A Systematic Review on Combined [18F]FDG and 68Ga-SSA PET/CT in Pulmonary Carcinoid

Pulmonary carcinoids (PCs) are part of a spectrum of well-differentiated neuroendocrine neoplasms (NENs) and are classified as typical carcinoid (TC) and atypical carcinoid (AC). TC differ from AC not only for its histopathological features but also for its “functional imaging pattern” and prognosis. ACs are more undifferentiated and characterized by higher aggressiveness. Positron emission tomography/computed tomography (PET/CT) with somatostatin analogs (SSA) labeled with Gallium-68 (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE) has widely replaced conventional imaging with gamma camera using 111In- or 99mTc-labelled compounds and represents now the gold standard for diagnosis and management of NENs. In this setting, as already described for gastro-entero-pancreatic NENs, 18F-Fluorodeoxiglucose ([18F]FDG) in addition to 68Ga-SSA can play an important role in clinical practice, particularly for ACs that show a more aggressive behavior compared to TCs. The aim of this systematic review is to analyze all original studies collected from the PubMed and Scopus databases regarding PCs in which both 68Ga-SSA PET/CT and [18F]FDG PET/CT were performed in order to evaluate the clinical impact of each imaging modality. The following keywords were used for the research: “18F, 68Ga and (bronchial carcinoid or carcinoid lung)”. A total of 57 papers were found, of which 17 were duplicates, 8 were reviews, 10 were case reports, and 1 was an editorial. Of the remaining 21 papers, 12 were ineligible because they did not focus on PC or did not compare 68Ga-SSA and [18F]FDG. We finally retrieved and analyzed nine papers (245 patients with TCs and 110 patients with ACs), and the results highlight the importance of the combined use of 68Ga-SSA and [18F]FDG PET/CT for the correct management of these neoplasms.


Introduction
Pulmonary carcinoids (PCs) are rare malignant neoplasms being part of well-differentiated pulmonary neuroendocrine neoplasia (NEN) arising from stem cells of the bronchial epithelium known as Kulchitsky cells [1]. Even though in the majority of cases NENs arise at the gastroenteropancreatic level, PCs are the second most frequent location and represent about 25% of primary lung neoplasm with an approximate annual incidence of 2.3-2.8 cases per million [2]. No age and sex prevalence have been reported, and neither external environmental toxin or other risk factors have been detected [3]. PCs can be classified into two categories according to histological features: typical carcinoids (TCs) are well-differentiated, low-grade (less than two mitoses per 2 mm 2 ), absence of necrosis and less aggressive; by contrast, atypical carcinoids (ACs) are poorly differentiated, intermediate-grade (more than two mitoses per 2 mm 2 ) and necrosis is potentially present. These different histological patterns are strictly correlated with prognosis [4]. Typical carcinoids (TCs) have a good prognosis as a result of less aggressive behavior, while atypical carcinoids (ACs) are more aggressive at diagnosis with a higher risk of lymph node and distant metastases [5].
Based on histological features, approximately 60 to 80% of PCs share the unique feature of over-expressing somatostatin receptors (SSTR), particularly in lower grade lesions characterized by low Ki-67 proliferation index [6]. During the gradual progression of carcinogenesis NENs may show a dedifferentiation with development of more aggressive tumor cell clones. This behavior, results in a loss of somatostatin receptors and utilization of glucose metabolism that correlates with a worse prognosis. Although final diagnosis of PCs is made through histopathologic examination, nonetheless, non-invasive imaging methods can provide information aiding in the prediction of the histopathologic subtype of carcinoid and reliably guide the patient management and invasiveness of surgery [7]. In this context, nuclear medicine plays a crucial role in the characterization of these neoplasms.
In this systematic review we analyze all papers published on both TCs and ACs studied by both [ 18 F]FDG and 68 Ga-SSA PET/CT, focusing on the impact of their combined use in clinical practice.

Search Strategy
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) method [8], and the search was carried out in the following databases: PubMed (Medline) and SCOPUS. The search terms used were as index terms or free-text words, and the complete strategy was as follows: " 18 F, 68 Ga AND (bronchial carcinoid or carcinoid lung".

Data Collection
Basic information about studies (authors, publication year, country of study, study design, patients' characteristics, and technical aspects) was collected.
Two researchers independently reviewed the retrieved papers. Only original articles in English up till 2022 were included. In case of disagreements between researchers when reviewing abstracts, articles were included in the full-text review phase for a final evaluation. The references of all selected articles were also manually reviewed to identify any potentially omitted publications.
This systematic review has been prepared following the PRISMA guidelines.

Search Results
We found 37 papers in Scopus and 20 in PubMed. Out of these 57 papers, 17 were duplicates, 8 were reviews, 10 were case reports, and 1 was an editorial. Of the remaining 21 papers, 12 were ineligible because they did not focus on PC or did not compare 68 Ga-SSA and [ 18 F]FDG ( Figure 1). We carefully read the remaining nine papers, searching for additional papers in their references.
Results are summarized in Tables 1 and 2. Results are summarized in Table 1 and Table 2.

Radiological Imaging of Pulmonary Carcinoids
Differential diagnosis of solid pulmonary nodules is always a radiological challenge. Despite being substantially different for histological pattern and a prognosis rarely seen in morphological features, such as regular margins and calcification, permit to discriminate PCs from benign nodules or hamartomas; suspicious imaging features to not overlook in the evaluation of lung nodules, which include interval growth of a solid component that is ≥6 mm, spiculated margins, interval increase in density, or a new microcystic component. Persistent part-solid nodules with solid components ≥6 mm should also be considered highly suspicious. The presence of these features may prompt further diagnostic evaluation.
Several studies showed that TC or RM cannot always characterize solid lung nodules even when intravenous iodate contrast medium is performed [17].
The Fleischner Society recommendations for pulmonary nodules, revised in 2017, suggests that for solitary solid lung nodule >8 mm (>250 mm 3 ) CT at 3 months, PET-CT, or tissue sampling should be considered [18].
It is also important to point out that both TCs and ACs show very similar radiological characteristics and for these reasons in most cases morphological exams such as X-ray, contrast enhancement TC or MRI, do not allow to recognize them.

Conventional Somatostatin Receptors Imaging
Somatostatin receptors (SSTR) are over-expressed by neuroendocrine tumors (NENs) [19] and somatostatin receptor scintigraphy (SRS) with 111 In-pentetreotide (Octreoscan ® , Mallinckrodt Medical, St. Louis, MO, USA), was first introduced in the 1980s, exploiting the specific binding of a radiolabeled somatostatin analogue (octreotide) to high-affinity somatostatin receptors (mainly type 2) expressed by most neuroendocrine tumors [20]. Thanks to this feature, for many years Octreoscan ® has been used in nuclear medicine for localizing, staging and follow-up of tumors with high SSTR expression. Although it has been one of the gold-standard modalities used for the diagnosis of NENs, many studies have shown several limitations, such as unfavorable tumor-to-noise ratio, low spatial resolution, and moderate receptor affinity [21]. For these reasons, research has relied on the use of other radiopharmaceuticals. Two new 99m Tc-labelled SST analogs were introduced in the 1990s: [ 99m Tc]Tc-N4-[Tyr3] Octreotate (Demotate ® , POLATOM, Otwock, Poland) and [ 99m Tc]Tc-EDDA/HYNIC-[Tyr3] Octreotide (Tektrotyd ® , POLATOM, Otwock, Poland), which have been broadly used in medical practice in patients with several SSTR+ cancers [22][23][24]. With the advent of the new portable 68 Ge/ 68 Ga generators, 68 Ga-labelled radiopharmaceuticals became available for clinical use with PET/CT. Many are the advantages, and in particular better spatial resolution of PET versus SPECT, shorter scan time and less patient exposure to radiation [25,26].
The introduction of 68 Ga-SSA PET/CT has indeed improved the diagnostic work-up for the evaluation of lung neuroendocrine tumors which was previously, as mentioned before, only based on traditional imaging such as conventional ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and somatostatin receptor scintigraphy, becoming one of the gold standard examinations in the diagnosis and management of well-differentiated neuroendocrine tumors [27][28][29]. Three DOTA-peptides (DOTA-TOC, DOTA-NOC and DOTA-TATE) have been purposed in clinical practice for the diagnosis of NENs. DOTA-TATE is also suitable for peptide receptor radionuclide therapy (PRRT) when labelled with 177 Lutetium [30,31]. The main difference among such compounds is a slightly different affinity for SSR subtypes (mainly type 2, but as well type 3 and type 5), (Table 3). Nevertheless, they have not demonstrated significant diagnostic differences in clinical practice. Current guidelines recommend PET/CT with 68 Ga-DOTA-peptides for staging, restaging, characterization of a bronchial mass and localization of an occult primary neuroendocrine cancer when metastasis of an undetected primary tumor has been demonstrated [19,32]. For 68 Ga-SSA PET/CT examination, fasting is not required, and it is recommended to have intravenous administration of the labelled compound (dose of 100-200 MBq), with acquisition time varying according to the different conjugated peptide: 45-60 min for 68 Ga-DOTA-TATE, and 60-90 min for 68 Ga-DOTA-TOC and 68 Ga-DOTA-NOC. The amount of labeled peptide injected is less than 50 µg. In the case of patients treated with "cold" somatostatin analogs, appropriate temporary medication withdrawal prior to PET is not strictly necessary. One-day withdrawal is usually prescribed for shortacting somatostatin analogs and three to four weeks for long-acting ones. However, currently, there is no evidence that the interruption of somatostatin analogs administration, prior to PET with 68 Ga-SSA, is required; it might ameliorate the target-to-background ratios. 68 Ga-SSA PET/CT, for the staging of neuroendocrine lung tumors, should be routinely performed in addition to conventional imaging techniques, but that alone may not be sufficient to make a correct diagnosis, and it may not identify small distant metastases (especially bone, liver and lymph nodes), [33]. As previously mentioned, PCs express SSTRs on their surface depending on their differentiation. The density of these receptors correlates with the degree of tumor differentiation, with TCs exhibiting the highest density and being the most well-differentiated [19]. For this reason, 68 Ga-SSA PET/CT offers the possibility to differentiate in vivo histopathological subtypes of PCs (TC and AC) also from poorly differentiated tumors (Large Cell Neuro-Endocrine Carcinoma of the lung, LCNEC and Small Cell Lung Cancer, SCLC). This approach is clinically relevant both for therapeutic and prognostic purposes, since TCs have a much better prognosis with a reported five-year survival of 87-100%, in contrast to ACs, that have a lower, reported five-year survival rate of 25-69% [34]. Moreover, 68 Ga-SSA PET/CT may also play a key role for patients for whom biopsy, for a variety of reasons, cannot be performed.
In summary, 68 Ga-SSA PET/CT represents the gold standard imaging modality for the diagnosis and staging of well-differentiated neuroendocrine tumors; in particular, there is solid scientific evidence in GEP/NEN neoplasms [35].
In the last two decades, as reported in the following sections, several studies have evaluated the role of quantitative analysis of 68 Ga-SSA PET/CT scans for in vivo characterization of PCs (typical versus atypical), adding relevant information on the evaluation of disease extent with the impact of the clinical management of patients [9,36]. A systematic review and meta-analysis regarding 104 patients affected by PCs, published by Jiang et al., reported a higher SUV max on 68 Ga-SSA PET/CT in TCs as compared with ACs (36.5 versus 9, respectively) [37].
Finally, the European Society of Medical Oncology (ESMO) guidelines, published in 2021, suggested the use of 88 Ga-SSA PET/CT in addition to contrast-enhanced CT in TNM staging [17].  Table 4). Some of them are overexpressed in cancer cells [38]. According to the study of Mamede et al., a close correlation between Glut-1 expression and [ 18 F]FDG uptake was observed in lung cancer cells [39].

[ 18 F]FDG PET/CT Imaging
In the management of NENs, however, the role of [ 18 F]FDG PET/CT is still a matter of debate, particularly for the evaluation of well differentiated tumors [40,41] but there is solid scientific evidence, that in high-grade tumors there is an upregulation of Glut and glucose metabolism with, often, a loss of SSTR. Indeed, the increase of [ 18 F]FDG uptake correlates with the aggressiveness of neoplasia and indicates a worse prognosis [6,42].
In the majority of cases a median activity of 3 MBq/Kg body weight is injected intravenously into euglycemic fasting patients. PET acquisition starts after 60 min [19,29]. As a glucose analog [ 18 F]FDG is not specific for tumors, increased activity can also be seen in inflammation or infection by reason of glycolytic activity in leukocytes. Several studies described a high accumulation of [ 18 F]FDG in the collapsed lung distal to endobronchial carcinoids secondary to obstructive pneumonia [35,36], whereas 68 Ga-SSA showed little uptake in the collapsed lung, despite the presence of SSTR on inflammatory cells [43,44].
In addition to visual assessment, [ 18 F]FDG uptake can be also quantitatively evaluated. The most used parameters in clinical practice are maximum and mean standardized uptake value (SUV max and SUV mean ), but metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are also valuable tools in several clinical settings [16].
A study by Jiang et al. [37] showed that the best SUV max cutoff value to distinguish TCs from ACs is 3.7, with 73.9% sensitivity and 65.4% specificity; despite that, the area under the curve of SUV max cutoff value for [ 18

Combined 68 Ga-SSA and [ 18 F]FDG PET/CT in Pulmonary Carcinoids
In the last few years, it has emerged that combined imaging with [ 18 F]FDG and 68 Ga-SSA PET/CT for the evaluation of PCs can provide useful information, particularly as a reliable tool in the preoperative assessment of tumor biology. The preoperative distinction between TC and AC is essential both to plan the best surgical strategy and for prognostic purposes. In order to assess the role of combined analysis in the preoperative workup of patients with proven PCs, we systematically analyzed the available literature. We considered only studies regarding PCs in which combined imaging, with both 68 Ga-SSA PET/CT and [ 18 F]FDG PET/CT, was performed (Tables 1 and 2).
One of the first papers that compared the combined use of 68 Ga-SSA and [ 18 F]FDG in PCs dates back to 2009 [9]. Kayani and coll. evaluated the performance of 68 Ga-DOTA-TATE and [ 18 F]FDG in 18 PCs, of which there were 11 TCs and 2 ACs, and they correlated tumor uptake of each radiopharmaceutical with its metabolic grade at histology. They found a significantly higher uptake of 68 Ga-DOTA-TATE in all TCs as compared to ACs. [ 18 F]FDG uptake was variable in TCs with a SUV max less than 3.4 in about half of patients; in contrast ACs were avid of [ 18 F]FDG, with a higher uptake in high grade tumors. Histological grade correlated with the uptake of both radiopharmaceuticals.
Jindal et al. [7] evaluated the distribution of [ 18 F]FDG and 68 Ga-DOTA-TOC in 20 patients with PCs (13 TCs, 7 ACs) to assess the possibility of differentiating the two histopathologic variants based on the different uptake patterns. It was found that the uptake of 68 Ga-DOTA-TOC was significantly greater in TCs than in ACs (range of SUV max 8.8-66 vs. 1.1-18.5, respectively, p < 0.001). Authors also showed that SUV r was significantly higher in TCs than ACs (p < 0.001) and they concluded that SUV r is a better predictor of the histopathologic variety of PCs compared with the SUV max .
In a prospective study, Venkitaraman and his group [10] compared the diagnostic role of both 68 Ga-DOTA-TOC PET/TC and [ 18 F]FDG PET/TC in patients with suspicious PC, using pathological evaluation (surgery or biopsy) as the gold standard. From 32 patients included in the study 26 resulted in carcinoids (21 TCs and 5 ACs). TCs showed higher 68 Ga-DOTA-TOC SUV max values than ACs, whereas on the contrary [ 18 F]FDG PET SUV max values resulted higher in ACs than in TCs. 68 Ga-DOTA-TOC performed better than [ 18 F]FDG In particular 68 Ga-DOTA-TOC showed excellent diagnostic ability, with a sensitivity of 96% (100% for TCs and 80% for ACs) and specificity of 100%, while [ 18 F]FDG had a sensitivity of 78% (62% for TCs and 100% for ACs) and a specificity of 11%. PPV and NPV for 68 Ga-DOTA-TOC and [ 18 F]FDG were 100% and 86% vs. 69% and 17%, respectively, with an accuracy of 97% vs. 59%.
Lococo et al. [11] in their multicenter study retrospectively evaluated the detection rate (DR) of both 68 Ga-DOTA-peptide and [ 18 F]FDG performed in 33 patients with pathologically confirmed pulmonary carcinoid (23 TCs and 10 ACs). Overall, 68 Ga-DOTA-peptide was positive in 26 cases (DR 79%), while [ 18 F]FDG was positive in 18 cases (DR 55%). Regarding histologic subtypes, 68 Ga-DOTA-peptide PET/CT was significantly superior to [ 18 F]FDG in detecting TCs (91% vs. 35%), while [ 18 F]FDG PET/CT was significantly better in detecting AC (100% vs. 50%). Authors also proposed, in order to predict the histological diagnosis, other semiquantitative parameters beyond SUV max , such as SUV T/L (targetto-liver ratio) for [ 18 F]FDG, SUV T/S (target-to-spleen ratio) for 68 Ga-DOTA-peptides, and SUV r (SUV max of 68 Ga-DOTA-peptides divided by SUV max of [ 18 F]FDG). [ 18 F]FDG SUV max and SUV T/L resulted significantly higher in ACs, whereas SUV T/S , 68 Ga-DOTA-peptides SUV max and SUV r were significantly higher in TCs, and a cutoff value of 1.19 for this latter parameter was accurate to distinguish TCs from ACs (sensitivity 82.6%; specificity 90%).
The same group some years later [12] retrospectively confirmed the utility of both radiopharmaceuticals for the assessment of PCs in a larger monocentric cohort of patients (n = 62, 55 TCs and 7 ACs) that underwent [ 18 F]FDG and/or 68 Ga-DOTA-TOC followed by surgical resection. Twenty-six patients underwent only 68 Ga-DOTA-TOC, fifty-two patients only [ 18 F]FDG and twenty patients performed both examinations. Overall, the diagnostic performance of 68 Ga-DOTA-TOC was superior compared to [ 18 F]FDG; in particular, by using a SUV max threshold of 2.5, the DR was 88.4% vs. 53.8%, respectively, and was even more remarkable using a SUV max threshold of 1.5, where the DR reached 100% vs. 80.8%. Nevertheless, considering both SUV max thresholds, 68 Ga-DOTA-TOC performed better only in TCs, while in ACs, the [ 18 F]FDG diagnostic ability was superior. PET results also correlated with histopathological features; in particular 68 Ga-DOTA-TOC positivity showed a significant correlation with a low mitotic rate, while 68 Ga-DOTA-TOC negativity seemed to be associated with presence of necrosis.
Komek et al. [13] also evaluated the diagnostic performance of the combined use of [ 18 F]FDG and 68 Ga-DOTA-TATE PET/TC in patients with proven diagnoses of PC. Among 20 patients retrospectively included in the study, 17 underwent surgery, while 3 were only biopsies; 13 resulted in TC and 7 AC. Only 3 cases, all atypical PC had lymph node involvement, and one of those also presented bone metastasis. DR for TC was 100% with 68 Ga-DOTA-TATE, while [ 18 F]FDG detected 11 of 13 cases (84%). In ACs, DR was 100% for both. [ 18 F]FDG showed significantly higher SUV max values in ACs, while 68 Ga-DOTA-TATE showed significantly higher SUV max values in TC. The authors also found a negative correlation between [ 18 F]FDG and 68 Ga-DOTA-TATE SUV max values, suggesting that those findings can predict in vivo the histological subtype.
Zidan et al. [14] in their retrospective work also analyzed the combined use of [ 18 F]FDG and 68 Ga-DOTA-TATE PET/TC in 56 patients with histological diagnosis of well differentiated PC (22 TCs and 34 ACs), focusing in particular on their role for a selection of patients suitable for peptide receptor radionuclide therapy (PRRT). [ 18 F]FDG avidity was assessed comparing tumor-to-liver uptake, with a Deauville Score-like scale: 0, no uptake; 1, above blood-pool and less than liver; 2, equal to the liver; 3, moderately above the liver; 4, markedly above the liver. Scores 3 and 4 were considered as [ 18 F]FDG positive, 0-2 as negative. 68 Ga-DOTA-TATE avidity was graded based on the modified Krenning scale: 0, no uptake; 1, less than the liver; 2, equal to the liver; 3, equal to the liver but less than the spleen; 4, equal or more than the spleen or SUV max ≥ 30 in absence of the spleen. Thus, patients were grouped in four different molecular imaging (MI) phenotype: 1, lesions negative on both tracers; 2, lesions 68 Ga-DOTA-TATE positive and [ 18 F]FDG negative; 3, lesions positive on both tracers; 4, lesions [ 18 F]FDG positive and 68 Ga-DOTA-TATE negative. Scores 2 and 3 (50% of patients) were considered suitable for PRRT. Overall, 34% of patients showed tumor heterogeneity having more than one MI phenotypes, regardless of the histological subtype, with similar proportions of TCs and ACs. In the subgroup of 16 patients that finally underwent PRRT, excluding one case with a score 4 that was treated despite being unsuitable for therapy for uncontrolled symptoms and palliative debulking of the disease that had PD, the DR was 85% (46% PR and 39% SD), highlighting the importance of this dual-tracer approach to identify patients that can benefit the most from this therapy.
Deleu et al. [15] recently found in a cohort of 64 patients with pathological diagnosis of PC (52 TCs and 12 ACs), higher 68 Ga-SSA SUV max in TCs and higher [ 18 F]FDG SUV max in ACs. For both techniques, SUV max values were significantly different between TCs and ACs. Furthermore, the authors also aimed to assess the ability of 68 Ga-SSA PET/CT to detect lymph nodes and distant metastases relying on pathological specimens. In a total of 267 hylo-mediastinal lymph node stations from 56 patients that underwent dissection or biopsy, the sensitivity and the specificity for regional lymph node involvement by 68 Ga-SSA PET/CT was 80% and 75%, respectively, applying a SUV max cutoff value of 2.1, with the true positive rate that topped to 100% using a SUV max cutoff value of 4.0. Moreover, all 12 lesions from 10 patients were seen by 68 Ga-SSA PET/CT as suspicious for distant metastases and afterward biopsied confirmed to be metastatic (PPV of 100%).
An interesting recent multicentric study [16] investigated the use of 68 Ga-DOTA-TATE and [ 18 F]FDG, in 61 patients with histologically confirmed lung carcinoids, for predicting the nature of pulmonary carcinoids (typical vs. atypical) and for the evaluation of their prognostic role. PET images were visually analyzed and SUV max of the lung lesion was calculated for semiquantitative analysis. SUV max was also calculated for the spleen, liver, and blood and divided by SUV max of the lung lesion in each patient to obtain lesion-tospleen SUV ratio (L-S SUVr), lesion-to-liver SUV ratio (L-L SUVr), and lesion-to-blood-pool SUV ratio (L-BP SUVr). Using both radiopharmaceuticals, PET examination were classified as follows: score 1 [ 18 F]FDG and 68 Ga-SSA negative; score 2, 68 Ga-SSA positive and [ 18 F]FDG negative; score 3, 68 Ga-SSA negative and [ 18 F]FDG positive; score 4, both PET/CT positive. Authors also calculated, for each patient, the ratio of SUV max on 68 Ga-SSA over that on [ 18 F]FDG (SUVr). This retrospective study showed that dual radiopharmaceutical approach provides complementary information about different biological features of PCs, and thus helping in the prediction of histological diagnosis. Authors also suggested in distinguishing TCs and ACs both qualitative and semiquantitative analysis; in particular, the SUVr whose best value to predict the final diagnosis was 1.05 (AUC 0.889). Finally, the results of this study demonstrated also their prognostic role in predicting PFS. Only histological subtypes were correlated both with PFS and OS at a multivariate analysis and among PET/CT features, only [ 18 F]FDG and 68 Ga-SSA were independently related to PFS. Concerning SUVr, this variable is significantly related to the OS only at univariate analysis but may give useful information in a presurgical field where an exact histological diagnosis is not yet known.

Conclusions
From the few published papers, it emerges that PET/CT with 68 Ga-labeled SSA should always be performed in patients with suspicion of pulmonary NENs for staging purposes and to decide therapeutic options. [ 18 F]FDG PET/CT is indicated in atypical carcinoids and in typical carcinoids during the follow-up, when progression of the disease is known or suspected, to define the biological switch to a more aggressive form (Figures 2 and 3). The combined approach with these two functional imaging modalities in clinical practice enables more accurate staging, definition of aggressiveness and tumor biology, with a prognostic role. Nevertheless, more data should be published on homogeneous series of patients in order to evaluate the real impact of dual imaging on overall survival and progression-free rate of this disease.

Conflicts of Interest:
The authors declare no conflict of interest.