European Journal of Radiology

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1 European Journal of Radiology 82 (2013) Contents lists available at SciVerse ScienceDirect European Journal of Radiology jo ur n al hom epage: MRI signal changes in the skull base bone after endoscopic nasopharyngectomy for recurrent NPC: A serial study of 9 patients Hui Li a,b,1, De-ling Wang a,b,1, Xue-wen Liu a,b, Ming-yuan Chen a,c, Yun-xian Mo a,b, Zhi-jun Geng a,b, Chuan-miao Xie a,b, a State Key Laboratory of Oncology in Southern China, Guangzhou, People s Republic of China b Medical Imaging and Minimally Invasive Interventional Center, Cancer Center, Sun Yat-sen University, Guangzhou, People s Republic of China c Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University, Guangzhou, People s Republic of China a r t i c l e i n f o Article history: Received 11 August 2012 Received in revised form 4 October 2012 Accepted 9 October 2012 Keywords: Nasopharyngeal carcinoma Nasopharyngectomy Endoscopy Magnetic resonance imaging a b s t r a c t Purpose: This study was focused on the serial changes in magnetic resonance images (MRI) of the skull-base bone that occur after endoscopic nasopharyngectomy in patients with local recurrent nasopharyngeal carcinoma (rnpc). Materials and methods: Nine patients with histologically proven rnpc were enrolled in this study. Two experienced radiologists independently reviewed all presurgical and postsurgical MR images for each patient. Results: At 36 sites on the skull base, the MRI signal underwent a change after surgery, which took the form of a heterogeneous pattern of hypointense regions with moderate contrast enhancement on T1WI. The onset of changes ranged between 2 weeks and 3 months after surgery. For 21 of the sites, the changes subsided over the course of follow-up, while in 6 they remained stable. At 9 sites, the alteration MRI signal became more pronounced with time. Changes were more common on the homolateral side of the skull base with respect to the recurrent tumor (P < 0.05). The skull-base bone adjacent to the resection boundary had a higher incidence of signal change than nonadjacent areas (P < 0.05). Conclusions: MRI changes in the skull base bone, having a number of distinguishing characteristics, appear to be a common sequel to endoscopic nasopharyngectomy for rnpc Elsevier Ireland Ltd. All rights reserved. 1. Introduction Nasopharyngeal carcinoma (NPC) is highly prevalent in the southeastern part of China. The standard treatment for newly diagnosed NPC consists of a combination of radiotherapy and chemotherapy [1]. Although patient outcomes have improved over recent years, local recurrences are not uncommon, with recurrence rates of 19 25%, 5 years after completion of the combined therapy [2]. Reirradiation, the most common treatment for locally recurrent NPC (rnpc), has been shown to increase survival rates [3]. However, the effectiveness of a second course of radiation is limited by the high rate of complications such as brain necrosis, cranial nerve dysfunction, and skull base fibrosis, even when stereotactic radiotherapy or brachytherapy are used. Corresponding author at: Medical Imaging and Minimally Invasive Interventional Center, Cancer Center, SunYat-sen University, 651, Dongfeng Road East, Guangzhou , People s Republic of China. Tel.: ; fax: address: xchuanm@sysucc.org.cn (C.-m. Xie). 1 These two authors have equal contribution to the article. Curative nasopharyngectomy has been reported to be an effective salvage treatment for locally persistent or recurrent disease. Various surgical approaches have been used for radical resection of rnpc [4,5]. Wide excision of nasopharyngeal tumors by an open surgical approach is difficult, because the nasopharynx is narrow, deep, surrounded by solid bone, and adjoins numerous important structures. However, with the advent of endoscopic surgical techniques, minimally invasive endoscopic nasopharyngectomy for tumor resection has been reported to be effective for small rnpcs [6,7]. Invasion of the skull base by NPC occurs by posterosuperior extension of the tumor into the floor of the sphenoid bone and the clivus, which form the superior margin of the nasopharynx. Skull-base invasion is an unfavorable prognostic factor for NPC, and is classified as T3 according to the 2002 American Joint Committee on Cancer (AJCC) staging system for NPC. However, diagnosis is complicated by the fact that many other factors can cause MRI signal changes in the area during and after treatment for NPC [8]. These include the effects of radiation, bone marrow edema, and fibrosis. In addition, although endoscopic nasopharyngectomy is a minimally invasive procedure, the excised regions of the tumor often lie so close to the skull base that the surgery itself can directly cause changes in the MRI signal X/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.

2 310 H. Li et al. / European Journal of Radiology 82 (2013) Inconclusive MRI signals in the skull base make it difficult for the clinician to distinguish benign post-treatment changes from tumor recurrence or skull-base osteomyelitis, each of which must be recognized and treated promptly. Although the use of endoscopy to surgically excise NPC has been well described [9,7], the MRI signal alterations occurring in the bones of the skull base that follow this procedure have received little attention. In this article, we present the cases of 9 patients with early local rnpc whose recurrent tumor was treated using endoscopic nasopharyngectomy. We review a series of MRI scans for each both patient, obtained both before surgery and during a follow-up of up to 45 months. 2. Materials and methods 2.1. Patients This study had several enrollment criteria. First, all patients were pathologically diagnosed with locally recurrent NPC by examination of biopsies obtained via endoscopy. Second, all patients were treated with endoscopic nasopharyngectomy for locally recurrent NPC no more than 2 weeks after being diagnosed with recurrent tumors. It was required that the tumors be confined to the nasopharyngeal cavity (rt1), the postnaris or nasal septum (rt2a), or the superficial parapharyngeal space (rt2b). Patients were not admitted to the study if there was preoperative MRI evidence of skull-base invasion. Similarly, there could be no preoperative evidence of low-intensity bone marrow on T1-weighted imaging and Gd-DTPA enhancement of the abnormal tissue. Complete medical records and postsurgical imaging studies were obtained for each patient, and there could be no local recurrence, recurrent nodal disease, or distant metastasis within 6 months after surgery. Between April 2006 and December 2010, 9 patients with locally recurrent rnpc were enrolled in this study, including 8 males and 1 female with a median age of 49 years (range: yr). Eight patients were diagnosed with undifferentiated NPC, while 1 had differentiated, nonkeratinizing, rnpc. Each patient had previously received 1 cycle of irradiation, with a total dosage ranging between 66 and 83 Gy. The nasopharynx and retropharyngeal lymph nodes were always within the primary target of irradiation. Patients with gross lymphadenopathy were treated with whole neck irradiation. Most patients (7/9; 77.8%) were treated with conventional techniques, although 22.2% (2/9) were treated with intensitymodulated radiation therapy (IMRT). The recurrent tumors were diagnosed months after completion of irradiation. According to the 2002 staging system of the sixth edition of the American Joint Committee on Cancer, the disease was classified as rt1n0m0 in 6 patients, rt2an0m0 in 2, and rt2bn0m0 in the remaining patient Surgical technique Patients were given a general anesthetic and placed in the supine position. Rigid 4-mm endoscopes (Karl-Storz, Tuttlingen, Germany) with 0 and 30 lenses were used. Details of the surgical procedure have been reported in a previous article [6]. Briefly, a curved incision was made in the posterolateral wall of the nasopharynx, and the mucoperiosteum in the roof and posterior wall were separated from the surface of the sphenoid and clivus. The mucoperiosteum was progressively separated from the medial pterygoid plate, the basilar pterygoid, and the roof of the nasopharynx, after which the mucous membrane was freed, from the base of the foramen lacerum and the petrous apex to the posterior and superior aspect of the pharyngeal recess. Along the anterior side of the Eustachian tube, toward the fossa of the Rosenmuller, the Eustachian cartilage and soft tissue were separated from the nasopharynx. Finally, the posterior wall of the nasopharynx at the level of the soft palate was freed from the prevertebral muscle, which was subsequently turned upward to meet the resection margin of the nasopharyngeal roof and posterior wall Imaging protocol MRI examinations were performed using a 1.5-T unit (GE Signa EXCITEII 1.5, General Electric Medical Systems, USA) with a combined head and neck coil. The scanned region extended from the suprasellar cistern to the sternal end of the clavicle. The following sequences were obtained for each patient: noncontrast-enhanced T1-weighted images (T1WI); fast spin-echo (FSE) imaging in the axial, coronal, and sagittal planes (repetition time of ms and echo time of ms, two excitations, 22-cm field of view (FOV), frequency matrix, 5.0 mm section, and 1.0 mm intersection gap); non-contrast-enhanced T2- weighted images (T2WI) in the axial plane (repetition time of and echo time of ms, two excitations, 22-cm FOV, frequency matrix, 5.0-mm section, and 1.0-mm intersection gap); contrast-enhanced T1WI in the axial and sagittal planes; and contrast-enhanced, fat-suppressed T1WI in the coronal plane (repetition time of ms and echo time of ms, one excitation, 22-cm FOV, frequency matrix, 5.0-mm section, and 1.0-mm intersection gap). A bolus injection of gadopentate dimeglumine (0.1 mmol/kg body weight) was administered for contrast-enhanced sequences Image assessment All patients underwent MRI no more than 2 weeks (range: 7 14 days; mean: 11 days) before the salvage surgery and were subjected to repeat MRI scans 2 weeks and 3 months later and semi-annually thereafter. Two experienced radiologists independently evaluated the MR images. Any disagreements were resolved by consensus. All MR images were viewed on a picture-archiving and communication workstation (Centricity RA1000 Workstation V. 3.0, GE Healthcare). Postoperative MRI scans of the nasopharynx were assessed, with particular attention being paid to the mucous membranes of the nasopharynx, the nasal concha, the parapharyngeal space, and the masticator space. Scans were also examined for evidence of mastoiditis (left, right, and bilateral) or sinusitis (including the sphenoidal sinus, maxillary sinus, ethmoidal sinus, and frontal sinus) to detect whether mastoiditis and/or sinusitis were relevant to MRI signal changes observed postoperatively. Postoperative mastoiditis and/or sinusitis changes were classified as de novo, increased, or decreased relative to pre-operative scans. Signs of mastoiditis and/or sinusitis 2 weeks 3 months postoperatively were used as a reference standard of comparison for subsequent scans until follow-up ceased. The following sites of the skull base were examined for MRI alterations: the clivus, basilar sphenoid, petrous apex, basilar pterygoid, medial pterygoid plate, lateral pterygoid plate, large and small wings of the sphenoid, and basilar occiput. Any abnormalities found were classified as being either adjacent or nonadjacent to the resection boundary and either homolateral or contralateral to the recurrent tumor. In the latter case, if the abnormality found in the clivus, basilar sphenoid, or basilar occiput was not clearly on one side or the other, it was considered contralateral if the area occupied was diffuse. MRI alterations of skull-base bone were evaluated as to the time of onset, whether or not clear margins existed, and whether the signal was hypointense, isointense, or hyperintense compared to that of normal bone marrow on T1WI. The contrast enhancement pattern was also categorized as being homogeneous or heterogeneous, and as strong, moderate, or absent. Enhancement was considered to be strong if the degree of enhancement was similar to that of

3 H. Li et al. / European Journal of Radiology 82 (2013) Fig. 1. T1WI and contrast-enhanced T1WI in the axial plane before the salvage surgery (A and B) and 2 weeks after surgery (C and D). (A and B) Locally recurrent NPC tumor on the right side of nasopharynx with moderate enhancement on contrast-enhanced T1WI (arrow). (C and D) The soft tissue surrounding the excised region appeared edematous, with moderate enhancement on contrast-enhanced T1WI (arrow). normal mucosa, moderate if the degree of enhancement was less than that of normal mucosa, and absent if the lesion showed no relative increase in signal. months (median: 19 mos), and no evidence of in situ local recurrence, recurrent nodal disease, or distant metastasis was found for any patient during follow-up Statistical analysis A two-sided chi-square test was used to compare the incidence of MRI signal changes in different groups of skull base bone (adjacent or nonadjacent to the resection boundary and adjacent or nonadjacent to the resection boundary). A P-value of less than 0.05 was considered to be statistically significant. Analyses were performed using SPSS software, version 13.0 (SPSS, Chicago, IL, USA). 3. Results 3.1. Clinical characteristics All endoscopic nasopharyngectomies were done through an endonasal approach. Patients received radical en bloc resection with negative surgical margins. No patient had a second course of radiation after surgery. The median time of nasopharyngeal mucosal epithelialization was 12 weeks (range: 8 24 wks). The duration of follow-up for the 9 patients ranged from 12 to Postoperative changes of the nasopharynx and surrounding structures MRI scans after surgery showed all patients to have mucosal defects in the nasopharynx. For patients with rt2a-stage disease, the posterior column of the nasal septum and nasal concha were also excised, and for rt2b tumors, the parapharyngeal tissues were included the excised regions. Unilateral or bilateral edema of muscles in the parapharyngeal space and masticator space was evident in scans taken 2 weeks and 3 months after the procedure. These regions were hypo-intense in T1WI scans, hyper-intense in T2WI scans, and showed modest T1WI contrast enhancement. The edematous regions appeared to be reduced in size when viewed again 6 months after surgery (Fig. 1). Unilateral or bilateral mastoiditis was evident in all patients when assessed at 2 weeks and again at 3 months after surgery. Paranasal sinusitis was found in the sphenoidal sinus of all patients, while maxillary and ethmoidal sinusitis were found in 7 (77.8%) and 6 (67.7%) of the 9 patients, respectively. Defects of the mucous

4 312 H. Li et al. / European Journal of Radiology 82 (2013) Table 1 Postoperative MRI findings of each patient. Patient (stage) Nasal concha a Parapharyngeal space a Masticator Mastoiditis b Sinusitis c No. ab-normal space a skull base Time of onset after surgery 1 (rt1) L/de novo S,M,E/increased 4 3 mos 2 (rt1) B/increased S,M/de novo 3 3 mos 3 (rt2a) + L/de novo S,M,E/increased 5 3 mos 4 (rt1) R/de novo S,M/de novo 3 3 mos 5 (rt2a) + B/increased S,M,E/increased 3 3 mos 6 (rt2b) + R/increased S,M,E/increased 7 3 mos 7 (rt1) B/increased S,E/increased 2 3 mos 8 (rt1) R/increased S,M,E/increased 6 2 wks 9 (rt1) L/de novo S/increased 3 3 mos a, region not excised; +, region excised. b L, left; R, right; B, bilateral. c S, sphenoidal sinus; M, maxillary; E, ethmoidal sinusitis. membranes were evident in all 9 patients. The incidence and localization of mastoiditis and/or sinusitis and changes in mastoiditis and/or sinusitis after endoscopic surgery are reported in Table 1. The duration of follow-up for the 9 patients ranged from 12 to 45 months (median: 19 mos). We observed that edema in muscles of parapharyngeal space and masticator space began to lessen 6 months after the surgery in all 9 patients, and normalized gradually in 5 patients (Patients 1, 2, 4, 7, and 9). Edema of muscles in the parapharyngeal space was still evident in the remaining 4 patients (Patients 3, 5, 6, and 8) at the end of the follow-up period (mean: 16 mos after surgery, range: mos). No mass-like mucosal thickening was found in any of the patients in this study. Although repeat MRI scans showed that mastoiditis/sinusitis decreased from 2 weeks to 3 months postoperatively, it remained evident at the end of the study Location and incidence of MRI signal changes at various sites in the skull base MRI scans taken before surgery showed none of the 9 patients to have any abnormality in the bone of the skull base. Specifically, the cortex was intact and the bone marrow signal was homogeneously hyperintense on T2WI and non-contrast T1WI, and showed no enhancement on contrast-enhanced T1WI. After nasopharyngectomy, signal alterations were detected at 36 sites in the skull-base bone (Tables 1 and 2), which generally took the form of a heterogeneous pattern of hypointensity with a diffuse margin on T1WI, and of a heterogeneous pattern of moderate contrast enhancement on contrast-enhanced T1WI (Fig. 2). Changes adjoining the resection boundary were found in the basilar sphenoid, clivus, basilar pterygoid, medial pterygoid plate, and petrous apex. Affected sites not adjacent to the resection boundary included the lateral pterygoid plate, the large and small wings of the sphenoid, and the basilar occiput. A significantly larger number of affected sites adjoined the resection boundary (n = 29), compared to those that did not (n = 7) (P < 0.05). Of the 36 Table 2 Location of MRI signal changes in each skull-base site. Skull-base site No. skull-base changes Patient(s) Clivus 8 1, 2, 3, 4, 5, 6, 8, 9 Basilar sphenoid 7 2, 3, 4, 5, 6, 7, 8 Medial pterygoid plate 5 1, 2, 3, 6, 8 Petrous apex 5 1, 3, 4, 7, 9 Basilar pterygoid 4 1, 5, 6, 8 Large wings of sphenoid 3 6, 8, 9 Lateral pterygoid plate 2 6, 8 Small wings of sphenoid 1 6 Basilar occipital 1 3 Total 36 sites that showed postoperative signal change, most were located on homolateral versus the contralateral side with respect to the recurrent tumor (n = 30 vs. n = 6, respectively; P < 0.05) Evolution of postoperative MRI signal alterations in the skull base Of the 36 skull-base sites that showed MRI signal abnormalities after surgery, 6 were apparent 2 weeks after nasopharyngectomy, while the remaining sites were detectable after 3 months. In the follow-up MRI 6 months after surgery, abnormalities in 9 of the sites had minimized, while in 12 sites the MRI signal of the bone marrow appeared to have been restored to the normal homogeneous hyperintense pattern on T2WI and non-contrast T1WI images, and failed to show enhancement in contrast-enhanced T1WI images (Fig. 3). Patients 3, 5, and 6 showed abnormalities in nine other regions of the skull-base (i.e., clivus n = 3, basilar sphenoid n = 3, medial pterygoid plate n = 2, and basilar pterygoid n = 1) that appeared either to be more pronounced or to show a pattern of contrast enhancement that went from moderate to strong at the 6-month postoperative scan and represented persistent skull base changes at the end of follow-up (mean: 18 mos, range: mos). The remaining six sites in Patients 2, 6, and 8 (i.e., clivus n = 2, basilar sphenoid n = 2, lateral pterygoid plate n = 1, and small wings of sphenoid n = 1) showed no obvious changes in size or shape through the follow-up period (mean: 22 mos, range: mos). 4. Discussion MRI has been proven to be a valuable tool for both diagnosing NPC and identifying postoperative skull bone lesions [10,11]. However, the sensitivity of MRI to bony abnormalities makes this technique prone to identifying postsurgical changes that may be due not to pathological processes, but rather to the consequence of surgery and healing. To our knowledge, no retrospective study surveying the changes in the MRI features of the skull base bone after nasopharyngectomy has been published. Here, we reported nine early local rnpc cases treated by endoscopic nasopharyngectomy, describing the characteristics of changes that occurred following endoscopic nasopharyngectomy, and providing information that can be used to distinguish these changes from locally recurrent NPC and from skull base osteomyelitis caused by radiation therapy. MRI signal alterations in the skull base could be detected 2 weeks and 3 months postoperatively. These sites tended to have low signal intensity on T1WI, with a heterogeneous pattern of moderate contrast enhancement. Most of these abnormalities (21/36) appeared to have receded 6 months after surgery, and likely represented normal healing processes rather than recurrent disease or other pathological processes. For example, during the nasopharyngectomy procedure, the mucoperiosteum in the nasopharynx was

5 H. Li et al. / European Journal of Radiology 82 (2013) Fig. 2. T1WI and contrast-enhanced T1WI of the skull-base bone 2 weeks after surgery. (A F) The clivus (thick arrows in A and B and thin arrows in E and F), basilar sphenoid (thin arrows in A D), right pterygoid plate (thick arrows in C and D), and right petrous apex (thick arrows on E and F) showed heterogeneous regions of hypointensity on T1WI and a heterogeneous pattern of moderate contrast enhancement on contrast-enhanced T1WI. separated from the surface of the skull-base bone, which would be expected to injure the subaponeurotic loose connective tissue overlying the skull-base bone. Unilateral or bilateral mastoiditis and paranasal sinusitis were also common in scans taken 2 weeks and 3 months after surgery. Many of the sites of transient postsurgical changes were likely the result of regional hyperemia and inflammation in the soft tissue adjoining the excised regions, or of reactive changes in the bone marrow such as edema, ischemia

6 314 H. Li et al. / European Journal of Radiology 82 (2013) Fig. 3. T1WI and contrast-enhanced T1WI of the skull-base bone 6 months after surgery. (A F) Abnormal regions of the skull-base bone were minimized on non-contrast T1WI, and slightly enhanced on contrast-enhanced T1WI (thin and thick arrows, respectively). and inflammation. It must also be considered that the NPC patients enrolled in this study had received radiotherapy before the surgery, which has been shown to reduce the activity of both osteoblasts and osteoclasts in the bone marrow [12,13]. In contrast to the transient nature of many of the changes, MRI abnormalities at 9 sites of the skull-base bone appeared to be more pronounced or to show a pattern of contrast enhancement that went from moderate to strong. In the follow-up study, this

7 H. Li et al. / European Journal of Radiology 82 (2013) type of MRI signal changes did not associated with tumor recurrence that may be due to the inflammation of bone marrow. In this study, most of the sites (8/9) that showed this kind of signal change during follow up were located in the clivus, basilar sphenoid, or medial pterygoid plate. Given the close proximity of these sites to the paranasal sinus and nasopharynx, it is possible that the signal changes were due, at least in part, to persistent infection of the paranasal sinus and nasopharynx. MRI signal alterations were more likely to be detected on the same side of the skull as the recurrent tumor. Most of the patients (8/9) in the study were in the early stages of recurrence (rt1 or rt2a), and the nasopharyngeal tumors of all patients were unilateral. In order to resect the tumor completely, it was necessary to resect more tissue from that side [14,15]. Because this would be expected to cause a greater range of damage to the subaponeurotic loose connective tissue on that side, this might explain the higher frequency of homolateral MRI changes after surgery. We also found that regions of the skull-base bone that adjoined the resection boundary were more likely to show subsequent MRI signal changes. In particular, the basilar pterygoid and clivus were the most frequent sites of postoperative signal changes. The basilar pterygoid and clivus collectively form the posterior wall and roof of the nasopharynx. Thus, they would be expected to be particularly susceptible to damage following the separation of the mucoperiosteum from the medial pterygoid plate, basilar pterygoid, and the roof of the nasopharynx. The skull-base bones adjacent to the resection boundary might also be expected to be more exposed to regional hyperemia and inflammation after surgery, and thus to show subsequent MRI signal changes. However, we also found signal changes in sites that were distant from the resection boundary, including the lateral pterygoid plate, the large and small wings of the sphenoid, and the basilar occiput (Patients 3, 6, and 8). In these three patients, signal changes were also found in the skull base bone adjacent to the resection boundary in the basilar sphenoid, clivus, basilar pterygoid, and medial pterygoid plate. Signal changes of such distant sites may be related to inflammation of adjacent skull-base bone. Accurate diagnostic imaging after nasopharyngectomy not only enables the effectiveness of various treatments to be compared, but is also important in determining the prognosis for individual cases [14,16]. Some characteristics of benign changes after endoscopic nasopharyngectomy were found in this study and could give some help to distinguish these changes from locally recurrent NPC and from skull base osteomyelitis caused by radiation therapy. In particular, local recurrences of NPC in the nasopharynx or bone of the skull base usually appeared as an identifiable mucosal mass lesion, with tumor invasion of the skull base typically visible on MRI as a growing, focal soft tissue mass that erodes the cortex, sometimes reaching the bone marrow. In contrast, most of the MRI signal changes we identified were close to the resection boundary, did not affect the cortex the skull-base bone, and appeared to stabilize or subside over the course of follow-up. Similarly, skull-base osteomyelitis secondary to irradiation typically causes symptoms such as a foul odor, headache, and epistaxis, and presents on MRI as a widespread erosion of the skull base with evidence of a diffuse infiltrative soft tissue mass [17]. In the current study, the abnormalities of the skull-base that were identified did not appear to be diffuse, and the surrounding soft tissues, while edematous, did not appear to form a soft tissue mass. 5. Conclusions After transnasal, endoscopic resection of recurrent nasopharyngeal carcinoma, we observed a number of signal changes on skull-base MRI that were of low-signal intensity on T1WI with contrast enhancement. Regions adjoining the site of resection were more likely to show signal changes. Most of these signal changes appeared to stabilize or resolve over the course of follow-up. These characteristics should allow such benign signal changes to be readily distinguished from more serious events such as local recurrence or osteomyelitis. Ethical approval Approval obtained. Conflict of interest The authors have no conflicts of interest to declare. References [1] Ng SH, Chan SC, Yen TC, et al. Comprehensive imaging of residual/recurrent nasopharyngeal carcinoma using whole-body MRI at 3 T compared with FDG- PET-CT. European Radiology 2010;20: [2] Chua DT, Hung KN, Lee V, Ng SC, Tsang J. 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