The role of Fluorine-18-Fluorodeoxyglucose positron emission tomography in staging and restaging of patients with osteosarcoma
Natale Quartuccio1*, Giorgio Treglia2*, Marco Salsano3, Maria Vittoria Mattoli4, Barbara Muoio5, Arnoldo Piccardo6, Egesta Lopci7, Angelina Cistaro8
1	Department of Radiological Sciences, Nuclear Medicine Unit, University of Messina, Messina, Italy
2	Department of Nuclear Medicine and PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
3	Institute of Radiology, Catholic University of the Sacred Heart, Rome, Italy
4	Institute of Nuclear Medicine, Catholic University of the Sacred Heart, Rome, Italy
5	School of Medicine, Catholic University of the Sacred Heart, Rome, Italy
6	Nuclear Medicine Unit, Galliera Hospital, Genoa, Italy
7	Nuclear Medicine Unit, Humanitas Hospital, Milan, Italy
8	Positron Emission Tomography Center IRMET, Euromedic inc., Turin, Italy. Coordinator of the AIMN PET-Pediatric Study Group
Radiol Oncol 2013; 47(2): 97-102.
Received 23 October 2012 Accepted 14 November 2012
Correspondence to: Angelina Cistaro, MD, Coordinator of the AIMN PET-Pediatric Study Group, Positron Emission Tomography Centre IRMET S.p.A., Via O. Vigliani 89, Turin 10136, Italy. Phone: +39 0113160158; Fax: +39 0113160828; E-mail: a.cistaro@irmet.com
*Natale Quartuccio and Giorgio Treglia equally contributed to this article sharing the first authorship
Disclosure: The authors have no conflicts of interest to disclose.
Background. The objective of this study is to systematically review the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) with Fluorine-18-Fluorodeoxyglucose (FDG) in patients with osteosarcoma (OS). Methods. A comprehensive literature search of published studies through October 10th, 2012 in PubMed/MEDLINE, Embase and Scopus databases regarding whole-body FDG-PET and FDG-PET/CT in patients with OS was performed. Results. We identified 13 studies including 289 patients with OS. With regard to the staging and restaging of OS, the diagnostic performance of FDG-PET and PET/CT seem to be high; FDG-PET and PET/CT seem to be superior to bone scintigraphy and conventional imaging methods in detecting bone metastases; conversely, spiral CT seems to be superior to FDG-PET in detecting pulmonary metastases from OS
Conclusions. Metabolic imaging may provide additional information in the evaluation of OS patients. The combination of FDG-PET or FDG-PET/CT with conventional imaging methods seems to be a valuable tool in the staging and restaging of OS and may have a relevant impact on the treatment planning.
Key words: osteosarcoma; bone sarcoma; 18F-Fluorodeoxyglucose; PET/CT; positron emission tomography
Introduction
Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents, with a peak of incidence at the age of 15-19 years.1 OS is a tumour derived from primitive mes-enchymal cells originating from bone and rarely from soft tissue.2 Although OS can occur in any bone, it is most common in the metaphyses of long
bones: distal femur, proximal tibia, proximal hu-merus, and around the knee.3-5 OS has a high tendency to metastatic spread: 80% of all metastases arise in the lungs (20% of them at initial diagnosis) but metastases can also develop in bone and rarely in lymph nodes.6-9 The 5-year survival rate for OS patients with metastases is 20% compared to 65% for patients with localised disease.10
Usually, the treatment scheme for patients with OS is comprised of pre-operative chemotherapy, surgical removal of all detectable tumour sites and/or local treatment, followed by post-operative chemotherapy. The prognosis for patients with metastatic disease or recurrent disease remains poor.1112 In order to correctly evaluate patients with OS in staging and restaging, a variety of diagnostic imaging modalities may be used, such as radiography, computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy.13 Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET) has been successfully used to evaluate different malignant tumours1415, such as musculoskeletal tumours.16 Tumour cells have a metabolic activity higher than normal cells and usually show an increased uptake of FDG, a glucose analogue. Like many other malignant tumours, OS have an increased rate of glycolysis, and consequently demonstrates an increased uptake of FDG. Standardised uptake value (SUV) can be used as semi-quantitative measure of the metabolic activity of a specific region of interest.17 Through the use of hybrid devices, integrating the high sensitivity of FDG-PET with the high spatial resolution of computed tomography (CT), a better diagnostic accuracy of PET/CT than PET and CT alone in detecting malignant tumours, such as OS, can be achieved.16-18 Several studies have shown the potential role of FDG-PET and PET/CT in the diagnosis of OS; however, a systematic review of published data in this field was lacking.
The purpose of this study is therefore to systematically review published data on the diagnostic performance of FDG-PET or PET/CT in patients with OS in order to assess the accuracy of these functional imaging methods in this setting.
Materials and methods
Search strategy
A comprehensive computer literature search of the PubMed/MEDLINE, Embase and Scopus databases was conducted in order to find relevant published articles on the diagnostic accuracy of FDG-PET and FDG-PET/CT in patients with osteo-sarcoma (OS). We used a search algorithm based on a combination of the terms: (a) "sarcoma" or "sarcomas " or "osteosarcoma" or "osteogenic sarcoma " or "bone sarcoma " or "bone sarcomas" or "pediatric tumors" or "pediatric tumours" or "pediatric sarcomas" or "pediatric sarcoma" or "childhood sarcomas" or "bone tumors" or "bone
tumours" or "osseous sarcomas" or "skeletal sarcomas" or "skeletal sarcoma" or "musculoskeletal sarcomas" and (b) "positron emission tomography" or "Positron emission Tomography And Computed Tomography" or "PET". No beginning date limit was used; the search was updated until October 10th 2012. Only articles in English language were selected. To expand our search, references of the retrieved articles were also screened for additional studies.
Study selection
Studies or subsets in studies investigating the diagnostic accuracy of FDG-PET or FDG-PET/CT in patients with OS were eligible for inclusion. Review articles, editorials or letters, comments, conference proceedings, articles not in the field of interest of this review, and case reports were excluded from this review. Only those studies or subsets in studies that satisfied all of the following criteria were included in the systematic review: (1) FDG-PET or FDG-PET/CT performed in patients with OS; (2) articles on the diagnostic accuracy of FDG-PET and FDG-PET/CT; (3) sample size of at least 10 patients with OS were included in the systematic review in order to select only the most relevant articles about the role of FDG-PET in osteosarcoma. Furthermore, this choice allowed reducing the publication bias. In fact, articles with a low number of patients usually report positive findings which further studies with a higher number of patients may exclude. When a possible overlap in patient data was found, the most complete article was included.
Four researchers (NQ, GT, MS and MVM) independently reviewed the titles and abstracts of the retrieved articles, applying the selection criteria mentioned above. Articles were rejected if they were clearly ineligible. The same four researchers then independently reviewed the full-text version of the remaining articles to determine their eligibility for the inclusion. Disagreements were resolved in a consensus meeting.
Data extraction
For each included study in the systematic review, information was collected concerning the basic study (authors, year of publication, journal, country of origin), device used (PET or PET/CT), and patient characteristics (number of patients undergoing PET or PET/CT, mean age, sex, and number of patients with OS). Finally, the main findings of all articles included in this review are shown in the results.
TABLE 1. Characteristics of the studies included in the systematic review
Authors
Year
Journal
Country
Study Design
Device used
Number of patients performing PET
Mean age (years)
Sex (%male)
Number of OS
Garcia et al.23	1996	J Nucl Med	USA	Prospective	PET	48	40	50	18
Schulte et alJ9	2000	J Nucl Med	Germany	Prospective	PET	202	28	63	44
Franzius et al.29	2001	Ann Oncol	Germany	Retrospective	PET	71	14	63	32
Iagaru et al.30	2006	Nucl Med Commun	USA	Retrospective	PET and PET/CT	106	45	49	21
Kneisl et al.20	2006	Clin Orthop Relat Res	USA	Retrospective	PET	55	NA	51	38
Tateishi et al.25	2007	Radiology	Japan	Retrospective	PET and PET/CT	117	42	59	19
Völker et al.24	2007	J Clin Oncol	Germany	Prospective	PET	46	13	52	11
Charest et al.21	2009	Eur J Nucl Med Mol Imaging	Canada	Retrospective	PET/CT	212	47	52	24
Piperkova et al.26	2009	Clin Nucl Med	USA	Retrospective	PET/CT	93	50	36	15
London et al.27	2011	Pediatr Radiol	Australia	Retrospective	PET/CT	41	13	63	20
Bandopadhyaya et al.28	2012	ISRN Oncol	India	Prospective	PET/CT	22	21	63	22
Cistaro et al.31	2012	Pediatr Blood Cancer	Italy	Retrospective	PET/CT	18	14	61	11
Fuglo et al.21	2012	Eur J Nucl Med Mol Imaging	Denmark	Retrospective	PET/CT	30	30	47	14
OS = osteosarcoma; NA = not available
Results
Literature search
The comprehensive computer literature search from the PubMed/MEDLINE, Embase, and Scopus databases revealed 28316 articles. Reviewing titles and abstracts, 13 articles comprising a total sample size of 289 patients with OS were selected applying the inclusion criteria mentioned above.19-31 These 13 studies were retrieved in their full-text version and included in this systematic review. No additional studies were found screening the references. The characteristics of the studies included are shown in Table 1.
Literature data discussion
Initial assessment: grading and staging
In 2000, Schulte et al.19 firstly demonstrated that FDG-PET, although never replacing biopsy, is a useful tool for estimating the biologic activity of skeletal lesions, including OS lesions. The authors evaluated the efficiency of FDG-PET in grading 202
patients with primary bone tumours, 44 of them with OS. FDG uptake was evaluated semi-quanti-tatively by determining the tumour-to-background ratio (T/B). Although sarcomas showed significantly higher T/B values than benign lesions, in a few cases it was not possible to discriminate between benign and malignant lesions. Using a T/B cut-off level of 3.0 for malignancy, the sensitivity (SS), specificity (SP), accuracy, positive predictive value (PPV), and negative predictive (NPV) of FDG-PET were 93%, 66.7%, 81.7%, 78.7% and 87.9%, respectively. No false negative findings occurred for patients with OS.16 In 2006, Kneisl and co-workers20 investigated the usefulness of FDG-PET in detecting occult non-pulmonary metastases at the initial work-up of 55 patients with bone sarcoma, 38 of them with OS. Only one of 38 OS patients (3%) has been upstaged by FDG-PET. Thus, according to the authors, in consideration of the high cost of the study, the ability of PET scan to detect occult non-pulmonary metastases has a minimal influence in the clinical management of OS patients at initial work-up.20 In 2009, Charest et al.21 evaluated the diagnostic performance of FDG-PET/CT
for detection of soft tissue and osseous sarcomas in 212 patients, including 24 OS. SS of FDG-PET/ CT for diagnosis of OS was 94.7%, detecting 12/12 tumours in the initial assessment and 6/7 tumours in the restaging, with mean SUV of 8.9.21 Further confirming results were documented in 2012 by Fuglo et al.22 who retrospectively studied a group of 89 patients with high-grade soft tissue sarcomas (59) and bone sarcomas (30, 14 of which were OS) in the initial assessment. Limiting the analysis to the detection efficiency of FDG-PET/CT for distant metastases from bone sarcoma the SS, SP, accuracy, PPV and NPV were 88%, 95%, 95%, 87% and 98%, respectively. In the lymph nodal based analysis FDG-PET/CT showed also high SS, SP, accuracy and NPV (100%, 90%, 91% and 100%, respectively) but a very low PPV (20%) due to confounding inflammatory tissue with high glucose metabolism in most of the patients of the study.22
Comparison with conventional imaging: staging and restaging
In 1996, Garcia et al.23 compared the diagnostic accuracy of FDG-PET and 99mTc-sestaMIBI scintig-raphy in 48 patients with suspected recurrent/residual musculoskeletal sarcomas, including 18 OS. FDG-PET appeared to be more sensitive to 99mTc-sestaMIBI scintigraphy in detecting active muscu-loskeletal sarcomas, with overall SS, SP, PPV and NPV of 98%, 90%, 98% and 90%, respectively.23
Völker et al.24 also evaluated the impact of FDG-PET for initial staging and therapy planning in 46 pediatric sarcoma patients, 11 of them with OS, demonstrating that the combination of FDG-PET with the conventional imaging is a valuable tool for the initial staging of OS and it has a relevant impact on therapy decisions. In fact, FDG-PET and conventional imaging reached the same efficiency in the detection of primary tumors (accuracy: 100%). In addition FDG-PET showed a higher SS than conventional imaging regarding the detection of nodal metastases (95% versus 25%) and bone metastases. In particular, bone scintigraphy showed a higher number of false-negative lesions compared with FDG-PET. Instead CT was more reliable than FDG-PET in depicting lung metastases, owing to their small size. Additionally combination of FDG-PET and conventional imaging changed the treatment planning in some cases.24 In the same year, Tateishi et al.25 demonstrated that the staging accuracy of combined PET/CT and conventional imaging is significantly higher than that of FDG-PET alone (p<0.0001). The authors retrospectively compared
the diagnostic accuracy of FDG-PET/CT, FDG-PET and conventional imaging (bone scintigraphy, chest radiography, diagnostic CT of the chest and abdomen and locoregional MRI) in detecting nodal and distant metastases in a group of soft-tissue and bone sarcomas (including 19 OS). The standard of reference was histology or adequate follow-up. FDG-PET/CT showed to be superior to FDG-PET and conventional imaging in detecting nodal metasta-ses. Similar results were documented comparing the ability of imaging modalities in detecting distant metastases. The authors conclude that the inclusion of FDG-PET/CT to the initial imaging work-up yields to a more accurate preoperative staging of bone and soft-tissue sarcomas (mainly because of the more accurate M-staging) and this is important in determining the appropriate treatment.25
In 2009, Piperkova et al.26 retrospectively reviewed 93 patients with bone and soft tissue sarcomas (15 of them with OS) who underwent FDG-PET/CT scan. The authors analyzed the results differentiating for FDG-PET alone, CT alone and combined FDG-PET/CT. For the initial staging, the combined FDG-PET/CT revealed the best performance, when compared with FDG-PET and CT alone, with a SS, SP, PPV, and NPV of 100%. Also for the re-staging group, the combined FDG-PET/ CT revealed the best results with SS and SP of 100% and 95.9%, respectively. The authors concluded that in bone and soft tissue sarcomas for the initial staging and re-staging FDG-PET/CT has higher accuracy than FDG-PET and CT alone.26
In 2011, London et al.27 evaluated the performance of FDG-PET/CT compared to the conventional imaging in detecting malignant lesions with particular attention to lung metastases and predicting a histological response to chemotherapy in 41 children with primary bone tumours (20 patients with OS). On a lesion based analysis, the SS, SP, and accuracy of FDG-PET/CT were 81.8%, 97.5%, and 95.9%, respectively. In the lung lesion analysis, the SS, SP, and accuracy of FDG-PET/CT were 80.0%, 95.8%, and 93.0%, respectively. The authors concluded that FDG-PET/CT appears more accurate than the conventional imaging in detecting malignant lesions in childhood primary bone tumors, excluding lung lesions.27
In their prospective study in 2012, Bandopadhyaya et al.28 evaluated 22 biopsy proved OS patients undergoing FDG-PET/CT and 99mTc-Dimercaptosuccinic acid (99mTc-DMSA) whole body scintigraphy and compared the detection efficiency of the two imaging modalities. In detecting the primary lesion 99mTc-DMSA scintigraphy
showed the same SS (100%) of FDG-PET but lower SS in depicting lung metastases probably because the limited resolution of gamma camera respect to PET/CT, which instead reported a SS of 100%.28
Comparison with conventional Imaging: evaluation of pulmonary lesions
Franzius et al.29 compared FDG-PET and spiral thoracic CT in detecting pulmonary metastases from malignant primary osseous tumors in 71 patients, including 32 patients with OS. In OS patients, FDG-PET revealed a SS, SP, and accuracy of 50%, 100%, and 92%, respectively. In all 71 patients (32 with OS and 39 with Ewing sarcoma), spiral thoracic CT revealed a SS, SP, and accuracy of 75%, 100%, and 94%, respectively. The authors concluded that spiral CT seemed to be superior compared to FDG-PET in detecting pulmonary metastases from malignant primary bone tumors, although a positive FDG-PET result can be used to confirm abnormalities seen on thoracic CT scans as neoplastic.29 In 2006, Iagaru et al.30 published a retrospective study of 106 patients with the histological diagnosis of osseous and soft tissue sarcomas (21 of them with OS), assessing the ability of FDG-PET and FDG-PET/CT versus chest CT in detecting pulmonary metastases. Overall, concordant PET and CT detection of pulmonary metastases was noted in 27 patients (67.5%). For all the patients, the SS and SP for FDG-PET were 68.3% and 98.4%, respectively. CT had a SS of 95.1% and SP of 92.3%. The authors demonstrated that CT of the chest was more sensitive than PET in detecting pulmonary metastases from OS; a significant portion of pulmonary nodules >1 cm on CT are PET-negative; sub-centimeter CT lesions should not be considered false positive if inactive on PET; a negative PET scan in the presence of suspicious CT findings in the chest cannot reliably exclude pulmonary metastases from osseous and soft tissue sarcomas.30 In 2012 Cistaro et al.31 studied 18 patients, 11 of which with OS, who had undergone FDG-PET/CT scan. They firstly attempted to find a SUVmax cut-off value helpful in discriminating the nature of the pulmonary nodules in pediatric bone sarcoma patients. They showed that a SUVmax threshold >1.09 was highly suggestive of malignancy when the nodule diameter was > 6 mm. No significant advantage was found in the semi-quantitative analysis (SUV max and SUV ) for the assessment of lesions below 6
ratio/
mm. In the entire group of patients 18F-FDG-PET/ CT had a SS of 90.3%, a SP of 87.5%, a PPV of 87.5%, and a NPV of 90.3% and an accuracy of 88.9%.31
Conclusions and general remarks
From this systematic review on the role of FDG-PET and FDG-PET/CT in patients with OS, we are led to conclude that:
1)	The combined metabolic and morphological information of FDG-PET/CT imaging allows a high diagnostic accuracy for the detection of OS; FDG-PET/CT is significantly more accurate than FDG-PET alone and improves staging and restaging in patients with OS.
2)	With regard to the staging and restaging of OS, the SS, SP, and accuracy of FDG-PET and PET/ CT seem to be high; FDG-PET and PET/CT seem to be superior to bone scintigraphy and conventional imaging methods in detecting bone metastases; conversely, spiral CT seems to be superior to FDG-PET in detecting pulmonary metastases from OS. A combination of FDG-PET/CT with conventional imaging methods is a valuable tool for staging and restaging of OS and may have a relevant impact on the treatment planning.
3)	Most of the articles included in this systematic review evaluated the diagnostic accuracy of FDG-PET or PET/CT in mixed populations with different types of sarcomas, including some patients with OS. Further large prospective and multicenter studies evaluating the diagnostic accuracy of FDG-PET/CT in patients with OS are needed.
References
1.	Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009; 115: 1531-43.
2.	Ritter J, Bielack SS. Osteosarcoma. Ann Oncol 2010; 21: 320-5.
3.	Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999; 341: 342-52.
4.	Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosar-coma study group protocols. J Clin Oncol 2002; 20: 776-90.
5.	Bielack S, Jürgens H, Jundt G, Kevric M, Kühne T, Reichardt P, et al. Osteosarcoma: the COSS experience. Cancer Treat Res 2009; 152: 289-308.
6.	Bacci G, Rocca M, Salone M, Balladelli A, Ferrari S, Palmerini E, et al. High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 2008; 98: 415-20.
7.	Bielack SS, Carrle D, Hardes J, Schuck A, Paulussen M. Bone tumors in adolescents and young adults. Curr Treat Options Oncol 2008; 9: 67-80.
8.	Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ. Osteosarcoma. J Am Acad Orthop Surg 2009; 17: 515-27.
9.	Kager L, Zoubek A, Pötschger U, Kastner U, Flege S, Kempf-Bielack B, et al. Cooperative German-Austrian-Swiss Osteosarcoma Study Group. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003; 21: 2011-8.
10.	Posthuma De Boer J, Witlox MA, Kaspers GJ, van Royen BJ. Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature. Clin Exp Metastasis 2011; 28: 493-503.
11.	Kim DH, Kim SY, Lee HJ, Song BS, Kim DH, Cho JB, et al. Assessment of Chemotherapy Response Using FDG-PET in Pediatric Bone Tumors: A Single Institution Experience. Cancer Res Treat 2011; 43: 170-5.
12.	Wuisman P, Enneking WF. Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg Am 1990; 72: 60-8.
13.	Xu J, Shen J, Ding Y, Shen HY, Zeng ZP, Ma RF, et al. The clinical value of combined use of MR imaging and multi-slice spiral CT in limb salvage surgery for orthopaedic oncology patients: initial experience in nine patients. Radiol Oncol 2012; 46: 189-97.
14.	Chen J, Zhao Y, Li X, Sun P, Wang M, Wang R, et al. Imaging primary prostate cancer with 11C-Choline PET-CT: relation to tumour stage, Gleason score and biomarkers of biologic aggressiveness. Radiol Oncol 2012; 46: 179-88.
15.	Kim JS, Jeong YJ, Sohn MH, Jeong HJ, Lim ST, Kim DW, et al. Usefulness of F-18 FDG PET/CT in subcutaneous panniculitis-like T cell lymphoma: disease extent and treatment response evaluation. Radiol Oncol 2012; 46: 279-83.
16.	Lakkaraju A, Patel CN, Bradley KM, Scarsbrook AF. PET/CT in primary musculoskeletal tumours: a step forward. Eur Radiol 2010; 20: 2959-72.
17.	Treglia G, Cason E, Fagioli G. Recent applications of nuclear medicine in diagnostics (first part). italJ Med. 2010; 4: 84-91.
18.	Treglia G, Salsano M, Stefanelli A, Mattoli MV, Giordano A, Bonomo L. Diagnostic accuracy of 18F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiol 2012; 41: 249-56.
19.	Schulte M, Brecht-Krauss D, Heymer B, Guhlmann A, Hartwig E, Sarkar MR, et al. Grading of tumors and tumorlike lesions of bone: evaluation by FDG PET. J Nucl Med 2000; 41: 1695-701.
20.	Kneisl JS, Patt JC, Johnson JC, Zuger JH. Is PET useful in detecting occult nonpulmonary metastases in pediatric bone sarcomas? Clin Orthop Relat Res 2006; 450: 101-4.
21.	Charest M, Hickeson M, Lisbona R, Novales-Diaz JA, Derbekyan V, Turcotte RE. FDG PET/CT imaging in primary osseous and soft tissue sarcomas: a retrospective review of 212 cases. Eur J Nucl Med Mol imaging 2009; 36: 1944-51.
22.	Fugl0 HM, J0rgensen SM, Loft A, Hovgaard D, Petersen MM. The diagnostic and prognostic value of 18F-FDG PET/CT in the initial assessment of highgrade bone and soft-tissue sarcoma. A retrospective study of 89 patients.
Eur J Nucl Med Mol imaging 2012; 39: 1416-24.
23.	Garcia R, Kim EE, Wong FC, Korkmaz M, Wong WH, Yang DJ, et al. Comparison of fluorine-18-FDG PET and technetium-99m-MIBI SPECT in evaluation of musculoskeletal sarcomas. J Nucl Med 1996; 37: 1476-9.
24.	Völker T, Denecke T, Steffen I, Misch D, Schönberger S, Plotkin M, et al. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 2007; 25: 5435-41.
25.	Tateishi U, Yamaguchi U, Seki K, Terauchi T, Arai Y, Kim EE. Bone and soft-tissue sarcoma: preoperative staging with fluorine 18 fluorodeoxyglucose PET/CT and conventional imaging. Radiology 2007; 245: 839-47.
26.	Piperkova E, Mikhaeil M, Mousavi A, Libes R, Viejo-Rullan F, Lin H. Impact of PET and CT in PET/CT studies for staging and evaluating treatment response in bone and soft tissue sarcomas. Clin Nucl Med 2009; 34: 146-50.
27.	London K, Stege C, Cross S, Onikul E, Graf N, Kaspers G, et al. 18F-FDG PET/ CT compared to conventional imaging modalities in pediatric primary bone tumors. Pediatr Radiol 2012; 42: 418-30.
28.	Bandopadhyaya GP, Gupta P, Singh A, Shukla J, Rastogi S, Kumar R, et al. (99m)Tc-DMSA (V) in evaluation of osteosarcoma: comparative studies with (18)F-FDG PET/CT in detection of primary and malignant lesions. iSRN Oncol. 2012; 2012: 371830.
29.	Franzius C, Daldrup-Link HE, Sciuk J, Rummeny EJ, Bielack S, Jürgens H, et al. FDG-PET for detection of pulmonary metastases from malignant primary bone tumors: comparison with spiral CT. Ann Oncol 2001; 12: 479-86.
30.	Iagaru A, Chawla S, Menendez L, Conti PS. 18F-FDG PET and PET/CT for detection of pulmonary metastases from musculoskeletal sarcomas. Nucl Med Commun 2006; 27: 795-802.
31.	Cistaro A, Lopci E, Gastaldo L, Fania P, Brach Del Prever A, et al. The role of (18) F-FDG PET/CT in the metabolic characterization of lung nodules in pedi-atric patients with bone sarcoma. Pediatr Blood Cancer. 2012; 59: 1206-10.