High Resolution T2-Weighted Dixon Based Whole Body Magnetic Resonance Imaging in Detecting Bone Metastasis; Initial Results

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1 Acta Medica Anatolia Volume 4 Issue High Resolution T2-Weighted Dixon Based Whole Body Magnetic Resonance Imaging in Detecting Bone Metastasis; Initial Results Ali Özgen 1, Nalan Alan Selçuk 2, Orhan Önder Eren 3, Özlem Uysal Sönmez 3, Hasan Atilla Özkan 4, Başak Oyan Uluç 3 1 Department of Radiology, Yeditepe University, İstanbul, Turkey 2 Department of Nuclear Medicine, Yeditepe University, İstanbul, Turkey 3 Department of Oncology, Yeditepe University, İstanbul, Turkey 4 Department of Hematology, Yeditepe University, İstanbul, Turkey Abstract Introduction: Whole body magnetic resonance imaging (WB-MRI) has been used in detecting bone metastasis. Conventional MR sequences used in whole body imaging are mostly T1W and STIR. Our aim is to determine the value of high resolution T2- weighted mdixon (T2WmD) WB-MRI in detecting bone metastasis in comparison to bone scintigraphy and positron emission tomography-computed tomography (PET-CT). Methods: Sixteen patients were enrolled in the study. Twelve patients with malignant disease (4 patients with breast cancer, 4 patients with thyroid medullary carcinoma, 2 patients with multiple myeloma, 1 patient with monoclonal gammopathy, and 1 patient with neuroendocrine tumor) were imaged with high resolution T2WmD based WB-MRI and PET-CT while 4 patients with prostate cancer were imaged with WB-MRI and bone scintigraphy. Images were reviewed by a nuclear medicine specialist and by a radiologist blinded to each other s findings. Results: Twelve patients were diagnosed as having bone metastasis both by nuclear medicine imaging and by WB-MRI. PET-CT and bone scintigraphy revealed 4 lesions that could not be detected by WB-MRI in 2 patients whereas WB-MRI detected 16 additional small lesions that could not be shown by PET-CT or bone scintigraphy in 3 patients. Conclusion: We conclude that high resolution T2WmD based WB-MRI is a very promising method in detecting bone metastasis and further studies with larger patient populations are suggested. Keywords: Magnetic resonance imaging, bone scintigraphy, PET-CT, bone metastasis. Received: Accepted: Introduction Metastatic disease of bone may accompany up to 70% of cancer patients (1,2). After the lungs and liver, bone is the most common organ affected by metastases (2,3). Detection of skeletal involvement in cancer patients is very important for staging of the disease and therefore choosing the optimal therapy. Prevention or treatment of possible complications such as pain, instability, and fractures due to metastatic involvement of bones are also mandatory in evaluating cancer patients. Many nuclear medicine and radiological imaging methods have been used in detecting bone involvement of malignant disease (4). In the last decade, studies on whole body magnetic resonance imaging (WB-MRI) in detecting bone metastasis without using ionizing radiation has gained some popularity. Although bone scintigraphy and positron emission tomographycomputed tomography (PET-CT) have been traditionally used, many MR imaging protocols with or without gadolinium based contrast medium have been implemented in search for early and accurate detection of bone metastasis in WB-MRI (5-10). Besides some conventional sequences, short tau inversion recovery (STIR) sequence for obtaining better contrast-to-noise ratio (CNR) and T1-weighted imaging with or without gadolinium based contrast medium have been used extensively in WB-MRI (6-10). Dixon imaging method could also provide relatively high resolution images and good CNR. Although this technique has been widely used in imaging of the abdomen and the extremities, to the best of our knowledge, has not been used in as a single sequence in WB-MRI. The aim of this study is to evaluate the value of high resolution T2-weighted mdixon (T2WmD) imaging as a single sequence in detection of bone metastasis in comparison to skeletal scintigraphy and PET-CT. Correspondence: Ali Özgen, Department of Radiology, Yeditepe University, Istanbul, Turkey Conflict of Interest: None draliozgen@hotmail.com 159

2 Materials and Method Patients This prospective study was approved by the institutional ethics committee. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Between July 2015 and March 2016, 16 adult patients, 9 female and 7 male, with malignant disease were involved in the study. Pathologically proven diagnosis were breast cancer in 4 patients, prostatic carcinoma in 4 patients, thyroid medullary carcinoma in 4 patients, multiple myeloma in 2 patients, monoclonal gammopathy in 1 patient, and neuroendocrine tumor in 1 patient. Mean age of the patients was 54 years (range, years). All patients were referred to nuclear medicine and radiology either from oncology or hematology departments for detection of possible bone metastasis. Indication of nuclear medicine imaging was made by patient s clinician. Patients with prostatic carcinoma were imaged with bone scintigraphy whereas other patients were imaged routinely with PET-CT. All patients were also imaged by WB-MRI within one week of nuclear medicine imaging independent of nuclear medicine findings. MRI protocol All MR examinations were performed on a 3.0T machine (Ingenia; Philips Medical Systems, Best, The Netherlands) with automatic moving tabletop. Combination of one posterior and two anterior coils covering whole torso and extremities, and one headneck coil covering the head and neck area with a total of 106 channels. The acquired sequence was coronal turbo spin echo T2WmD (TR /TE 70) with 4 images; water-only, in-phase, opp-phase, and fatonly. Acceleration factor was 4. Field of view was 300x550 mm for each station. Voxel size was 1x1x4 mm 3, intersection gap was 0.4 mm. Fifty-five to sixty coronal water-only and in-phase images obtained from 6 stations were fused using manufacturer s standard software (Figure 1). Image time for each station were between 2 minutes 10 seconds and 2 minutes 17 seconds. Each MRI examination was performed in minutes. All MRI examinations were reviewed by the same radiologist with 16 years of experience blinded to nuclear medicine examinations. Bone scintigraphy After 2-3 hours patients were given 20 mci 99m Tc monodiphosphonate from antecubital vein, anterior and posterior images were obtained using a 256x1024 matrix resolution low energy high resolution gamma camera (Forte, Philips, The Netherlands). SPECT images were also taken whenever necessary. All bone scintigraphy examinations were reviewed by the same nuclear medicine specialist with 12 years of experience blinded to MRI examination findings. PET-CT imaging After 1 hour injection of 18 F-FDG, images were obtained using a PET-CT (Discovery IQ, General Electric, USA) and reconstructed using ordered subset expectation maximization (OSEM) method. All PET-CT images were reviewed by the same nuclear medicine specialist with 12 years of experience blinded to MRI examination findings. Figure year-old female patient with thyroid medullary carcinoma. A. Coronal fused water-only T2WmD image. B. Coronal fused in-phase T2WmD image. Metastatic lesions are located in sacrum, iliac bone and humerus (arrows). Note lesions are more prominant in in-phase images. 160

3 Image analysis For bone scintigraphy, visual analysis was used instead of a semiquantitative analysis. For PET-CT interpretation, focally increased 18 F-FDG uptake was considered as malignant unless a benign lesion was noted on the corresponding CT images. For MRI interpretation, high intensity areas on wateronly and/or low intensity areas on in-phase images noted in medullary bone with or without cortical involvement were considered malignant unless a benign etiology was suspected. Lesions with low level of suspicion on each imaging modality were followed-up and not considered as malignant. Bone biopsy, contrast enhanced MRI, or high resolution CT examinations were planned if a lesion was considered suspicious and had the ability altering the diagnosis or staging. Final diagnosis was made on consensus and confirmed by imaging, histological examination, and/or follow-up. Results All patients well tolerated WB-MRI examinations. WB-MRI images were also considered diagnostic in all patients. Minor artifacts at the edge of some images of upper extremity scans were not considered important and did not prevent optimum interpretation of bones. Both signal-to-noise and contrast-to-noise ratios were considered satisfactory by the radiologist in a qualitative fashion. Of 16 patients, 12 patients were diagnosed as having bone metastasis based on consensus; 4 patients with prostate cancer, 3 patients with breast cancer, 3 patients with thyroid medullary carcinoma, and 2 patients with multiple myeloma. Two bone biopsies under CT guidance were performed by the same radiologist to confirm metastasis and to obtain definite histopathological diagnosis. No additional imaging was necessitated in any of the patients. Follow-up of the patients did not alter the initial diagnosis in any of the patients. Overall, 81 separate lesions in 12 patients were noted both by bone scintigraphy/pet-ct and WB- MRI. In all patients, diagnosis were successfully made by bone scintigraphy or PET-CT examinations and also by WB-MRI, resulting in 100% agreement. Each bone scintigraphy and PET-CT detected 2 more lesions in 2 patients, who already had other metastatic lesions, located on ribs (3 lesions) and skull (1 lesion). Two of the lesions, 1 in skull and 1 in ribs, were retrospectively detected by WB-MRI whereas other 2 lesions could not be detected. Size of these lesions could not be exactly determined due to very low resolution of nuclear medicine imaging modalities. On the other side, WB-MRI detected 16 more lesions, equal or smaller than 12 mm, in 3 patients who already had other lesions all located in vertebrae, pelvic bones and femur (Figures 2 and 3). Only 2 of them were retrospectively regarded as suspicious on PET-CT while 9 of them could not be imaged by neither scintigraphy nor PET-CT. We also noted that CNR of lesions seen in in-phase imaging were higher than in water-only images and in-phase images documented 7 more lesions than water-only images all equal or smaller than 6 mm. A) B) Discussion C) Figure year-old male patient with prostatic carcinoma. A. Bone scintigraphy showing multiple metastatic lesions. B. Wateronly and C. In-phase T2WmD images showing smaller metastatic lesions that could not be differentiated on bone scintigraphy (arrows). Note in-phase images also documented 2 more small lesions (thin arrows). Although scintigraphy and PET-CT are the traditional methods of imaging in detecting bone metastasis, WB-MRI with the advantage of not having ionizing radiation have been studied in this area of diagnosis. Various MR sequences with or without gadolinium based contrast medium have been studied. Conventional MR sequences used in whole body 161

4 A) B) C) imaging are mostly T1W and STIR sequences (6-10). T1W images provides relatively higher resolution and anatomic detail in a reasonable scan time while STIR images provides higher CNR in a longer scan time and lower resolution. Diffusion weighted imaging (DWI) has been recently introduced in WB-MRI and also used in detection of bone metastasis especially with T1W imaging (8,10). Main disadvantage of DWI is very low resolution, relatively longer scan times, and low specifity. Fat suppressed T2-weighted (T2W) imaging might theoretically supply higher resolution and good CNR in a reasonable scan time. However, fat saturated T2W images used in whole body imaging result in some artifacts caused by large field of view due to magnetic inhomogenity. Dixon method could provide a homogenous fat suppression even in areas of high magnetic susceptibility. T2WmD sequence can provide 4 sets of image types using chemical shift effect in a single session; water-only, in-phase, Figure year-old female patient with breast carcinoma. A. Coronal PET-CT image showing metastatic lesions (arrows). B. Water-only and C. In-phase T2WmD images showing smaller metastatic lesions in pelvic bones that could not be differentiated on PET-CT image (arrows). Note metastatic lesions are more prominant in in-phase images than in wateronly images. opp-phase, and fat only while scan times remain almost the same (11). Therefore, this technique has been used in the last decade mostly in imaging of the abdomen and the extremities. To the best of our knowledge, there has been only a single study in the literature including T2WmD imaging together with other MR sequences and no study evaluating the value of T2WmD imaging as a single sequence in whole body MR imaging in detecting bone metastasis (12). In the literature, there were many studies about value of WB-MRI in detecting bone metastasis in comparison to bone scintigraphy and PET-CT (5-14). Bone scintigraphy is more sensitive in bone forming osteoblastic tumors like prostate and breast carcinomas than in osteolytic tumors. Although, WB-MRI is shown to be equal or superior to bone scintigraphy, clear superiority of MRI or PET-CT over each other was not accepted in consensus (4,14). However, 18F NaF PET-CT was shown to have the highest sensitivity and specifity in detecting bone metastasis in comparison to MRI, SPECT, 18F PET-CT, CT, and bone scintigraphy (4). In previous studies on WB-MRI, slice thickness were generally between 6-8 mm (6-10). Spatial resolution were also relatively low and pixel sizes were between mm 2 (6-10). Therefore, to the best of our knowledge, we present the highest spatial resolution as 1x1 mm, and minimum voxel size as 4 mm 3 in WB-MRI in the literature. High resolution images with small voxel size theoretically might result in ability to detect smaller lesions. Besides, we presented a very short imaging time in comparison to other studies in the literature. We believe that using a 3.0T scanner with dedicated coils while using a relatively new MR sequence adapted for whole body imaging resulted in this consequence. Although we present better results in detecting bone metastasis in comparison to scintigraphy and PET-CT in general, there were some lesions mostly located in rib cage that could not be detected with WB-MRI. This situation is consistent with the literature and believed to be caused by respiratory movements that would result in motion artifacts in MR images (10,14). This shortcoming of some MR sequences including T2WmD technique could probably be at least partially overcomed using respiratory triggered or breath hold imaging techniques in the future. Our study has some limitations. First, we had very limited number of patients included in this study for an eligible statistical analysis. Second, although observers were highly experienced in their fields, we 162

5 lack interobserver variation data for both nuclear medicine and radiology examinations. Third, we lack comparison of T2WmD imaging with 18F NaF PET-CT imaging, which has the highest sensitivity and specifity in detecting bone metastasis. Finally, although lesions accepted as metastasis were confirmed by multiple imaging modalities and follow-up, we lack histological reference standard for every lesion due to ethical and logical reasons. In conclusion, T2WmD imaging as a single sequence may show equal or better results in detecting bone metastasis from prostatic carcinoma in comparison to bone scintigraphy and bone metastasis from breast carcinoma, medullary thyroid carcinoma, and multiple myeloma in comparison to PET-CT. Lack of ionizing radiation, short imaging time, relatively high resolution, and no need of contrast medium usage are the main advantages of this imaging method. This high-resolution imaging may further allow very early detection of bone metastasis. Further studies with larger patient populations are needed to reveal exact value of this WB-MRI technique. References 1. Bussard KM, Gay CV, Mastro AM. The bone microenvironment in metastasis; what is special about bone? Cancer Metastasis Rev. 2008;27(1): Yu HH, Tsai YY, Hoffe SE. Overview of diagnosis and management of metastatic disease to bone. Cancer Control 2012;19(2): Vassiliou V, Andreopoulos D, Frangos S, Tselis N, Giannopoulou E, Lutz S. Bone metastases: assessment of therapeutic response through radiological and nuclear medicine imaging modalities. Clin Oncol. (R Coll Radiol) 2011;23(9): O Sullivan GJ, Carty FL, Cronin CG. Imaging of bone metastasis: An update. World J Radiol. 2015;7(8): Wu Q, Yang R, Zhou F, Hu Y. Comparison of wholebody MRI and skeletal scintigraphy for detection of bone metastatic tumors: a meta-analysis. Surg Oncol 2013;22: Minamimoto R, Loening A, Jamali M, Barkhodari A, Mosci C, Jackson T, et al. Prospective Comparison of 99mTc-MDP Scintigraphy, Combined 18F-NaF and 18F-FDG PET/CT, and Whole-Body MRI in Patients with Breast and Prostate Cancer. J Nucl Med 2015;56: Jambor I, Kuisma A, Ramadan S, Huovinen R, Sandell M, Kajander S, et al. Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial. Acta Oncol 2016;55: Mosavi F, Johansson S, Sandberg DT, Turesson I, Sörensen J, Ahlström H. Whole-body diffusionweighted MRI compared with 18F-NaF PET/CT for detection of bone metastases in patients with high-risk prostate carcinoma. AJR Am J Roentgenol. 2012;199(5): Adams HJA, Kwee TC, Vermoolen MA, de Keizer B, de Klerk JM, Adam JA, et al. Whole-body MRI for the detection of bone marrow involvement in lymphoma: prospective study in 116 patients and comparison with FDG-PET. Eur Radiol. 2013;23(8): Del Vescovo R, Frauenfelder G, Giurazza F, Piccolo CL, Cazzato RL, Grasso RF, et al. Role of wholebody diffusion-weighted MRI in detecting bone metastasis. Radiol Med 2014;119: Del Grande F, Santini F, Herzka DA, Aro MR, Dean CW, Gold GE, et al. Fat-suppression techniques for 3-T MR imaging of the musculoskeletal system. Radiographics 2014;34(1): Costelloe CM, Madewell JE, Kundra V, Harrell RK, Bassett RL Jr, Ma J. Conspicuity of bone metastases on fast Dixon-based multisequence whole body MRI: clinical utility per sequence. Magn Reson Imaging 2013;31(5): Davila D, Antoniou A,Chaudhry MA. Evaluation of osseous metastasis in bone scintigraphy. Semin Nucl Med. 2015;45(1): Khalafallah AA, Snarski A, Heng R, Hughes R, Renu S, Arm J, et al. Assessment of whole body MRI and sestamibi technetium-99m bone marrow scan in prediction of multiple myeloma disease progression and outcome: a prospective comparative study. BMJ Open 2013;3:e doi: /bmjopen