BJRD13677 1..15

In head and neck oncology, the information provided by positron emission tomography (PET)/CT and MRI is often complementary because both themethods are based on different biophysical foundations. Therefore, combining diagnostic information from both modalities can provide additional diagnostic gain. Debates about integrated PET/MRI systems have become fashionable during the past few years, since the introduction and wide adoption of software-based multimodality image registration and fusion and the hardware implementation of integrated hybrid PET/MRI systems in pre-clinical and clinical settings. However, combining PET with MRI has proven to be technically and clinically more challenging than initially expected and, as such, research into the potential clinical role of PET/MRI in comparison with PET/CT, diffusion-weighted MRI (DWMRI) or the combination thereof is still ongoing. This review focuses on the clinical applications of PET/MRI in head and neck squamous cell carcinoma (HNSCC). We first discuss current evidence about the use of combined PET/CT and DW MRI, and, then, we explain the rationale and principles of PET/MR image fusion before summarizing the state-of-the-art knowledge regarding the diagnostic performance of PET/MRI in HNSCC. Feasibility and quantification issues, diagnostic pitfalls and challenges in clinical settings as well as ongoing research and potential future applications are also discussed. Pre-therapeutic work-up of head and neck squamous cell carcinoma (HNSCC) requires clinical evaluation, panendoscopy with biopsy and cross-sectional imaging. Crosssectional imaging is indicated to provide accurate staging at the time of diagnosis. This may be achieved using a variety of imaging modalities, including contrast-enhanced CT (CECT), MRI with or without diffusion-weighted (DW) sequences (DW MRI), ultrasonography with or without fine-needle aspiration cytology (FNAC), positron emission tomography (PET)/CT or a combination of these techniques. During recent years, the technology for both PET/CT and MRI has evolved steadily, resulting in increased image quality, robustness and rapidity of acquisition. By providing combined metabolic and morphological information, PET/ CT has significantly improved diagnostic and prognostic information in HNSCC, thereby facilitating patient management. Clinical MRI has evolved towards higher field strengths (3T), faster sequences, whole-body imaging, as well as functional imaging capabilities, including DW MRI and perfusion imaging. Despite all these technical advances, considerable expertise is required for the diagnostic interpretation of head and neck imaging studies because of the complex regional anatomy, the variable appearance of primary and recurrent tumours and functional phenomena mimicking disease. Since information provided by PET/CT and MRI is complementary in many clinical situations, it seems to make sense to combine the two modalities. From a technical point of view, the integration of PET with MRI in one imaging system has proven to be quite complex. However, the first software algorithms for multimodality data fusion and a first generation of hybrid PET/MRI systems are now available for clinical use. Consequently, the discussion about integrated PET/MRI systems has become fashionable, and an initial euphoria has been generated about potential applications of this new hybrid technology in oncological imaging and especially in the head and neck. To date, however, facts and scientific data assessing the clinical usefulness of hybrid PET/MRI systems remain scarce, and it appears difficult to assess where PET/MRI may be preferable over PET/ CT, DW MRI or the combination of these two powerful modalities. The purpose of the present article is to summarize current evidence about the combined use of PET/CTand MRI in HNSCC, to explain the rationale and principles of PET/MRI data fusion and to review the existing knowledge regarding the performance of hybrid PET/MRI in clinical head and neck oncology. CURRENT EVIDENCE ABOUT POSITRON EMISSION TOMOGRAPHY/CT IN HNSCC PET/CT has established itself as a robust, rapid and reliable technique providing reproducible data even in patients with limited cooperation. Acquisition of a total bodyCTscan takes only a few seconds and allows unparallelled detection of pulmonary nodules as well as a complete overview of all anatomic regions. The combination of PET and CT is highly synergistic, resulting in increased sensitivity and specificity for tumour staging as well as effective patientmanagement in clinical routine. Themetabolic information from PET radiotracers can be complemented by the full diagnostic capability of CECT during the same session, although this may not be done in a majority of institutions. Positron emission tomography radiotracers and quantification issues PET radiotracers that can be used for PET/CT examinations in HNSCC patients include 18-fludeoxyglucose (FDG) for the quantification of glucose metabolism, 18-fluorothymidine (FLT) for the quantification of tumour cell proliferation, 18fluoroethyltyrosine (FET) for the quantification of tumour growthrelated protein synthesis, as well as new tracers specifically designed for imaging of apoptosis and epidermal growth factor receptor (EGFR). Themost commonly used PETradiotracer forHNSCC in clinical routine is FDG. It is a glucose analogue that is taken up by metabolically active tumour cells using facilitated glucose transport. Because FDG is not a specific tracer for HNSCC, it may also become trapped in other cells with high glucose metabolism, including inflammatory lymph nodes, scar tissue or certain benign salivary gland tumours, such as Whartin tumours. Quantification of tracer uptake is commonly performed in the clinical setting using the standardized uptake value (SUV). The SUV is a semi-quantitative metric defined as the ratio between the tissue radioactivity concentration (in megabecquerel per kilogram) at a time t and the injected radioactivity (in megabecquerel) extrapolated to the same t normalized to body weight (in kilograms) multiplied by a decay correction factor. As reported by several investigators, SUVmean and SUVmax metrics are imperfect quantification tools since they depend on a variety of factors, including data acquisition and reconstruction protocols, selection of regions of interest (ROIs) for measurements, statistical noise, partial volume effect and tumour size. Therefore, while the SUV derived from static whole-body images is simpler and more clinically feasible than more rigorous kinetic analysis, there are a number of approximations implicit in the use of uptake ratios that may lead to variability and bias. Despite these drawbacks, quantification of tracer uptake by means of SUV is widely used in clinical routine. Positron emission tomography/CT for staging and restaging of HNSCC FDG PET/CT and SUV measurements have proven to be highly accurate for the follow-up of HNSCC after radio-chemotherapy, allowing reliable exclusion of residual or recurrent disease. Although the high sensitivity and high negative predictive value in the treated neck are consistent findings in most reported studies, the specificity and positive predictive value of FDG PET/CT can vary substantially, leading to a considerable number of false-positive assessments. In the T staging of primary HNSCC, most authors have reported FDG PET/CT to be as sensitive as CT/MRI. Some authors, however, have found PET/CT to be slightly superior to CT/ MRI, the reported sensitivity for oral cavity HNSCC being 96% for PET/CT, 85% for MRI and 78% for CT. Because CECT and MRI have a superior anatomic resolution, current practice is not in favour of routinely using PET/CT for the T staging of primary HNSCC. Regarding the staging of nodal disease in primary HNSCC, FDG PET/CT appears to be superior to conventional anatomic MRI sequences. However, direct comparison with DW MRI is still missing. Occult lymph nodes in the clinically negative neck (clinical N0 disease) represent a diagnostic challenge for PET/ CT and MRI, as both techniques are not sensitive enough to reliably detect subcentimetre metastatic nodes. In skilled hands, ultrasonography has been shown to be superior to CT and MRI because of its high spatial resolution and the ability to routinely perform power Doppler and ultrasonography FNAC. The superiority of ultrasonography FNAC over CT and MRI is indisputable when dealing with small metastatic neck nodes, and ultrasonography FNAC performs significantly better than any other imaging technique in the N0 neck. Nevertheless, it is important to realize that micrometastases, which may occur in up to 8% of all N0 necks, are beyond detection by any currently available imaging modality. Several authors have shown that FDG uptake will increase significantly over time in lymph nodes harbouring metastatic cancer lesions, whereas inflammatory neck nodes tend to show a decreased or stable FDG activity over time. However, as recently shown, the use of dynamic PET/CT examinations performed between 60 and 115min after injection of FDG does not allow correct identification of those patients in whom elective neck dissection should be performed. Therefore, most authors currently agree that FDG PET/CT, CECT, MRI or ultrasonography FNAC are not reliable enough to exclude lymph node metastases in the clinical N0 neck. There is general agreement that FDG PET/CT is the method of choice to detect distant metastases and synchronous tumours. In locally advanced disease and in patients with N2 or N3 necks, PET/CT may reveal distant metastases and second primary tumours in up to 14% of cases. However, false-positive assessments have also been reported in up to 25% of patients. The utility of PET/CT to identify unknown primary tumours in patients with metastatic neck nodes has been demonstrated by several reports, and PET/CTmay be currently recommended early in the work-up of these patients