the combination of F-18-FDGPET/CT scan and Ga-68-DOTA-peptides PET/CT scan indifferentiating seven patients with bronchial masses includingthree BCs (two TCs and one AC). The TCs had mild F-18-FDG uptake and high Ga-68-DOTA-TOC uptake. The AChad moderate uptake of F-18-FDG and high 68Ga DOTA-TOC uptake.

Kayani et al. [19] compared Ga-68-DOTA-peptides andF-18-FDG PET/CT findings in 18 patients with pNETs, in-cluding 13 BCs (11 TCs and 2 ACs). TCs showed significant-ly higher uptake of Ga-68-DOTA-peptides and significantlylower uptake of F-18-FDG than did pNETs of higher grade.Moreover, no false-positive uptake of Ga-68-DOTA-TATEwas observed in this study population, but there were threesites of false-positive uptake of F-18-FDG due toinflammation.

Jindal et al. [20] studied 20 patients with BCs (13TCs and 7 ACs) by using F-18-FDG and Ga-68-DOTA-TOC. TCs showed a higher uptake of Ga-68-DOTA-TOC than ACs, while the latter showed increasedF-18-FDG uptake. The ratio of SUVmax of Ga-68-DOTA-TOC uptake to that of F-18-FDG was signifi-cantly higher in TCs than in ACs (p<0.001).

Lastly, Venkitaraman et al. [22] performed the first pro-spective study on the comparison of Ga-68-DOTA-TOC andF-18-FDG in 32 patients with clinical suspicion of BC. Thesensitivity of Ga-68-DOTA-TOC PET/CT was superior inpatients with TC compared to those withAC (100 versus80%,respectively), whereas the sensitivity of F-18-FDG PET/CTwas superior in patients with ACs compared to those with TCs(100 versus 62 %).

Based on the data from the medical literature, the mostfrequent uptake pattern for TCs at dual tracer PET/CT imagingis increased uptake of radiolabeled somatostatin analoguesand mild, low, or absent uptake of F-18-FDG (Fig. 2). Con-versely, ACs usually present increased F-18-FDG uptake withvariable uptake of radiolabeled somatostatin analogues(Fig. 3).

Therefore, based on literature data, Ga-68-DOTA-peptidesseem to be the PET tracers of choice in the initial evaluation ofpatients with clinical suspicion of BC. In this setting, Ga-68-somatostatin analogues PET/CTcould be performed primarilyand, if negative, F-18-FDG PET/CT could be performed sub-sequently. In fact, a negative Ga-68-somatostatin analoguesPET/CT may substantially rule out the presence of TCs, but itseems not sufficient to exclude the presence of ACs (whichoccasionally present low uptake of Ga-68-somatostatin ana-logues but are often F-18-FDG-avid tumors).

It should be noted that other PET tracers beyond F-18-FDGand Ga-68-somatostatin analogues can be used in the assess-ment of pNETs, like carbon-11-hydroxytryptophan and 18F-DOPA. Reports about the use of these tracers in BCs are few[48–50] and the results still controversial.

In conclusion, the combination of Ga-68-DOTA.peptidesand F-18-FDG PET/CT seems to be very useful in predictingthe histology in patients with clinical suspicion of pNETs,allowing a “tailored” therapeutic approach in such patients.Further large prospective studies and cost-effectiveness anal-yses are needed to validate this diagnostic strategy.

Conflicts of interest None

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