Role of Whole-Body Diffusion-Weighted MR in Assessment of Neoplastic Leisons

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1 Med J Cairo Univ, Vol 81, No 2, March: , 2013 wwwmedicaljournalofcairouniversitycom Role of Whole-Body Diffusion-Weighted MR in Assessment of Neoplastic Leisons NAGUI M ABDELWAHAB, MD; MARYSE Y AWADALLAH, MD and AYA M BASSAM, MSc The Department of Radiodiagnosis, Faculty of Medicine, Cairo University Abstract Purpose: The aim of this work is to evaluate the value of whole body diffusion weighted imaging (DWI) in detection of metastatic bone disease, using bone scintigraphy as comparison Patients and Methods: Fifteen patients (5 males 10 females), with known primary malignant tumor (confirmed histologically) underwent both whole body MR1 including diffusion weighted whole body imaging with background body signal suppression (DWIBS) and skeletal scintigraphy to detect metastasis Results: All extraosseous lesions (detected by other modalities as computed tomography and ultrasound) were detected and most of bone lesions (detected by bone scan) were also detected Conclusion: We concluded that WB-MRI that included DWI holds great promise, and has shown utility in the identification of both bony and visceral metastases However, more optimization is required for WB-DWI to become a routine screening tool, and large-scale studies are needed to fully gauge its impact in oncology Key Words: DWIBS Whole body MRI DWI Neoplastic lesions Metastatic lesions Introduction DIFFUSION-WEIGHTED sequence (DWI) of the entire body is a new promising technique feasible to evaluate multifocal disease [ii Technological advances and the development of the concept of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) have opened the path for routine clinical wholebody DWI Whole-body DWI allows detection and characterization of both oncological and nononcological lesions throughout the entire body [2] Diffusion-weighted imaging provides important information about the movement and functional status of the microenvironment of water in tissue Correspondence to: Dr Maryse Y Awadallah, The Department of Radiodiagnosis, Faculty of Medicine, Cairo University Changes in diffusion of water within pathological tissue may occur before they are seen on standard MR imaging [3] There is growing interest in the application of DWI for the evaluation of the patient with cancer DWI measurements are quick to perform (typically 1-5 minutes) Practical implementation of whole body DWI, using the DWIBS concept, is relatively easy, since it can be performed on most modem MRI scanners and does not require any contrast agent administration Furthermore, compared to SPECT/CT and PET CT, MRI scanners are more widely available and whole body DWI is less expensive [4] DWI is a powerful imaging tool that provides unique information related to tumor cellularity and the integrity of the cellular membrane The technique can be applied widely for tumor detection, tumor characterization and monitoring of tumor response [5] WB-MR imaging using DW sequences is more sensitive than scintigraphy, supplying additional information on non bone-related lesions Whole body diffusion imaging technique might help the clinicians to accept the whole body MR imaging as a routine method for the diagnostic work-up and consider it as an alternative to bone scan and/or PET ill Patients and Methods Fifteen patients (5 males and 10 females), referred to the Radiology department of Kasr Al- Ainy Hospitals from the outpatient clinic of the Clinical Oncology department, their ages ranged between 34 to 70 years, with known primary malignant tumor (confirmed histologically) underwent whole body MRI including diffusion weighted whole body imaging with back ground body signal 213

2 214 Role of Whole-Body Diffusion-Weighted MR suppression (DWIBS), skeletal scintigraphy and any other modality to detect extraosseous metastases as computed tomography and ultrasound 8 patients, breast carcinoma; 2 prostate carcinoma; 2 bladder carcinoma; one each, thyroid malignancy, bronchogenic carcinoma and endometrial carcinoma The number of metastatic lesions detected in the 15 patients was categorized into bony metastatic lesions (detected by bone scan) and extra-osseous metastatic lesions (detected by other modalities as computed tomography, ultrasound and other MRI sequences) These findings were then compared to the findings of whole body diffusion MRI Inclusion criteria: Pathologically diagnosed primary tumours with bone and/or soft tissue metastases Exclusion criteria: Claustrophobia or other contraindications to MRI MR technique: All MR studies were performed on a 15-T MR imaging unit (Intera, Philips medical system) Patients were placed in the supine and feet-first position on the extended patient table platform, allowing covering of most of the body of adult patients from the head to the tibia DWIBS pulse sequence: The DWIBS were acquired axially with the Q body coil under free breathing conditions using an EPI single-shot pulse sequence The gradients of the DWI were applied along the X, Y and Z axes before and after a 180 inversion pre-pulse to obtain fat-saturated, isotropic images with DWI sensitivity using the following parameters for a single stack: B-value 1,000mm2/s, TR (Repetition time)/te (Echo time)/ir (Inversion recovery) (8773/70/180ms); field of view (FOV): Right/left 350mm, anterior/posterior 258mm, feet/head 420mm; slice thickness 6mm; size of reconstructed voxel was 156 x 156x6mm In all patients, five of the above-described stacks were acquired one after the other in order to image from the head to the middle of the tibia Overall, the required imaging time corresponded to about 25min Other pulse sequences parameters: The whole body MRI also included Tl, T2 and STIR pulse sequences with the following parameters Table (1): MRI parameters in whole body Tl, T2 and STIR Parameters T1 T2 STIR TR TE FOV: Right/Left Anterior/Posterior Feet/Head Slice thickness 8mm 8mm 8mm Gap l mm lmm lmm Skeletal scintigraphy: Standard skeletal radionuclide scintigraphy was performed within a month from WB MRI The examination was performed 3 hours after injection of 15-20mCi ( MBq) of 99TC-MDP Images were collected using a dual-head whole-body scanner with a high-resolution, low-energy collimator Qualitative image analysis: The DW images have to be processed on the workstation The 3D data sets from the different axial series are combined, reformatted and viewed along any axis as maximum intensity projections as a unique series The multiplanar reformatted images can be displayed as a whole-body image in the coronal plane Inverted black-and-white gray scale source MR DWIBS images (b=1,000mm2/s) were analyzed on the workstation which seem more familiar to clinicians, as they have some resemblance to the usual displays seen in scintigraphy or in PET Qualitative analysis can be performed directly from the reformatted view on the three planes Signals from normal tissue such as blood vessels, fat, muscle, and bowel are suppressed However, other normal structures such as the spleen, prostate, testes, ovaries, endometrium, and the spinal cord remain visible The lesions were only categorized according to the subjectively rated signal pattern, signal intensity and morphology without taking into account the apparent diffusion coefficients, which were not quantified Malignant lesions generally exhibit considerably greater signal intensities and variability on their profile than benign ones In addition to diffusion-weighted sequence, T1- weighted, T2-weighted and STIR images were also evaluated to combine information, to accurately detect pathology and rule out artifacts from the diffusion-weighted sequence series The skeletal scintigrams were also analyzed; the increased uptake pattern of the identified lesions

3 Nagui M Abdelwahab, et al 215 was rated according to the clinical experience No quantitative measurements were considered Statistical analysis: Data were statistically described in terms of mean±standard deviation (±SD), median and range, or frequencies (number of cases) and percentages when appropriate All statistical calculations were done using computer programs SPSS (Statistical Package for the Social Science; SPSS Inc, Chicago, IL, USA) version 15 for Microsoft Windows Number of cases gib&lif 1 Breast carcinoma (533)% 0 Prostatic carcinoma (133) O Bladder carcinoma (133) s Bronchogenic carcinoma (67) Thyroid lymphoma (67) 0 Endometrial carcinoma (67) Fig (1): Classification of 6 pathological entities which were examined in the 15 cases Resufts This study included 15 patients; 5 males, 10 females with age range from 33 years to 70 years (mean age 595 years), suffering from known primary malignant tumor with metastases Table (2): Number and percentage of the cases who had pure bone metastases and mixed bone and extraosseous metastases Type of metastases Pure bone metastases Number of cases Percent (%) 667% 333% 100% Table (3): Number and percentage of bony metastatic lesions detected by whole body DWI as compared to bone scan Item Mixed bone and extraosseous Total metastases Bone scan WB DWI Number of bony metastatic lesions Percent (%) 100% 947% The total number of bony metastatic lesions which was diagnosed in the 15 cases was 113 lesions, while the total number which was diagnosed by WB DWI was 107 lesions, representing 947% The WB DWI showed all the extraosseous lesions detected by other modalities as computed tomography, ultrasound and other MRI sequences Also, it showed the bony lesions detected by bone scan in the following sites: Vertebra, sternum, femur, acetabulum, humerus, scapula, tibia, shoulder, pelvic bone, greater trochanter, clavicle, coracoid process and sacrum On the other hand, lesions in skull and lateral condyle of femur and one rib lesion were missed The sensitivity of WB DWI in detecting metastatic bony lesions was 100% with positive predictive value=947% While the sensitivity of WB DWI in detecting metastatic ribs lesions was 100% with positive predictive value=952% The sensitivity of WB DWI in detecting extraosseous lesions was 100% with positive predictive value=100% Table (4): Sites, number and percentage of bone metastatic lesions detected by whole body DWI as compared to bone scan Site Bone scan WB DWI Percentage of lesions detectedby WB DWI as compared to bone scan (%) Vertebra Strenum Ribs Femur Acetabulum Humerus Scapula Tibia Skull Shoulder Pelvic bone Lateral condyle 1 o o Greater trochanter Clavicle Coracoid process Sacrum Table (5): Sites, number and percentage of soft tissue metastatic lesions detected by whole body DWI as compared to other modalities as computed tomography, ultrasound and other MRI sequences Site Liver Lung Kidney Suprarenal glands Lymph nodes Percentage of lesions Other WB detected by WB DWI modalities DWI as compared to bone scan (%)

4 216 Role of Whole-Body Diffusion-Weighted MR --ro 4 I s i 0 1 # I r t t LA i a I L a (Fig 2) tvp 4 I' 1 lipqr wit N Misr % # (Fig 4) Figs (2-5): A case of bronchogenic carcinoma in a male patient 51 years old, referred to us complaining of left lower limb pain Bone scan showing single osseous metastatic lesion at the lower end of left femur (Fig 2) WB DWI showing metastatic osseous lesion, in addition to a malignant lesion is seen in the right lung (the primary bronchogenic carcinoma) and mediastinal lymph nodes metastases (Fig 3) The source axial image (b-value 1000) showing the primary lung lesion (Fig 4) WB MRI (STIR and T1) showing metastatic lesion in the lower end of left femur, primary right bronchogenic carcinoma and mediastinal lymph node (Fig 5a,b) (Fig 5A) (Fig 5B) (Fig 6) 4 Tir 1-11rNi os 471" L? 14 t I -- - e infii c et "If'tf ; 1 Ir 'II -!4P ik 4,, EA '1! IR rca-,, 1 kr* ' ' ' 7 r 4, Kla! el it Att/,- 1eti, - i ) t 1 ii 4 % - (Fig 7) $ 4 ' Ai 111: ' 0, 01 el 11 6 Iti `-- i ik Pi? iii A L, ' i - 4, il { 2 III Ot -t,f iiikt II ' M 4e A 4 T 1 IN C 2 i OP - Pifit I % L -:tr" I( 1 i- 1 i llit A,, 7 7 ) ri ill -* ip bii, ' ṭrio t

5 I Nagui M Abdelwahab, et al 217 (Fig 9B) Figs (6-10): A case of pathologically proven thyroid lymphoma, with thyroidectomy, in a female patient 64 years old Bone scan (posterior view) showing metastatic lesions at sacrum, DV2, 7 and 8 and posterior segment of left 7th rib (Fig 6) WB DWI showing metastatic lesions at sacrum, DV2, 7 and 8, posterior segment of left 7th rib, right axillary lymph node, liver and bilaterally enlarged kidneys with multiple infiltrations (Fig 7) The source axial image (ADC=10, it was stated that if it is less than 12 in liver lesions then it is malignant if not then it's benign lesion) showing multiple liver metastases (Fig 8) The source axial image (b-value 1000) and (ADC) showing bilateral renal infiltrations (the bright lesions seen in diffusion images became dark in ADC images) (Fig 9a,b) WB MRI (DWI and STIR) showing axillary lymph node (LN) affection (Fig 10) - a MEM (Fig 11) (Fig 12) 0 j, 3,' _,t,, 1-i 49 A I I r S _ #L1% 400, :_,Ai,4wi A dr, 411 L 1 7 T 4 rf- Oh, ;t A -is- -is_a Li 70% 4,0 1, , _, E: I - - A Jet,,k S 4# 01 0 (Fig 13A) (Fig 13B) (Fig 13C)

6 218 Role of Whole-Body Diffusion-Weighted MR Figs (11-14 ): A case of cancer prostate in a male patient 70 years old, referred to us for follow-up Bone scan showing multiple osseous lesions at right scapula, sternum, right 9th and 10th ribs, DV 10 and its costovertebral junction and left greater trochanter (Fig 11) WB DWI: The primary malignant lesion is seen (prostatic carcinoma), in addition to multiple metastatic lesions in the right scapula, left humerus, sternum, left 9th rib, right 9th 10thand 12th ribs, DV 10 and its costovertebral junction, left greater trochanter, bilateral suprarenal glands metastases and right apical lung metastasis (Fig 12) The source axial image (b-value 1000) showing bilateral suprarenal glands infiltrations, bilateral 9th ribs metastases and right 10th rib and 10th dorsal vertebra metastases (Fig 13 a,b,c) WB MRI (DWI and T1) showing right 12th rib metastases (Fig 14) (Fig 14) Discussion The development of skeletal or organ metastases is often difficult to detect and usually not found until clinical symptoms present or is discovered during tumor staging with radiological imaging If metastatic disease is present, the usual sites are in bones, liver, brain, and lung [6] Determination of metastatic disease is accomplished using radiological imaging, such as plain film X-ray, Tc99m bone scintigraphy, computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI) [7] Indeed, these radiological procedures are the cornerstone for the detection and staging of metastatic lesions, and, if possible, classifying the type of lesion as well as the extent and localization of metastatic sites However, until recently, most sensitive radiological procedures were limited to only "regional" or "local" coverage and could not interrogate the full body [6] Bone is a most common site of distant metastasis (50-70%), especially in patients with prostate and breast cancer [8] Bone metastases causes much of the morbidity and disability in patients suffering from tumors The standard procedure for visualizing bone metastases in patients with a malignant underlying disease is skeletal scintigraphy However, in several studies whole body magnetic resonance imaging (WB-MRI) has shown better results than skeletal scintigraphy [9] Whole body DWI can be used to detect metastases because DWI is sensitive to the random (Brownian) motion of water molecules In biologic tissue, the presence of impeding barriers (eg, cell membranes, fibers, and macromolecules) interferes with the free displacement (diffusion) of water molecules Consequently, the signal intensity in DWI depends on the separation and permeability of these impeding boundaries Rol The degree of restriction to water diffusion in biologic tissue is inversely correlated to the tissue cellularity and the integrity of cell membranes The motion of water molecules is more restricted in tissues with a high cellular density associated with numerous intact cell membranes (eg, tumor tissue) Diffusion-weighted imaging (DWI) is increasingly applied in the evaluation of cancer patients [iii The principle is that tumors with high cellularity have restricted diffusion of water molecules, which results in higher signal intensity than the surrounding normal tissue [12] In this study the lesions were classified into two main groups; bone metastases (113 lesions) and soft tissue metastases (23 lesions); we used bone scan for detecting bone metastases and other radiological modalities as computed tomography, ultrasound and other MRI sequences to detect extraosseous metastases In our study whole body diffusion MRI was capable to detect all extraosseous lesions (23 lesions) and almost all bony lesions (107 lesions) The missed lesions were 4 lesions in the skull, one lesion in the rib and one lesion in the lateral condyle of the femur In our study according to the sites of the disease, WB DWI is capable for detecting all lesions in the spine, sternum, femur, humerus, scapula, tibia,

7 Nagui M Abdelwahab, et al 219 shoulder and pelvis detected by bone scan We found that whole-body DWI failed to detect a few lesions in the skull and ribs, as have other studies [91 Sakurada et al, 2009 suggested that the limitation in detecting ribs lesions is due to artifacts that are related to pulsation and breathing in the thorax, which make examination of the ribs, sternum and scapula more difficult [13] The reason for missed lesions in the skull is unclear, but may be induced by the interference of high signal in brain [14] It was stated that the normal adult bone marrow distribution becomes established by 25 years of age and that yellow bone marrow has low water content (10%-20%), which results in decreased signal intensity on DW images On the other hand, red bone marrow has increased cellularity and water content (40%-60%), thus resulting in higher signal intensity on DW images There are variable amounts of red bone marrow atrophy and trabecular bone loss after 40 years of age, particularly in women (possibly related to estrogen deficiency and osteoporosis, resulting in increased adiposity, which thus lowers the signal intensity of bone marrow on whole-body DW images as age increases This may explain why in our study the lateral condyle metastatic lesion detected by bone scan was missed by WB DWI in the female patient aged 38 years old [15-18] In our study whole body DWI also detected 2 rib lesions missed by bone scan which were found in retrograde analysis of the bone scan to show very faint tracer uptake, Figs (11-14 ) One of the potential powerful tools of this new whole body sequence is that it also provides additional information of the extraskeletal areas For this reason the technique can be applied for extraskeletal tumor detection and characterization [19] As for soft tissue lesions in our study all lesions were detected by whole body DWI which include liver, lung, kidneys, lymph nodes and suprarenal glands but for lymph nodes whole body MRI using other sequences (T1, T2 and STIR) were needed to ensure their presence especially for mediastinal lymph node Figs (2-5) It was stated that this is due to signal loss and artifacts due to severe tissue motion [13,20] Nevertheless, MRI is a versatile imaging modality, and the addition of other sequences may improve the evaluation of the mediastinal lymph nodes One of the cases was referred to us as query thyroid malignancy Bone scan revealed multiple bony metastatic lesions Whole body diffusion MRI detected the same bony lesions and in addition it showed infiltrations of both kidneys, liver and axillary lymph node raising the suspicion of lymphoma Biopsy was then taken from the thyroid gland and it was proven to be thyroid lymphoma Figs (6-10) Initial studies describing DWWB MR imaging have focused on the detection of osseous metastases in patients with primary malignancies that had the potential to metastasize to the skeletal system [121 Other recently preliminary results of DWWB MR imaging have demonstrated the additional value of this sequence, comparable to skeletal scintigraphy to detect bone metastases, related to wholebody MR imaging protocol without DW images Whole-body MR with DW imaging had a sensitivity of 96% for metastatic bone tumor where WBMR imaging without DW imaging had a sensitivity of 88% [21] In our study, the sensitivity of WB DWI in detecting metastatic bony lesions was 100% with positive predictive value=947% While the sensitivity of WB DWI in detecting metastatic ribs lesions was 100% with positive predictive value =952% The difference may be due to the small sample size The sensitivity of WB DWI in detecting extraosseous lesions was 100% with positive predictive value=100% This study shows that whole body DWIBS can discover both bone and extraosseous metastases The evidence is that in patients with lmown primary malignancy with proved metastases by other modalities were almost all detected by whole body DWIBS Limitations: Although whole body DWI reveals excellent clinical value, there are still some limitations of our study: The sample size is not large enough for powerful conclusion Furthermore, we were unable to perform a biopsy of all skeletal metastases determined in routine examinations Another limiting factor was the lack of a true gold standard The standard of reference we chose was, however, the most effective method to determine lesions Recommendations: The question of whether besides signal enhancement, quantitative assessment using the ADC values as well would further improve the results, possibly with threshold values between malignant and benign metastatic lesions, should be addressed in future studies Larger studies using this WB DWI

8 220 Role of Whole -Body Diffusion - Weighted MR sequence should be performed, and especially comparing with other whole-body techniques such as PET Conclusion: The introduction of whole-body MRI allows for rapid imaging of the whole body with high spatial resolution and has the potential to evaluate skeletal and visceral metastatic regions throughout the body Overall, DWIBS is an interesting new technique, the ability to show both bone and soft tissue metastases in one examination is the real temptations to use this technique The results of our study showed that DWI of the whole body is a competitive promising technique that can give a quick screening for patients with malignancy and suspected metastatic deposits Further refining of this technique is expected in the future to improve the positive predictive value which is (at the current study) considered real challenge for further improvement of this technique References 1- JOAN C VILANOVA and JOAQUIM BARCELO: Diffusion-weighted whole-body MR screening European Journal of Radiology, 67: , THOMAS C KWEE, TARO TAKAHARA, REIJI OCHI- AI, KAZUHIRO KATAHIRA, MARC VAN CAUTEREN, YUTAKA IMA, RUTGER AJ NIEVELSTEIN and PE- TER R LUIJTEN: Whole-body diffusion-weighted magnetic resonance imaging European Journal of Radiology, 70: , LE BIHAN D: Molecular diffusion nuclear magnetic resonance imaging Magn Reson Q, 7: 1-30, DELFAUT EM, BELTRAN J, JOHNSON G, ROUSSEAU J, MARCHANDISE X and COTTEN A: Fat suppression in MR imaging: Techniques and pitfalls Radiographics, 19: , DOW-MU KOH1,2 and DAVID J COLLINS1,2: Diffusion-weighted MRI in the body: Applications and challenges in Oncology American Journal of Roentgenology, 188: , JACOBS MA, PAN L and MACURA KJ: Whole-body diffusion weighted and proton imaging: A review of this emerging technology for monitoring metastatic cancer Semin Roentgenol, 44 (2): , HAMAOKA T, MADEWELL JE, PODOLOFF DA, HORTOBAGYI GN and UENO NT: Bone imaging in metastatic breast cancer J Clin Oncol, 22 (14): , COLEMAN RE: Clinical features of metastatic bone disease and risk of skeletal morbidity Clin Cancer Res, 12: , GHANEM N, LOHRMANN C, ENGELHARDT M, et al: Whole-body MRI in the detection of bone marrow infiltration in patients with plasma cell neoplasms in comparison to the radiological skeletal survey Eur Radiol, 16: , KWEE TC, TAKAHARA T, OCHIAI R, KOH D, OHNO Y, NAKANISHI K, NIWA T, CHENEVERT T, LUIJTEN P and ALAVI A: Complementary Roles of Whole-Body Diffusion-Weighted MRI and 18 F-FDG PET: The State of the Art and Potential Applications J Nucl Med, 51: , KOH DM and COLLINS DJ: Diffusion-Weighted MRI in the Body: Applications and Challenges in Oncology AJR, 188: , TAKAHARA T, IMAY Y, YAMASHITA T, YASUDA S, NASU S and VAN CAUTEREN M: Diffusion weighted whole body imaging with background body signal suppression (DWIBS): Technical improvement using free breathing, STIR and high resolution 3D display Radiat Med, 22: , SAKURADA A, TAKAHARA T, KWEE TC, et al: Diagnostic performance of diffusion weighted magnetic resonance imaging in esophageal cancer Eur Radiol, 19: , XU X, MA L, ZHANG JS, CAI YQ, XU B, CHEN LQ, SUN F and GUO XG: Feasibility of whole body diffusion weighted imaging in detecting bone metastasis on 30T MR scanner Chin Med Sci J, 23 (3): , HWANG S and PANICEK DM: Magnetic resonance imaging of bone marrow in oncology, Part 1 Skeletal Radiol, 36 (10): , GOODSITT MM, HOOVER P, VELDEE MS and HSUEH SL: The composition of bone marrow for a dual-energy quantitative computed tomography technique A cadaver and computer simulation study Invest Radiol, 29 (7): , SCHELLINGER D, LIN CS, FERTIKH D, et al: Normal lumbar vertebrae: Anatomic, age, and sex variance in subjects at proton MR spectroscopy-initial experience Radiology, 215 (3): , SYED FA, OURSLER MJ, HEFFERANM TE, PETER- SON JM, RIGGS BL and KHOSLA S: Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women Osteoporos Int, 19 (9): , VILANOVA JC and BARCELO J: Diffusion-weighted whole-body MR screening European Journal of Radiology, 67: , KOH DM, BROWN G, RIDDELL A M, et al: Detection of colorectal hepatic metastases using MnDPDP MR imaging and diffusion-weighted imaging (DWI) alone and in combination Eur Radiol, 18: , NAKANISHI K, KOBAYASHI M, TAKAHASHI S, et al: Whole body MRI for detecting metastatic bone tumor: Comparison with bone scintigram Magn Reson Med Sci, 4: 11-17, 2005