MRI in Lung Cancer

PET/MRI in Lung Cancer Li Fan, MD,*,† Andrew Sher,† Andres Kohan, MD,† Jose Vercher-Conejero, MD,† and Prabhakar Rajiah, MD, FRCR†

Introduction

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maging plays an important role in the diagnosis and management of lung cancer, which is the leading cause of cancer-related death in the world.1 Radiography is often the initial modality of diagnosis, but detection depends on the size and density of nodules. The sensitivity of detection may be improved by using the dual-energy subtraction technique, which generates a soft tissue reconstruction that is free of overlapping chest wall and bony structures, or by using tomosynthesis. Computed tomography (CT) has become the established modality for the screening, diagnosis, and staging of lung cancers. Radiation and the use of potentially nephrotoxic contrast media are the risk factors associated with it. Magnetic resonance imaging (MRI) does not involve radiation, but its use in lung cancer is limited by intrinsic low proton spin density, magnetic field inhomogeneities, and motion artifacts from cardiac and respiratory motion. However, novel sequences show potential in the evaluation of lung cancer. Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG-PET) is useful in determining the metabolic activity of the lung tumor. False-negative results are seen in small tumors and in bronchoalevolar carcinoma, whereas falsepositive findings are seen in cases of infection or inflammation.2 The hybrid imaging modality of PET/CT is now the standard of care in the staging of lung cancers, combining the morphologic information of CT with the metabolic information of PET.3 PET/MRI is a novel hybrid imaging technology that involves the fusion of 2 powerful imaging modalities: PET and MRI. MRI provides tissue characterization capabilities

*Department of Radiology, Changzheng Hospital of the Second Military Medical University, Shanghai, China. †Department of Radiology, University Hospitals Cleveland Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH. Financial Disclosure: Institutional research support from Philips healthcare. Address reprint requests to Prabhakar Rajiah, MD, Department of Radiology, University Hospitals Cleveland Case Medical Center, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: Prabhakar. [email protected]

http://dx.doi.org/10.1053/j.ro.2014.07.002 0037-198X/& 2014 Elsevier Inc. All rights reserved.

due to inherent soft tissue contrast, multiplanar acquisitions, and functional imaging (ventilation, perfusion, and diffusion) without the use of ionizing radiation, whereas PET enables high-sensitivity imaging of metabolism. In PET/MRI systems, MRI also provides anatomical localization and attenuation-correction (AC) information for the PET scan. Thus PET/MRI has the unique capability to provide structural, functional, and molecular imaging assessment in a single imaging study, which makes it ideal in the evaluation of malignancies including lung cancer. Anatomical correlation of novel radiopharmaceuticals with high specific binding to a tumor is also made possible. In addition, MRI allows image reconstruction, partial volume correction, and motion compensation for the PET images. However, the use of PET/MRI is also associated with several technical challenges. In this article, we review the technical details, scanning protocol, challenges, potential applications, and current status of PET/MRI in the evaluation of lung cancer.

Technical Details PET/MRI systems can be either integrated (concurrent), where the PET ring detector is contained inside a 3-T magnet (Biograph mMR, Siemens Healthcare, Erlangen, Germany),4 or sequential, where the PET and MRI scanners have a tandem arrangement with sequential scanning of the patient in the same position. With the Ingenuity TF system (Philips Healthcare, Cleveland, OH), the PET and MRI gantries are located 10 feet apart in the same room with the patient rotated between the scanners on a table, and images are generated using hardware fusion by known coordinates. With the Discovery Trimodality system (GE Healthcare, Milwaukee, WI), the PET/ CT and MRI scanners are located in different rooms with a shared patient transport system. A table moves between the rooms, and the fusion of images is provided by software.5,6 Integrated scanners have the advantage of higher anatomical and temporal registration of PET and MRI signals than the sequential scanners.6,7 291

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PET/MRI Scanning Protocol There is no standardized protocol or guideline for evaluating lung cancer using PET/MRI. Scanning time is an important consideration in PET/MRI as the addition of dedicated chest MRI sequences can extend imaging time up to 90 minutes. Hence, the protocol needs to be adapted to the clinical question being asked. A basic protocol that we use in our institution is listed in Table 1. Broadly, this involves the MR AC sequence and dedicated chest MRI sequences followed by PET acquisition.6 MR AC for lung cancer can be performed by using volume-interpolated 3-dimensional (3D) spoiled gradient echo sequence or a Dixon sequence. Other sequences for tissue characterization include T1-weighted (T1W) sequence, T2W sequence (eg, half-Fourier acquisition single-shot turbo spinecho sequence), short-tau inversion recovery (STIR) sequence, and fast T2W sequence. Diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) and dynamic contrast-enhanced MRI (DCE-MRI) are optional sequences that provide additional information. Real-time free-breathing cine steady-state free precession sequence is useful in the assessment of chest wall invasion. Sequences may be performed with electrocardiogram gating to minimize cardiac motion and respiratory gating or with breath-hold to minimize respiratory motion.

Technical Challenges There are several technical challenges associated with the use of PET/MRI, especially in the evaluation of lung cancer.

Signal Interference Between the 2 Modalities There is the potential for signal interference between the 2 technologies with each other. The static magnetic field, changing gradients, and radiofrequency pulses of the MRI scanner can interfere with the operation of the photomultiplier tubes of the PET and may induce noise. Conversely, the PET electronics can cause magnetic field inhomogeneities, eddy currents, and electromagnetic interference in the MR images, which are more prominent in high–field strength magnets. In the sequential systems, the physical separation of the 2 systems minimizes these effects, whereas in the integrated scanner, the presence of PET avalanche photodiodes makes it insensitive to magnetic fields. Recent advances in avalanche photodiode technology such as silicon photodiodes have allowed improvement in PET gain and temporal resolution.6

Attenuation Correction Accurate AC is very important to the quantification of PET data and interpretation of findings. Unlike PET/CT where the Hounsfield units of the CT scan (determined by electron density) can be converted into the attenuation coefficient of 511-keV x-rays by means of simple bilinear transformation, the signal intensity (SI) of MRI is determined by proton density and tissue relaxation and is not proportional to photon attenuation,8 making it difficult to use the MRI data for AC. There are 2 techniques of AC: segmentation based and template guided. Segmentation-based AC is preferred over template-guided AC method as it is more reliable, especially in whole-body (WB) PET/MRI.9,10 With template-guided AC, data sets are coregistered using an anatomical atlas template. In

Table 1 PET/MRI Scanning Protocol for Lung Cancer Preparation Overnight fasting Control of blood glucose 0 min Injection of standard dose of 18F-FDG adjusted to body weight Rest till image acquisition 30 min Whole-body MR attenuation-correction sequences 3D T1-weighted spoiled gradient echo Dixon-(in phase, opposed phase, water only, and fat only)—axial Dedicated MRI chest sequences T1-weighted sequence—axial T2-weighted sequence—axial Diffusion and ADC map—axial Pre contrast 3D volumetric interpolated T1-weighted gradient echo—axial and coronal Postcontrast 3D volumetric interpolated T1-weighted gradient echo—axial and coronal Real-time cine imaging—if chest wall invasion is assessed 60 min PET acquisition 70-80 min Discharge patient

PET/MRI in lung cancer the segmentation technique, the tissue is segmented into different classes and assigned corresponding attenuation coefficients based on the MR SI.11 A 3-segment model (air, soft tissue, and lungs) is performed in the Philips system using a T1W 3D spoiled gradient echo sequence (Fig. 1),12 whereas a 4-segment model (air, soft tissue, lung, and fat) is performed in Siemens system using a 3D 2-point Dixon volumetric breathhold sequence. Distinguishing air from bone can be performed (5 segmentation) only using an ultrashort echo time sequence, however it is used only in the head owing to the high noise, streak artifacts, and misinterpretation of tissue edges.13 Proper segmentation is essential to avoid mislabeling of critical tissues, which is a challenge at tissue interfaces, for example, mediastinal lymph nodes. AC sequences should also correct for MRI hardware. With the 3-segmentation model, a high correlation has been shown between the maximum standardized uptake value (SUVmax) of lung between PET/ MRI and PET/CT (r ¼ 0.70). The different SUVs may be because of the time delay between PET/CT and PET/MRI or biologic clearance of radiotracer.14

Alignment Bulk patient motion or physiological motion, such as respiration, digestion, and filling of the urinary bladder, can result in misalignment in hybrid imaging.6 Moreover, the time interval between the acquisitions of each modality will also contribute to the misalignment. Anatomical and temporal alignment is higher with integrated systems compared with sequential acquisition scanners.15 WB

293 PET/MRI is more accurate than PET/CT for urinary bladder alignment. Alignment of thoracic PET/MRI is more accurate with expiratory breath-holding or freebreathing than inspiratory MRI.15

Artifacts The common artifacts in PET/MRI are metal, truncation, motion, attenuation-related, and partial volume artifacts. Metal manifests low SI on MRI, resulting in segmentation errors. The tissue surrounding the metal will be segmented as air and the corresponding SUV will be underestimated.16 Truncation artifacts result from the difference in field of view between the PET and MRI. With arms-down position, severe truncation artifacts are seen in the arms of nearly all patients, whereas with the arms-up position, they are seen occasionally in the shoulders, breasts, abdomen, or hips.16 Motion artifact is mainly from physiological motion such as respiratory or cardiac motion. Respiratory motion can be minimized by using breath-hold, respiratory gating, or navigator gating of diaphragmatic motion. Cardiac motion is minimized by using electrocardiogram gating. MRI-based motion correction (using T1W MRI) of PET can also minimize the respiratory motion and improve the image quality, including tumor visibility, delineation, and SUVmax.7,17 Attenuation-related artifacts are caused by surface coils or positioning devices or oral ironbased MRI contrast media, which affects the MR attenuation map. Partial volume effect results in underestimation of tumor volume. This is corrected by partial volume correction techniques, such as using a 3D point spread function.6

Figure 1 A 3-segment model MR attenuation map creation. (A) Whole-body coronal reconstruction from a T1-weighted 3D spoiled gradient echo MR sequence is acquired. Subsequently, an attenuation map (B) is produced using the 3–tissue segmentation algorithm, defining tissue as air, soft tissue, or lung.

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Potential Applications of PET/MRI in Lung Cancer There are several scenarios in which PET/MRI may be useful in the evaluation of lung cancer. This includes detection of a lung nodule or mass, characterization of a lung nodule or mass, tumor staging, and determining prognosis, therapeutic response, and recurrence.

Detection of Lung Nodule or Mass CT is the modality of choice in the detection of lung nodules, and low-dose CT techniques are now recommended for screening of lung cancer in high-risk patients. MRI is less sensitive than CT for detection of pulmonary nodules owing to the lower spatial resolution, low proton density, and inhomogeneous magnetic field in the lungs. The detection of pulmonary nodules using PET/MRI depends on 3 major factors: nodule size, nodule density, and the MR sequence. Nodule Size PET is not generally recommended in the evaluation of lung nodules o10 mm due to the spatial resolution of current generation of PET scanners, which is 7-8 mm.18 On MRI, nodules o 5 mm cannot be detected on T1W or T2W sequences, but for nodules 45 mm, the sensitivity, specificity, and positive and negative predictive values of all sequences, except T2W half-fourier acquisition single-shot turbo spinecho, are close to 100%.19,20 Nodule Density Solid nodules are detected by MRI, but pure ground-glass opacity (GGO), which is a common presentation of minimally invasive adenocarcinoma (formerly bronchoalveolar carcinoma) is difficult to detect with routine MRI sequences. Furthermore, GGO can result in a false-negative PET scan because of low glucose metabolism.18,21 Calcified nodules are hard to detect on MRI because of signal loss. MR Sequence STIR, DWI, and T1W gradient echo sequences are used in the detection of lung nodules. STIR sequence has sensitivity 490% for detection of nodules 43 mm compared with CT.22 Using DWI, the detection rate of lung cancer (97%) was significantly higher than that with PET/CT (86%).23 Qualitative and quantitative assessments of the tumor were also higher with DWI than with PET/CT.24 The detection rate depends on the b value, with lower SI at higher b values, which makes detection of ground-glass nodules difficult at higher b values (1000 s/mm2).20 However, a study on 25 patients showed that DWI as a part of WB-[18F]-FDG-PET/MRI did not improve lesion detection.25 The complementary information of PET/MRI may overcome the shortcomings of the individual scans. In a study of 40 pulmonary nodules using a trimodality PET/CT-MRI protocol in which a 3D dual-echo gradient echo pulse sequence was used, there was no statistical difference in detection and localization of nodules compared with a low-dose CT.26 In

L. Fan et al another study of 69 pulmonary nodules, PET/MRI was shown to have high sensitivity in the detection of FDG-avid nodules and nodules Z5 mm in diameter, with low sensitivity for small and non–FDG-avid nodules.27 In routine clinical practice, PET/MRI is not currently used alone to diagnose a lung nodule but in conjunction with a CT scan.

Tissue Characterization of Lung Nodule or Mass Management of lung nodules depends on their aggressiveness. Imaging plays an important role in tissue characterization and when not possible, biopsy can be performed either using CT guidance or through bronchoscopy. PET/MRI provides complementary information on the characterization of lung nodules. Either subjective or objective evaluation of FDG-PET shows efficacy in differentiating benign from malignant lesions as small as 1 cm.2 With PET, a standardized uptake ratio r2.5 had 100% specificity for benign nodules larger than 1.2 cm.28 The SUVmean of malignant nodules has been reported to range widely from 5.5-10.1,18,29 and the sensitivity and specificity for detection of malignant nodules were 97% and 78%, respectively.30 The contrast ratio of the SUV to the lung (CR-lung) has been shown to be superior to SUVmax for diagnosing non– small cell lung cancers (NSCLCs).18 False-negative findings are seen in nodules less than 1 cm in diameter, GGO, low metabolic activity tumors, minimally invasive adenocarcinoma, or well-differentiated adenocarcinoma.18,21 False-positive findings can be found in active inflammatory nodules.18 With MRI, T1W and T2W sequences cannot distinguish benign and malignant nodules. STIR has some potential, but the sensitivity, specificity, and accuracy are not high (83.3%, 60.6%, and 74.5%, respectively).20 Malignant lesions have restricted diffusion, resulting in high SI on DWI and ADC. SI of malignant nodules is higher than that of benign nodules, but the threshold of SI depends on the different b values. For example, if b ¼ 500 s/mm2, SI Z 391 is the cutoff of malignant nodules with a sensitivity of 95%, specificity of 73%, and positive predictive value of 87%. Whereas if b ¼ 1000 s/mm2, SI Z 277 suggests a malignant nodule with a sensitivity of 93%, specificity of 69%, and positive predictive value of 85%.31 In addition, SI of DWI can differentiate the cell differentiation and subtypes of lung adenocarcinomas.32,33 With DWI, pooled sensitivity and specificity were 84% in distinguishing benign and malignant nodules in a metaanalysis of 10 studies with 586 nodules34 and 80% sensitivity and 93% specificity in another meta-analysis of 755 malignant and 294 benign pulmonary nodules.35 ADCmean exhibited a significant inverse correlation with SUVmax as well as with SUVmean assessed by FDG-PET/MRI in NSCLC.36 DCE-MRI also has high diagnostic capability for distinguishing malignant from benign pulmonary nodules, based on the hemodynamic parameters, SI-time curve, and morphologic enhancement patterns. There are many different dynamic MR protocols for the differential diagnosis of pulmonary nodules, with sensitivities ranging from 94%-100%, specificities ranging from 70%-96%, and accuracies greater than 94%.37 Alper et al38 found that early peak and maximum peak were

PET/MRI in lung cancer significantly higher in malignant nodules than in benign ones. Malignant nodules less than 3 cm usually manifested with homogeneous and apparent enhancement. A meta-analysis involving 44 trials with 2896 nodules showed that DCE-MRI, DCE-CT, PET, and single-photon emission computed tomography have similar diagnostic performance in the evaluation of pulmonary nodules.39 However, a recent study showed that DCE-MRI can be a more specific or accurate modality when compared with DCE-CT and coregistered FDG-PET/CT in the management of solitary pulmonary nodule.40 By combining PET and MRI, more methods are available in distinguishing a benign lesion from a malignant one.

Staging of Lung Cancer Accurate staging of lung cancer is imperative in determining the optimal treatment strategy and identification of patients who will benefit from therapy. The current TNM staging of lung cancer is listed in Table 2.41 PET/CT is the current clinical standard in staging of lung cancers.6 Studies have provided mixed results on the use of PET/CT and MRI in lung cancer staging. Some have shown that PET/CT and 3-T MRI are

295 comparable in lung cancer staging,42 whereas others have shown the converse, that PET/CT is superior to MR in N staging. The same study showed MR to be superior in T staging compared with PET/CT.43

T Staging T staging depends on the size and invasion of adjacent structures, as listed in Table 2. The role of PET/MRI in T staging of lung cancers is not clearly established, especially in lower T stages (Fig. 2). Owing to lower spatial resolution, MRI is not as accurate as CT in evaluating tumor size. PET is also not accurate in size, but it is accurate in the evaluation of metabolism. A recent study showed similar size measurements between PET/CT and PET/MRI in 14 lung lesions using region of interest activity edge detection.14 Another study showed similar T staging between PET/MRI and PET/CT in 90% of patients, whereas 1 patient exhibited a lower T staging (T1a) at PET/MRI compared with PET/CT (T1b).44 PET/MRI is also inferior to PET/CT in the detection of small satellite nodules in the same pulmonary lobe as the primary tumor (T3) or in an ipsilateral but different lobe (T4).6

Table 2 TNM Staging of Lung Cancer

T staging T1 Tumor o3 m; T1a o 2 cm, and T1b 2-3 cm No invasion proximal to lobar bronchus T2 Tumor size 3-7 cm; T2a 3-5 cm, and T2b 5-7 cm Invasion of bronchus 42 cm from carina Atelectasis or obstructive pneumonitis otwo-thirds lung Invasion of visceral pleura T3 Tumor size 47 cm Invasion of bronchus o2 cm from carina Atelectasis or obstructive pneumonitis of entire lung Invasion of parietal pleura, chest wall, diaphragm, phrenic nerve, and pericardium Nodules in same lobe T4 Involvement of carina, heart, great vessels, trachea, esophagus, and spine Nodules in other lobes in same lung N staging N0 No involvement of nodes N1 Ipsilateral peribronchial, hilar, and intrapulmonary lymph nodes N2 Ipsilateral mediastinal lymph nodes N3 Contralateral mediastinal, hilar, scalene and supraclavicular nodes M staging M0 No metastasis M1a Nodules in contralateral lung, pleural nodules, malignant pleural effusion, and malignant pericardial effusion M1b Distant metastasis

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Figure 2 Left lower lobe small cell lung cancer in an 85-year-old woman. (A) A coronal postcontrast Dixon water image demonstrates a large left lower lobe mass (arrow). Coronal (B) FDG-PET images demonstrate intense hypermetabolic activity that localizes to the mass on the fused (C) FDG-PET/MR image. No abnormal activity was seen in the lymph nodes or any other structure, making this is a T2N0M0 tumor. (Color version of figure is available online.)

Figure 3 Right upper lobe non–small cell lung cancer in a 58-year-old woman. (A) On the MRI, an axial postcontrast Dixon water image demonstrates a large right upper lobe mass (arrow) that abuts but does not invade the mediastinum. A right lower paratracheal lymph node (arrowhead) is noted as well. Axial (B) FDG-PET images demonstrate intense hypermetabolic activity that localizes to the 2 lesions on the fused (C) FDG-PET/MR images. (Color version of figure is available online.)

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Figure 4 Non–small cell lung cancer with chest wall invasion. (A) Coronal T2 turbo spin-echo sequence of the chest demonstrates a large right-sided tumor. The soft tissue contrast of MRI allows delineation of lateral chest wall invasion (arrow). (B) PET and (C) PET/MRI fusion images demonstrate intense hypermetabolic activity within the tumor, whereas adjacent soft tissue consolidation demonstrates low metabolic uptake (arrowhead) corresponding to atelectasis. Multiple hypermetabolic mediastinal lymph nodes are seen. (Color version of figure is available online.)

However, PET/MRI is useful in the evaluation of invasion into adjacent structures, especially the mediastinum and chest wall, and also pulmonary vasculature and bronchial tree owing to the higher soft tissue resolution of MRI.45 CT has sensitivity ranging from 40%-84% and specificity of 57%-94% in the assessment of mediastinal invasion.37 The absence of fat planes in T1W images is useful in determining invasion. STIR sequence can also depict adjacent structure invasion with marked high SI, in contrast to the routine T1W and T2W imaging. Contrast-enhanced MR sequences are better than contrast enhanced CT and T1W imaging in the evaluation of mediastinal and hilar invasion.46 The absence of fat planes; broad contact 43 cm with chest,

bone destruction, and soft tissue mass; and absence of movement of the tumor against the chest with cine imaging indicate chest wall invasion.20 PET/MRI could prove advantageous in the staging of superior sulcus tumors owing to the combination of high–spatial resolution MRI for the involvement of the brachial plexus, subclavian artery or vein, and metabolic information based on PET findings. Schwenzer et al44 revealed similar T staging in most patients with lung cancer comparing PET/CT and PET/MR images; in a patient, infiltration of the mediastinal pleura was questioned on PET/CT, whereas PET/MRI demonstrated an intact fat plane and thus was able to exclude pleural invasion (Fig. 3). Plathow et al43 found that WB-MRI can

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Figure 5 Metastatic mediastinal lymphadenopathy from non–small cell lung cancer. Axial postcontrast Dixon water image (A) demonstrates right upper paratracheal (arrow) lymphadenopathy. Axial FDG-PET images (B) at the same level demonstrate moderate to intense hypermetabolic activity within this lymph node, which is demonstrated also on the fused FDG-PET/MR image (C). (Color version of figure is available online.)

evaluate the correct T staging of lung cancer, whereas PET/ CT understaged the T staging without correct diagnosis of chest wall invasion (Fig. 4). N Staging N staging is the most important prognostic factor in determining survival.47 Mediastinoscopy is considered the gold standard. Although size criteria of 10 mm was used in imaging to diagnose lymph nodal involvement,20 this is neither sensitive (metastases can occur in normal-sized nodes) nor specific (may also be seen in inflammation). The challenge is to detect neoplasm in a normal-sized lymph node. Eccentric cortical thickening and obliteration of the fatty hilum are features suggestive of a malignant node.48 Conventional CT has a low sensitivity of 41%-68% and a specificity of 43%-97% in the detection of mediastinal nodal metastasis.48,49 With MRI, the SI of malignant lymph nodes is higher than that of benign ones on T1W and T2W sequences.50 The lymph node-to-tumor ratios of SI of lymph node-to-0.9% saline ratios (LSRs) of SI was also reported as an effective index to

differentiate the malignant lymph nodes from the benign ones.48,51 If the positive test threshold of LSRs was 0.6, the sensitivity was 93% and specificity was 87% on a per-patient basis.46 Cardiac-triggered or respiratory-triggered conventional or black-blood STIR or turbo spin echo imaging, or a combination of both, has been recommended for detection of metastatic lymph nodes.46,51 T2W triple-inversion blackblood fast spin-echo images at 3.0-T MRI had sensitivity of 53%, specificity of 91%, and accuracy of 86% in detection of mediastinal and hilar lymphadenopathy compared with histopathology.48 DWI is also useful in the evaluation of nodal disease. SI of metastatic lymph nodes with a b value of 1000 s/mm2 is higher than that of muscle and equal to or less than that of the primary lesion.52 If an ADC value of 1.85  103 mm2/s was used as a threshold value for mediastinal nodes, the accuracy, sensitivity, and specificity was 83.9%, 96.4%, and 71.4%, respectively.53 With FDG-PET, an SUVmax of Z2.5 is suggestive of a malignant lesion54 (Fig. 5) but false-positive results may be seen because of infection or inflammation. However the

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Figure 6 Incidentally discovered left adrenal gland metastasis in a patient with non–small cell lung cancer. Axial (A) postcontrast Dixon water image demonstrates a mass (arrow) within the left adrenal gland. Axial (B) FDG-PET image demonstrates increased FDG uptake, which on (C) fused FDG-PET/MR images localizes to the left adrenal gland, biopsy proven to be a metastasis from the non–small cell lung cancer primary. (Color version of figure is available online.)

spatial resolution of PET alone is inferior to that of PET/CT, the use of which improves specificity, positive predictive value, and accuracy. In a meta-analysis of 8699 patients, FDG-PET/CT had significantly higher sensitivity and specificity than contrast-enhanced CT and higher sensitivity than FDG-PET in staging NSCLC.55 Other metaanalysis studies also showed that integrated PET/CT has excellent specificity (Z90%) for mediastinal lymph node staging in patients with NSCLC.56,57 However, PET/CT has high false-positive results owing to inflammation or granulomas, resulting in a high negative predictive value.47 Recent studies showed that DWI is superior to PET/CT in N staging of NSCLC. In a meta-analysis of 2845 patients with NSCLC, DWI had higher specificity (95%) than PET/ CT (89%)58; in another study of 88 patients with NSCLC, DWI had higher accuracy (89%) than PET/CT (78%). Conversely, Yi et al42 reported no significant differences between PET/CT (105/150 patients; 70%) and 3.0-T WBMRI (102/150 patients; 68%) in correct N staging of lung cancer. Schwenzer et al44 evaluated the performance of PET/MRI in N staging of lung cancer using PET/CT as the reference

standard and found similar N staging in most cases between both the modalities. Only 1 patient showed a moderately FDGavid suprahilar lymph node at PET/CT but no FDG uptake at PET/MRI. This node was proved to be nonmetastatic by histologic examination. Kohan et al evaluated the N staging of 11 patients with lung cancer using PET/MRI in comparison with using PET/CT and revealed that PET/MRI showed similar performance to PET/CT in N staging and that PET/MRI had substantial interobserver agreement in N staging. All 4 readers agreed on the nodal stage in 9 of 11 PET/CT images and 7 of 11 PET/MR image sets (κ ¼ 0.86 for PET/CT and κ ¼ 0.70 for PET/MR images). With PET/CT, the 4 readers accurately assigned an N stage in 77% of images, whereas with PET/ MRI, the readers accurately assigned an N stage in 73% of images.59 M Staging PET/CT has higher sensitivity (91%-93%) and specificity (96%) than PET or CT alone in the detection of distant metastatic disease.60,61 The introduction of multichannel MR systems, parallel imaging technology, and moving tables has enabled WB-MRI to become possible and to be

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Figure 7 Incidental diagnosis of aortitis in a patient with non–small cell lung cancer. Sagittal (A) FDG-PET and (B) FDGPET/MR images demonstrate a known left lower lobe malignancy (arrow) while moderate uptake along the walls of the aorta (arrowhead) correspond with aortitis, the etiology of the patient’s new-onset chest pain. (Color version of figure is available online.)

used for metastatic workup.62,63 Both FDG-PET/CT and FDG-PET were more accurate than MRI and bone scintigraphy in evaluating bone metastasis, with PET/CT being better than PET alone.64,65 Diffuse bone infiltration may be better evaluated with MRI, but it may be difficult to do so on PET and may be typically overlooked on CT.66 Owing to high physiological uptake, PET is not suitable in the detection of brain and liver metastasis whereas MRI can accurately evaluate these lesions. Only 61% of the cerebral metastases detected by MRI can be found by FDG-PET.67 The sensitivity of PET/MRI (93%) is significantly higher than that of PET/CT (76%) in the detection of hepatic metastases.68 PET/MRI is inferior to PET/CT in the detection of small metastatic nodules in the contralateral lung (M1a).6 Yi et al compared the coregistered WB PET/MRI and WB PET/CT plus brain MRI in staging resectable lung cancer. In this study, lung cancer was correctly upstaged 25.9% (37 of 143 patients) in the PET/MRI group and 21.7% (26 of 120 patients) in the PET/CT plus brain MRI group.69 Coregistered PET/MRI did not appear to help identify significantly more correctly upstaged patients than PET/CT plus brain MRI in patients with NSCLC. However, PET/CT plus brain MRI can improve the detection of brain metastases (32 of 442 patients; 7%) in comparison with PET/CT only.70 WB-MRI with DWI has been shown to be as accurate for M staging assessment in patients with NSCLC compared with PET/CT, demonstrating an accuracy of 87.7% compared with 88.2% for PET/CT.71

Overall TNM Staging Few studies have been performed on the effectiveness of PET/MRI in the TNM staging of lung cancer. In an initial pilot study of 10 patients, PET/MRI was shown to have similar lesion characterization and tumor stage compared with PET/CT, although no dedicated MRI protocol and histopathologic gold standard was used (Fig. 6). Identical TNM scores were seen in 7 of 10 patients between PET/MRI and PET/CT, with higher mean tumor-to-liver ratios on PET/MRI compared with PET/CT.44 Another recent study on 22 patients showed no significant advantage of PET/MRI compared with PET/CT in thoracic staging in patients with NSCLC. All patients were correctly staged in both modalities compared with histopathology, with 100% agreement of T stage and 91% concordance of N stage (PET/MRI correctly diagnosing N stage in 91% and PET/CT in 92%). There was a statistically insignificant difference in SUVmean and SUVmax between the imaging modalities. There was also excellent correlation between tumor sizes in both modalities (r ¼ 0.99), although most of the tumors were larger in size. Infiltration of adjacent structures is better with PET/MRI than with PET/CT.47 Occasionally, incidental findings may be detected on PET/MRI (Fig. 7).

Prognosis, Therapeutic Response, and Recurrence Detection Determining prognosis, evaluating therapeutic response, and detection of recurrence with high accuracy is vital in determining the optimal treatment and minimizing side effects. DWI

PET/MRI in lung cancer and volume-based PET may provide this information. ADC and DWI have higher specificity and sensitivity than PET/CT in predicting treatment response to chemoradiation and survival in patients with stage III lung cancer.71,72 In patients with advanced lung cancer, progression-free survival and overall survival were different between responders and nonresponders when using DWI or FDG-PET, whereas no difference was found using CT.73 Although SUVmax used to be regarded as an independent prognostic factor in several studies,2,74 recent studies showed that volume-based PET parameters (metabolic tumor volume) and total lesion glycolysis) are significant prognostic factors for survival independent of TNM staging and better prognostic predictors than SUVmax in patients with lung cancer.75-78 Metabolic tumor volume and total lesion glycolysis were significantly associated with an increased risk of recurrence and death, whereas SUVmax was not a significant prognostic factor for overall survival and progression-free survival.74,75 Thus, using both PET and MRI has the potential to provide additive prognostic information. The response evaluation criterion in solid tumors uses the change of tumor size to determine response to therapy; however, at early stages of treatment, there may be no change in size, but in responders, a significant increase in ADC value compared with pretreatment levels has been shown.79 Parameters of DCE-MRI were also significant different between local control and local failure group of NSCLC.80 Several studies have evaluated the role of FDG-PET in assessing response to chemotherapy or radiation therapy and have shown promising results.2,81,82 A meta-analysis including 414 patients with lung cancer found that the predictive value of PET was superior to that of CT in assessing response to neoadjuvant therapy.83 Integrating PET data with MRI improves the diagnostic accuracy when assessing therapy response compared with when using MRI alone.66 DWI and FDG-PET have been shown to accurately detect recurrence. In a meta-analysis examining the diagnostic efficacy of PET and PET/CT in detecting recurrence in 1035 patients with lung cancer, no difference was found between PET and PET/CT either in sensitivity or in specificity, but the accuracy of PET/CT is better than that of PET.84

Conclusion Initial studies have shown the potential of PET/MRI in the evaluation of lung cancer. Although PET provides highly sensitive imaging of metabolism, MRI allows high soft tissue contrast, tissue characterization, multiplanar imaging, and functional imaging capabilities. The fusion of these powerful modalities has the potential to provide a 1-stop shop imaging modality in the evaluation of lung cancer without the use of ionizing radiation. PET/MRI has the potential to be used in the detection of lung nodules or masses, lesion characterization, staging, therapeutic response, and recurrence. The use of MRI improves staging accuracy by enabling precise delineation of adjacent structures such as mediastinum, chest wall, pulmonary vasculature, and bronchial tree. PET/MRI is a noninvasive modality for evaluating pharmacokinetics and

301 pharmacodynamics profile of novel drugs. Robust and efficient protocols have to be developed to limit scanning time. Large prospective randomized trials need to be performed to establish the utility of PET/MRI in the evaluation of lung cancers.

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