UNIVERSITÁ di PISA
Facoltà di Medicina e Chirurgia
Scuola di Specializzazione in Medicina Nucleare Direttore: Prof. Giuliano Mariani
Tesi di Specializzazione
Performance of Whole-Body Integrated [
18F] FDG PET/MR
in Comparison to PET/CT in Patients with Head and Neck
Squamous Cell Carcinoma
Relatore:
Chiar.mo Prof. Giuliano Mariani
Candidato:
Dr. Federica Guidoccio
INDEX
Abstract………... pag. 3
INTRODUCTION
Generalities on Head and Neck cancer……….pag. 5 Head and Neck cancer Imaging……...……….pag. 6 Generalities on PET/MR ………. pag. 8 Integrated PET/MR scanner……….pag. 10
MATERIALS AND METHODS………..pag. 13
RESULTS………..……… pag. 19
DISCUSSION………. pag. 22
REFERENCES……… pag. 25
TABLE
Abstract
Background: Recently a new whole body integrated PET/MR has been introduced; offering the opportunity to acquire PET/MR data simultaneously. Diagnostic evaluation of patients with tumours of head and neck is one possible application for this new modality.
Aim of this study was to evaluate the performance of PET/MR in patients with Head and Neck Cancer including in the evaluation an acquisition protocol which we composed for this new modalitis and a comparison of the quantification ability of the new device in terms of standardized uptake value (SUV) and its diagnostic outcome with that of PET/CT.
Methods: The study population comprised 28 patients with primary and recurrent Head and Neck Cancer who underwent a single-injection dual imaging protocol with PET/CT and subsequent PET/MR. PET/CT scans were performed applying standard clinical protocols. Subsequently. PET/MR was performed using whole-body Dixon MR-sequence for attenuation correction and a dedicated protocol for the neck. Acquisition time PET/MR was 125±24.6 min after injection and PET/CT was 76.2±16.6 min after injection. The mean injected activity of [18F] FDG was of 386±48 MBq. Artifacts and image quality, Intensity of [18F]FDG uptake, delineation, lesion characterization of all primary or recurrent tumours and cervical lymph nodes detected in PET/CT and PET/MR were analyzed and compared. Further SUVs for suspicious lesions in the head and neck and normal cervical muscles calculated in the two different modalities were compared.
Histopathology, imaging and clinical follow-up data were used as reference standards for the final lesions' classification.
Results: Artifacts and image quality was better for PET/MR than for PET/CT with statistically significant difference (p=0.004). Mean delination of primary/reccurent and lymph nodes concerning intensity of FDG uptake was similar for PET/MR and PET/CT, while PET/MR allowed statistically higher delineation of primary/reccurent and metastatic lymph nodes than PET/CT.
PET/MR characterization of primary/recurrent tumour resulted in 100% sensitivity and 75% specificity while sensitivity and specificity of PET/CT was 90.9% and 75% respectively. No substantial differences in sensitivity and specificity between PET/MR and PET/CT were observed concerning characterization of cervical lymph nodes.
Quantitative analysis revealed highly significant correlations between maximum and mean SUVs of all lesions evaluated at PET/CT and PET/MR.
SUVmean and SUVmax were significantly higher in PET/MR than PET/CT for
tumour lesions, while were significantly lower in PET/MR than PET/CT for cervical normal muscles.
Conclusion: Simultaneous PET/MR acquisition was feasible and delivered in a reasonable acquisition time high quality, diagnostically sufficient PET and MR images.
In particular, our data indicate that the combination of MR and PET was beneficial especially for assessment of the primary or reccurent tumour. Moreover, results of the quantitative analysis show that SUVs derived from [18F] FDG-positive lesions on PET/MR and in normal cervical muscles correlated well with those derived from PET/CT.
INTRODUCTION
Generalities on Head and Neck cancer
Head and Neck cancers are the fourth most common cancer in men in the European Union after lung, colorectal and prostate cancers. The epidemiology is characterised by a strong incidence gradient, with increasing rates from Northern to Mediterranean countries; Eastern countries have intermediate incidence rates. [1].
With an incidence of approximately 10–20 cases per 100.000, head-and-neck squamous cell carcinoma (HNSCC) comprises about 3% of the diagnosed malignancies each year [2].
Cancers of the head and neck are further classified according to the area of the head or neck where they originate. These areas are described below and labeled accordingly in the image of the head and neck cancer regions shown in Figure 1. Oral cavity: The oral cavity includes the lips, the front two-thirds of the tongue, the gums, the lining inside the cheeks and lips, the floor (bottom) of the mouth under the tongue, the hard palate (bony top of the mouth), and the small area of the gum behind the wisdom teeth.
Pharynx: The pharynx (throat) is a hollow tube about 5 inches long which starts behind the nose and leads to the oesophagus. The pharynx is divided into three parts: the nasopharynx (upper part of the pharynx, behind the nose); the oropharynx (middle part of the pharynx, including the soft palate, namely the back of the mouth, the base of the tongue, and the tonsils); the hypopharynx (lower part of the pharynx).
Larynx: The larynx, also called the voicebox, is a short passageway formed by cartilage just below the pharynx in the neck. The larynx contains the vocal cords. It also has a small piece of tissue, called the epiglottis, which moves to cover the larynx to prevent food from entering the air passages.
Paranasal sinuses and nasal cavity: The paranasal sinuses are small hollow spaces in the bones of the head surrounding the nose. The nasal cavity is the hollow space inside the nose.
Salivary glands: The major salivary glands are in the floor of the mouth and near the jawbone. Cancers of the salivary gland are relatively uncommon.
More than 90% of head and neck malignancies are squamous cell carcinomas (HNSCC).
In HNSCC, cervical lymph node metastasis is associated with an unfavorable prognosis. To plan HNSCC treatment properly, regional metastases must be detected accurately. The prevalence of lymph node metastases at initial presentation depends on the site origin of the tumor.
A particular feature of HNSCC is the high rate of synchronous or metachronous second tumours, which are most often seen in the lung or esophagus [3].
Head and Neck cancer Imaging
Imaging plays an important role for establishing the tumour size and extent, as well as to identify lymph node and distant
Morphological imaging is usually performed by computed tomography (CT) or magnetic resonance (MR) imaging [4,5].
MR provides several advantages over CT, such as increased soft-tissue contrast and reduced artifacts near metallic dental implants [6]. However, despite their high anatomical resolution, MR and CT have a limited diagnostic accuracy for the
extent of nodal involvement and for small primary tumours. Normal-sized lymph
nodes with metastasis or nonspecifically enlarged lymph nodes can lead to false results. Identifying the primary tumour can be challenging in small lesions, as slight asymmetries along the pharyngeal tube are often suspicious but not diagnostic for a primary tumour site [7]. After treatment, it is most often difficult to discriminate between tumour recurrence and post-therapeutic changes induced by surgery or chemo/radiation [8].
Numerous studies have demonstrated the high potential of [18 F]-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET); PET has become a powerful tool in the clinical routine workup of HNSCC also in the post-therapeutic setting [9].
The potential of PET to reveal small lymph node metastases and primary tumours associated with the advantage of whole-body staging within one examination have contributed to the important role of PET/CT for the staging, restaging, and treatment monitoring and planning [10, 11, 12]. Although post-acquisition software fusion of MR and PET has been proven to be useful for the evaluation of HNSCC, its drawbacks (e.g. time consuming, limited anatomical co-registration) limit its clinical use [13]. With the recent introduction of hybrid PET/MR scanners, a new method becomes available combining the superb soft-tissue contrast of MR with the functional information provided by PET. Moreover, endoscopic evaluation of the primary tumour, when appropriate, is desirable for detailed assessment of the primary tumour for accurate T staging. Fine-needle aspiration biopsy (FNAB) may confirm the presence of the tumour and its histopathologic pattern, but it cannot rule out the presence of tumour.
The treatment plan for an individual patient depends on numerous factors, including exact location of the tumour, stage of the cancer, and patient’s age and
general health. Treatment for HSNCC can include surgery, radiation therapy, chemotherapy, targeted therapy, or a combination of treatments.
Generalities on PET/MR
Positron emission tomography (PET)/magnetic resonance (MR) imaging is a new hybrid imaging modality combining two powerful diagnostic imaging tools. The individual strengths and weaknesses of these two imaging modalities are believed to be synergistic and complementary in that the advantages of either component compensates for the limitations of the other. Thus, PET/MR combines the highest anatomical detail as well as biochemical and functional information provided by MRI with the metabolic, molecular, and physiologic information from PET. The PET/MR combination has been debated since the 1990’s, starting at about the same time as PET/CT. However, while PET/CT was conceived out of a well-defined clinical need to combine functional and anatomical information from PET and CT, respectively, the developments toward an integrated PET/MR system begun by pre-clinical research endeavours [14, 15].
Following the successful adoption of PET/CT in clinical routine and of PET/MR for pre-clinical research applications, the industry has quickly adopted the idea of combining PET and MRI for human studies. The first simultaneous PET/MR design for human use was presented in 2006. This PET/MR prototype system was only intended for brain image and considered a proof of concept for a fully integrated PET/MR [16, 17]
To time of data three different scanner types for PET/MR acquisition exist shown in Figure 2:
1. Separate and sequential acquisition of PET/CT and MR system operated in an adjacent room (A).
2. Co-planar PET/MR: gantries arranged in line with the main scanner axis with a patient handling system mounted in between (B).
3. Integrated, simultaneous acquisition PET/MR system: fully integrated system (C).
1. The PET/CT–MR shuttle system was proposed by GE Healthcare in 2010. This device is based on a combination of a dual-modality, whole-body TOF-PET/CT and of a 3T MR system that are operated in adjacent rooms. Patients are shuttled from one system to the other having to get out of the imaging bed. The advantages of this system include CT-based attenuation correction, reliable PET quantification and higher flexibility in patients. Comparative studies of PET/MR versus PET/CT are readily accomplished without repeated PET and placing a different PET scanner at a different time-point.
Moreover, higher imaging flexibility is obtained, based on the availability of three imaging modalities, which can be combined for the characterization of the disease. The downside is a somewhat higher radiation dose of up to 3 mSv with a low dose CT based on the CT-component, longer acquisition times and potential misalignment between the imaging components. Overall, the tri-modality PET/CT–MR system allows to use the three different imaging modalities in the same patient virtually at the same time, and may help to develop reliable attenuation algorithms [18].
2. Co-planar PET/MR. In 2010 Philips Healthcare proposed a slightly more integrated approach to PET/MR. The system is based on a coplanar design concept that integrates a whole-body time of flight (TOF) PET system and a 3T MR system. The two components are joined by a rotating imaging bed platform mounted in between [19]
.3. Integrated PET/MR. The first whole-body integrated PET/MR scanner (Biograph mMR; Siemens Healthcare) has been introduced in late 2010. This new technology may repeat the success of PET/CT, in particular for oncologic indications, which are better addressed with MRI than with CT. With regard to soft-tissue contrast, CT is known to be clearly inferior to MRI. Antoch and Bockisch summarised key studies from the literature and from their own experience [20, 21] and conclude that PET/MR is expected to be more accurate than PET/CT for T-staging in all the indications in which MRI is more accurate than CT, while similar accuracies are to be expected for N-staging. For M-staging, potential advantages of PET/MRI will depend on the site of the metastases.
This combined imaging modality has now passed the level of an experimental research device and is increasingly being used clinically. Although most of the use of this new hybrid modality is still work in progress, the first clinical experience is now available for applications in oncology, and to a lesser extent for cardiac and neurologic applications. In general, the experience is limited to the use of 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG). Mainly in Europe there is a substantial preliminary experience with other tracers, including 18F-fluorocholine,
[11C] acetate, and 18F-fluoroethyltyrosine, as well as as well as [11C]-Pittsburgh compound B and [15O]- and [90Y]-carrying tracers.
Integrated whole body PET/MR scanner
In November 2010 the first fully integrated whole-body PET/MR scanner (Biograph mMR; Siemens Healthcare) that allows simultaneous acquisition of PET and MR data in humans was installed at the Department of Nuclear Medicine, Technische Universität Mnchen, Munich, Germany.
The integrated PET/MR scanner features several basic technical differences from a conventional PET/CT scanner. Two factors may affect the quality of the acquired PET data: the replacement of the photomultipliers tubes with avalanche photodiodes, and the attenuation correction of PET data acquired in the PET/MR scanner, which has to be derived from MRI scan information.
In conventional PET/CT scanners, attenuation correction is performed on the basis of a CT scan that is used to generate an attenuation map based on a transformation of the CT Hounsfield units into attenuation factors at 511 keV [22]. Since the MRI signal does not provide information on the radiodensity of the tissue and cannot directly be used for attenuation correction, several alternative approaches have been proposed, including anatomically based attenuation maps and automatic atlas-based pattern recognition approaches [23,24 ,25, 26,27] The procedure implemented in the Biograph mMR uses an MRI-based attenuation map that is generated on the basis of a 2-point Dixon MRI sequence.
The Dixon sequence allows segmentation of four different tissue types (fat, soft tissue, lungs, and background/air) throughout the body and the calculation of an attenuation map on the basis of the presumed radiodensity of these tissue types [26, 27, 28,].
Although neglecting attenuation by cortical bone, this technique has been reported to have comparable performances with respect to CT-based attenuation [26, 29]. Another difference between PET/MR and PET/CT is that the anatomic allocation of PET findings in the whole body has to be performed by means of the MRI data rather than by the information provided by CT.
The PET signal alone provides only limited anatomic information. In conventional PET/CT, low-dose CT information is used not only for attenuation
correction but also for anatomic allocation of PET findings, even when a fully diagnostic CT is not performed [30].
However, because of relatively long acquisition times, usually high-resolution sequences are acquired only in selected regions of interest and in one preferred anatomic orientation (nonisotropic). Also for PET/MR, time constraints may not allow covering the whole body with fully diagnostic MRI sequences, and predominantly nonisotropic data will be acquired. However, unexpected PET findings may also be detected in regions not covered by high-resolution MRI, and anatomic information may also be necessary to distinguish physiologic tracer uptake from pathologic findings throughout the body.
Thus, a fast method for rough anatomic allocation of the PET findings may be valuable also for regions in which diagnostic sequences have not been performed. In this context, a recently published paper concluded that images derived from the 2-point Dixon MRI sequence, which is performed for attenuation correction in a short time (19 s acquisition time) for each PET bed position (BP), may have considerable value for the anatomic allocation of PET findings throughout the body [29].
In a recent report, Eiber et al. have successfully established and simulated an efficient imaging protocol for primary staging of patients with HNSCC which is suitable for use in an integrated PET/MR scanner. The protocol, including whole-body Dixon MR-sequence for attenuation correction and T1w turbo spin-echo (TSE) sequence before and after intravenous administration of gadolinium-DTPA for local staging in head and neck, resulted time efficient and well tolerated by most patients. Moreover, the sequences used did not lead to a diagnostic deterioration compared to PET/CT. Therefore, in this study we evaluated the
diagnostic performance of this new dedicated PET/MR-protocol in comparison with PET/CT in a group of patients with HNSCC [31].
MATERIALS AND METHODS
Patients' Characteristics
The study population included 28 patients (23 men and 5 women with mean age 55±12 years) referred for [18F] FDG PET/CT for clinical staging or restaging of Head and Neck Squamous Cell Carcinomas (HNSCC). Patients were recruited consecutively for this prospective study during the period from August 2011 to April 2013. Exclusion criteria were standard contraindications for MR scans (magnetic metal implants, pacemakers, etc.). The study was approved the ethic comitee of our institution. All patients provided informed consent for participating in the study. Of the 28 patients, 19 were referred for staging after primary diagnosis of HNSCC, and 9 for restaging. Details of the patients’ characteristics are summarized in Table 1.
The mean injected activity of [18F] FDG was of 386±48 MBq.Patients fasted 6 h before tracer injection, and blood glucose levels were measured just before injection, with a cutoff of 150 mg/dL (mean 108.9±28.4mg/dL).
All patients agreed with written informed consent obtained prior to imaging to undergo a PET/MR scan directly after the PET/CT scan. Approval of the Ethics Committee was obtained; and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.
PET/CT Acquisition
PET/CT scans were acquired on a Biograph Sensation 64 PET/CT scanner (Siemens Healthcare).This LSO crystal-based tomograph has an average spatial resolution of 4.4 mm at 1 cm and of 5.1 mm at 10 cm from the centre of the transverse field of view (FOV) and a maximum sensitivity of 8.1 kcps/MBq at the centre of the FOV. Its axial FOV is 21.8 cm. Emission imaging was performed in three-dimensional mode (3D) with an acquisition time of 2-3 min per bed position (168×168 matrix, pelvis–neck) with 5–6 bed positions per patient.
The CT acquisition protocol included a low-dose CT (26 mAs, 120 Kv, 0.5 s per rotation, 5 mm slice thickness) from the skull to mid-thigh for attenuation correction with the arms down followed by the PET scan and a contrast-enhanced diagnostic CT of the thorax to pelvis (240 mAs, 120 kV, 0.5 s per rotation, 5 mm slice thickness) in the portal venous phase 80 s after the injection of 80 mL i.v. contrast agent (Imeron 300) with the arms elevated above the head.
Immediately afterwards, a diagnostic CT of the neck (reference quality 180 mAs, 120 kV, 0.5 s per rotation, 0.6 mm collimation) was performed 75 s after the additional administration of 30 mL i.v. contrast agent (Imeron 300) with the arms elevated above the head. PET/CT acquisition was started at a mean of 76.2± 16.6 min after tracer injection (59–117 min).
PET/MR Acquisition
PET/MR was performed on a fully integrated whole-body hybrid system (Biograph mMR; Siemens Healthcare). The PET/MR acquisition protocol was as follows. Initially, a coronal 2-point Dixon 3D volumetric interpolated breath-hold examination (VIBE) T1 weighted (T1w) MR sequence was performed. This was done for attenuation correction of the PET data as described previously [29].
Hereby, the table was moved to the head/neck, thorax, abdomen and pelvis and T2 HASTE MR sequence was acquired. Emission imaging was performed in 3D with an acquisition time of 4 min per bed position (172×172 matrix), for a total of 4 beds. In the thorax and abdomen, the images were acquired in the end-expiratory phase. For local staging in head and neck a short tau inversion recovery (STIR) T2 weighted sequence in axial orientation, a T1 weighted turbo spin-echo (TSE) sequence before and after intravenous administration of gadolinium-DTPA 0.1 mmol/kg body weight (Magnevist, Schering AG, Berlin, Germany) in an axial orientation and a T1 weighted TSE fat sat sequence in coronal orientation after contrast were performed. The acquisition time in the neck was 15 min per one bed position. Total acquisition time for PET/MR was about 31 min.
PET/MR was acquired at a mean of 125±24.6 min min after tracer injection (range, 87–168 min). Thus, on average the time difference between the start of PET/CT and the start of the PET/MR examinations was 48.6 ± 16.8 min. The average time elapsing between whole-body and neck PET/MR was 21 ± 11min
Image Reconstruction
To maintain comparability, similar reconstruction methods were used for the PET data acquired with the PET/CT and with the PET/MR scanners, respectively. Details on reconstruction of the PET data for PET/CT and PET/MR, including the use of the T1-weighted VIBE Dixon for attenuation correction, have been published recently [32]. PET data obtained on the PET/CT and PET/MR scanners were processed with comparable reconstruction and correction algorithms. For both modalities, emission data were corrected for randoms, dead time, scatter, and attenuation. A 3-dimensional attenuation-weighted ordered-subsets expectation maximization iterative reconstruction algorithm (AW OSEM 3D) was applied
with 3 iterations and 21 subsets, gaussian smoothing of 4 mm in full width at half maximum, and a zoom of 1. Attenuation maps were obtained from the CT data by bilinear transformation, as implemented in the postprocessing software of the PET/CT scanner, and were used for attenuation correction of the PET/CT data, as previously described All images were uploaded to a dedicated workstation (Syngo MMWP; Siemens Healthcare).
Qualitative Analysis
Qualitative analysis was performed by a nuclear medicine physician and by a radiologist specialized in head and neck imaging with substantial experience in PET/CT and PET/MR. All images were evaluated for the presence of artifacts, locoregional tumour and/or recurrence and lymph node cervical metastasis
according to Robbins classification [33]. To avoid any learning bias, datasets with CT or MR were analyzed in random order with a time interval of 8 weeks.
Artifacts and image quality were assessed on a 3-point score scale, with 0
indicating absence of relevant artifacts; 1, the presence of mild artifacts with sufficient image quality for morphologic retained; and 2, the presence of substantial artifacts with insufficient image quality for exact morphologic assessment.
The PET intensity uptake of all lesions in the PET dataset was rated on a 4-point scale, with 0 indicating no uptake on PET (in the case of a PET-negative lesion); 1, low uptake (less than liver); 2, moderate uptake (comparable to liver); and 3, high uptake (more than liver). As in previous studies, in the case of excessive numbers of PET-positive lesions in a single organ system, only up to five lesions per organ system were chosen to avoid bias from individual patients [32]
Lesion delineation was assessed using a four-point-scale (0: not identified, 1, uncertain finding [e.g. asymmetry], 2, clearly depictable, borders not exactly defined, 3, clearly depictable, borders exactly defined). Signs of malignant tumours and lymph node metastasis in CT and MR were evaluated as previously described [34]
Lesion characterization was based on its appearance on morphologic imaging and on uptake on PET and rated on a 5-point scale, with 1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant, and 5, definitely malignant.
Quantitative assessment
Quantitative output in terms of SUV of PET data acquired on the PET/CT and PET/MR scanners were compared as similar to previously study [32].
In brief, the SUVmax and SUVmean of the suspected lesions and of muscles of the
neck were calculated in the respective PET scans and compared.
To calculate the SUVs of the suspected tumour lesions, the axial slice with the maximum SUV of the lesion was first located using standard software for images of both scanners. A round isocontour region of interest (ROI) of 50% around the maximum was then created to calculate the mean SUV. To ensure placement of ROIs in corresponding locations, the two PET scans were coregistered using a dedicated software (TrueD; Siemens).
To avoid overrating of individual patients, the number of rated lesions was limited to five per patient. The maximaum axial diameter of soft tissue lesions was measured in the CT component of the PET/CT scans.
Reference standard
Histopathology and imaging follow-up data (contrast-enhanced spiral CT or PET/CT or contrast-enhanced MR) as well as available for clinical data were all used as reference standards for final classification of the primary tumour and of cervical lymph nodes. Of the 30 primary and recurrent lesions evaluated, 21 were confirmed by histology and 9 with follow-up. Furthermore, histopathology of the cervical lymph nodes was available in 18 of 28 patients, while in 10 patients final diagnosis was based on imaging follow up data. Median follow-up time 10 months (range, 2-26 months).
Statistical analysis
Results for delineation of the primary tumour are presented as mean and standard deviation. A nonparametric Wilcoxon matched-pairs signed rank test was used to calculate the statistical differences for both qualitative and quantitative analysis.
The Spearman’s rank correlation coefficient (ρ) was calculated to examine the
correlations between SUVmean and SUVmax derived from PET/MR and PET/CT. The diagnostic performance in assessing the lesions was evaluated by using a receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) was calculated and pair-wise comparison was made using the variance z-test.Statistical analysis was performed with statistical packages (SPSS version 13.0, SPSS; and Med-Calc version 23.0, MedCalc Software). A p value less than 0.05 was considered to indicate a statistically significant difference.
RESULTS
Reference standard
Histopathology (n = 17) and follow-up (n =4) data showed 22 primary/recurrent tumours including tonsillar (n = 5), oral cavity (n = 8), oropharinx (n = 4), and hypopharinx (n = 5) cancer.
Histopathology (n = 6) and imaging follow-up (n =12) data revaled 52 lymph node metastases which were located in 39 levels (level I in 4 patients, level II in 13, level III in 6, level IV in 3, level V in 3, level VI in 4, level VII in 2, lymph node of the internal carotid artery in 4). Only two patients presented multiple distant metastases in bone, lung, liver and retroperitoneum while one patient had histological evidence of thyroid metastasis. However, distant metastases were not included in the final analysis.
Qualitative Analysis Artifact and image quality
Several metal artifacts reduced image quality more frequently in PET/CT (10/28 score 1, 6/28 score 2) in contrast to PET/MR imaging (1/28 score 1, 1/28 score 2), with a statistically significant difference (Wilcoxon signed rank test, p = 0.004; Table 2). In CT, most artifacts were found in the oral cavity due to dental implants (Figure 3).
Primary Tumour
22 lesions eventually classified as malignat at the standard of reference were included in the statistical analysis for lesion delineation and PET intensity. Mean delineation of the primary tumour assessed on a four point-scale (0–3) was 2.27±0.43 for PET/MR and 1.95±1.17 for PET/CT, this difference being statistically significant (P = 0.004) (Table 2). The PET intensity of primary or recurrent lesions observed on PET/MR appeared on average slightly better discernible than those observed on PET/TC, but the difference was not statistically significant (Table 2).
Lesion characterization.
Overall, 30 lesions were rated as primary /recurrent lesions. One patient had secondary tumours in the nasal cavity (patient number 13 in the Table 1).
PET/CT correctly classified 26/30 (86.7%) primary or recurrent lesions, while lesion characterization was inaccurate in 4 cases (2 lesions were false positive, 1 was false negative and 1 was rated as indeterminate, score =3) At PET/MR, 28/30 (93%) primary lesions were correctly classified. PET/MR characterization included two false-positive results (the same as PET/CT).
In particular, PET/MR allowed correct characterization of 2 lesions misclassified at PET/CT, including one lesion in the floor of the mouth and one recurrence in the tongue, not correctly classified on PET/CT because of metal artifacts (Figure 4).
Overall, PET/MRI resulted in 100% sensitivity and 75% specificity for identifying primary or recurrent malignancies, and sensitivity and specificity in PET/CT was 90.9 % and 75% respectively (Table 3).
At ROC analysis the AUC value for PET/MR was 0.989, greater than for PET/CT (AUC = 0.889) (Figure 5), although this difference was not statistically
significant. (p = 0.146). ROC analysis indicated for PET/CT as well as PET/MR a cut off score of >2 for malignancy.
Lymph nodes
Lesion delination and Uptake intensity
Only the 52 nodal lesions that resulted to be malignant at the standard of reference were included in the statistical analysis for lesion delineation and PET intensity. PET/MRI allowed higher delieation of lymph node metastasis than PET/CT, with statistically significant difference (p = 0.01) (Figure 6). The PET intensity Uptake for the lymph node lesions was similar for the two modalities, with a mean vlaue of 2.58 ±0.8 for PET/CT and 2.67±0.76 for PET/MR (p = 0.13). (Table 2)
Lesion characterization. Overall, the sensitivity and specificity of PET/MR for identifying lymph nodal metastases was 98.1% and 98.8%, and for PET/CT. 94.2% and 96.8% respectively. Incorrect PET/MR and PET/CT nodal characterization included one false-negative, four false positives and six indeterminate findings. Only two nodal indeterminates (score 3) were different: in PET/CT they were considered as false-negatives and in PET/MR as true negatives (Table 4).
In the differentiation of benign from malignant lymph nodes ROC curve analysis per lymph node level resulted in an AUC of 0.983 for PET/CT and 0.995 for PET/MR, but no significance level was reached (Figure 5).
Quantitative assessment
The SUVs of 55 lesions were evaluated. Overall, the SUVmean and SUVmax
obtained from PET/CT and PET/MR did correlate significantly (ρ = 0.97 and ρ=0.96, respectively; p<0.001; Figure.7). Grouping the SUVs of the primary and
recurrent lesions and lymph node lesions separately, the maximum and mean SUVs also showed highly significant correlations between PET/CT and PET/MR (Table 5).
Correlation analysis of SUVs from PET/CT and PET/MR for cervical normal muscle revealed highly significant correlations for the respective maximum and mean SUVs (ρ = 0.76, ρ = 0.87 respectively; p = 0.003 and p = 0.001, Table 6, Figure 7).
However, SUVmean and SUVmax were significantly higher in PET/MR for all
lesions than PET/CT while PET/MR was significantly lower for normal cervical muscles in contrast to PET/CT.
DISCUSSION
Our study shows that simultaneous PET/MR acquisition in patients with squamous cell carcinoma of the head and neck is feasible, delivery sufficent diagnostic data at least compereble to short of PET/CT in a reasonable time. The results of this prospective comparison study demonstrate that integrated whole-body PET/MR is more accurate than PET/CT for the characterizion of malignancy in the head and neck. In particular, our data indicate that the combination of MR and PET was beneficial especially for assessing the primary tumour. Furthermore, PET/MR also allowed improving the delineation of both primary tumours and lymph node metastases. These results can mostly be attributed to the better performance of MR compared to CT in terms of higher soft-tissue contrast and lack of artifacts from dental implants. It is known that dentures (especially with extensive anchorage in the jaw or to other teeth) and
dental amalgams often create considerable beam hardening artifacts in CT. This kind of hardware usually does not degrade MR images [6]. In addition, MR better displays the lower neck without the degradation from shoulder artifact that can occur with CT.
Overall, PET/MRI resulted in 100% sensitivity and 75% specificity for identifying primary or recurrent malignancies, ensuing a tendency to higher sensitivity than PET/CT for the diagnosis. However, differences at ROC analysis were not statistically significant probably because of the small number of tumour lesions included.
Despite our efforts, two tumour lesions were incorrectly classified as malignant with both PET/MR and PET/CT (false-positive findings). In both cases, this was related to post-treatment changes, a well-documented reason for false-positive findings. (post-actinic inflammation respectively in hyphoparinx and right tonsil). Our results were different concerning image quality to that achived by other investigators employing sequential or separate PET and MR scanners [35]. Moreover, our quantitative results show that SUVs derived from [18F] FDG-positive lesions on PET/MR and in normal cervical muscles correlated well with those derived from PET/CT. These results indicate that relative proportions of tracer uptake in lesions and in cervical muscles are preserved between PET/MR and PET/CT, despite different technologies and different approaches to attenuation correction. This implies that [18F]FDG PET/MR acquired on this scanner is suitable for quantitative evaluation (e.g staging and restanging of head and neck cancer ), but care should be taken in comparing SUVs between PET/MR and other scanner types. It is of interest to note that SUVs in suspected malignant soft-tissue lesions were systematically higher on PET/MR than on PET/CT (Table 5) while cervical normal muscle were systematically lower on PET/MR. than on
PET/CT. This result can most likely be explained by the uptake mechanism of [18F]FDG in malignant lesions. As a glucose analog, [18F]FDG is taken up by tumour lesions, where phosphorylation prevents the glucose from being released again from the tumour lesion, once it has been absorbed. The 18F-FDG-6-phosphate formed when [18F]FDG enters the cell thus cannot move out of the cell
before radioactive decay.
As a consequence of trapping, the SUV in malignant lesions will increase over time. Indeed, the time between PET/CT scan and PET/MR neck scan was a mean 76.3 min.
In conclusion PET/MR allowed a higher charaterization for the primary and recurrent tumour than PET/CT. Furthermore PET/MR improved lesions delination of primary and recurrence tumour. No difference between PET/MR and PET/CT concerning charaterization of nodal status was observed.
REFERENCES
1. Berrino F, Gatta G.Variation in survival of patients with head and neck cancer in Europe by the site of origin of the tumours. Eur J Cancer. 1998; 34(14): 2154-61.
2. Guntinas-Lichius O, Wendt T, Buentzel J, et al. Head and neck cancer in Germany: a site-specific analysis of survival of the Thuringian cancer registration database. J Cancer Res Clin Oncol 2010; 136(1): 55–63.
3. Wolff HA, Wolff CR, Hess CF, et al. Second primary malignancies in head and neck cancer patients: high prevalence of curable-stage disease. Strahlenther Onkol. 2013; 189 (10): 874-80
4. Rumboldt Z, Gordon L, Gordon L, Bonsall R, Ackermann S. Imaging in head and neck cancer. Curr Treat Options Oncol 2006; 7(1):23–34.
5. Mukherji SK, Castelijns J, Castillo M. Squamous cell carcinoma of the oropharynx and oral cavity: how imaging makes a difference. Semin. Ultrasound CT MR 1998; 19(6): 463–75.
6. Wippold 2nd FJ. Head and neck imaging: the role of CT and MRI. J Magn Reson Imaging 2007;25(3):453–65.
7. King AD, Tse GMK, Yuen EHY, et al. Comparison of CT and MR imaging for the detection of extranodal neoplastic spread in metastatic neck nodes. Eur J Radiol 2004; 52(3):264–70.
8. Brouwer J, Bodar EJ, De Bree R, et al. Detecting recurrent laryngeal carcinoma after radiotherapy: room for improvement. Eur Arch Otorhinolaryngol 2004; 261(8): 417–422.
9. Al-Ibraheem A, Buck A, Krause BJ, Scheidhauer K, Schwaiger M. Clinical applications of FDG PET and PET/CT in head and neck cancer. J Oncol 2009:13, 208725.
10. Ha PK, Hdeib A, Goldenberg D, et al. The role of positron emission tomography and computed tomography fusion in the management of early-stage and advanced-stage primary head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006; 132(1):12–6.
11. Ishikita T, Oriuchi N, Higuchi T, et al. Additional value of integrated PET/CT over PET alone in the initial staging and follow up of head and neck malignancy. Ann Nucl Med 2010; 24(2):77–82.
12. Iyer NG, Clark JR, Singham S, Zhu J. Role of pretreatment 18FDG-PET/CT in surgical decision-making for head and neck cancers. Head Neck 2010; 32(9):1202–8.
13. Loeffelbein DJ, Souvatzoglou M, Wankerl V, et al. PET–MRI fusion in headand- neck oncology: current status and implications for hybrid PET/MRI. J Oral Maxillofac Surg 2011; 70(2): 473-83.
14. Pichler BJ, Kolb A, Nägele T, Schlemmer HP. PET/MRI: paving the way for the next generation of clinical multimodality imaging applications. J Nucl Med. 2010;51(33): 333-6;
15. Wehrl H, Judenhofer MS, Wiehr S, Pichler BJ. Pre clinical PET/MR: tecnhnological advices and new perspective in biomedical resarch. Eur J Nucl Med Mol Imagig. 2009; 36(suppl 1 ): S56-S68.
16. Schmand M et al. BrainPET: first human tomograph for simultaneous (functional) PET and MR imaging. J Nucl Med (2007) 48(6):45P;
17. Schlemmer HP, Pichler BJ, Schmand M, et al. Simultaneous MR/PET imaging of the human brain: feasibility study. Radiology. 2008;248(3) 1028– 1035.
18. Veit-Haibach P, Kuhn FP, Wiesinger F, et al. PET-MR imaging using a tri-modality PET/CT-MR system with a dedicated shuttle in clinical routine. MAGMA. 2013; 26(1): 25-35.
19. Zaidi H, Ojha N, Morich M, et al. Design and performance evaluation of a whole-body Ingenuity TF PET–MRI system. Phys. Med. Biol. 2011;56(10): 3091-3106
20. Antoch G, Vogt FM, Freudenberg LS, et al Whole-body dual-modality PET/CT and whole-body MRI for tumor staging in oncology. JAMA. 2003; 290(24):3199-206
21. Antoch G, Bockisch A. Combined PET/MRI: a new dimension in whole-body oncology imaging? Eur J Nucl Med Mol Imaging. 2009; 36 (suppl 1): S113– S120
22. Kinahan PE, Hasegawa BH, Beyer T. X-ray-based attenuation correction forpositron emission tomography/computed tomography scanners. Semin Nucl Med. 2003;33(3):166–179.
23. Hofmann M, Pichler B, Scholkopf B, Beyer T. Towards quantitative PET/MRI: a review of MR-based attenuation correction techniques. Eur J Nucl Med Mol Imaging. 2009; 36(suppl 1):S93–104,
24. Hofmann M, Steinke F, Scheel V, et al. MRI-based attenuation correction for PET/MRI: a novel approach combining pattern recognition and atlas registration. J Nucl Med. 2008;49(11): 1875–1883,
25. Keereman V, Fierens Y, Broux T, De Deene Y, Lonneux M, Vandenberghe S. MRI-based attenuation correction for PET/MRI using ultrashort echo time sequences. J Nucl Med. 2010; 51(5): 812–818.
26. Martinez-Möller A, Souvatzoglou M, Delso G, et al. Tissue classification as a potential approach for attenuation correction in whole-body PET/MRI: evaluation with PET/CT data. J Nucl Med. 2009;50(4):520–526,
27. Zaidi H. Is MR-guided attenuation correction a viable option for dual-modality PET/MR imaging? Radiology. 2007;244 (3):639–642.
28. Schulz V, Torres-Espallardo I, Renisch S, et al. Automatic, three-segment, MRbased attenuation correction for whole-body PET/MR data. Eur J Nucl Med Mol Imaging. 2011; 38(1):138–152.
29. Eiber M, Martinez-Moller A, Souvatzoglou M, et al. Value of a Dixon-based MR/PET attenuation correction sequence for the localization and evaluation of PET-positive lesions. Eur J Nucl Med Mol Imaging. 2011;38(9):1691–1701. 30. Steinberg J, Jia G, Sammet S, et al. Three-region MRIbased whole-body attenuation correction for automated PET reconstruction. Nucl Med Biol. 2010;37 (2):227–235
31. Eiber M, Souvatzogloub M, Pickhard A, et al. Simulation of a MR–PET protocol for staging of head-and-neck cancer including Dixon MR for attenuation correction. Eur J Radiol. 2012;81(10):2658-65
32. Drzezga A, Souvatzoglou M, Eiber M, et al. First clinical experience with integrated whole-body PET/MR: comparison to PET/CT in patients with oncologic diagnoses. J Nucl Med. 2012 ;53(6):845-55
33. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.pag 23-25.
34. Krestan C, Herneth AM, Formanek M, Czerny C. Modern imaging lymph node staging of the head and neck region. Eur J Radiol 2006; 58(3):360–6.
35.Kuhn FP, Huller M, Mander CE, et al. Contrast-Enhanced PET/MR Imaging Versus Contrast-Enhanced PET/CT in Head and Neck Cancer: How much MR information is Needed? J Nucl Med. 2014;55(4):551-8
