we retrospectively analyzed the data of patients with newly diagnosed , pathologically confirmed nasopharyngeal lymphoma or npc at our hospital from december 2014 to april 2015 . the main inclusion criterion was that the patients had successfully undergone conventional mri and ivim dwi of the nasopharynx before treatment . the main exclusion criteria were as follows : ( 1 ) obvious motion or susceptibility artifacts around the skull base and paranasal sinuses on ivim dwi images , which could prevent the ivim analysis , or ( 2 ) difficulty in performing ivim analysis because of a small tumor volume , which leads to poor signal - to - noise on dwi images . in total , 102 patients including 82 with npc ( 80 nonkeratinizing , 2 keratinizing ) and 20 with lymphoma ( 15 b - cell non - hodgkin , 5 t - cell non - hodgkin ) were enrolled in the present study . the mean ( sd ) tumor volumes for lymphoma and npc were 11.884 ( 13.610 ) and 9.795 ( 10.772 ) cm , respectively . for patients with npc , the distribution of the t staging according to the 7th edition of the american joint committee on cancer was as follows : t1 , n = 8 ( 9.8% ) ; t2 , n = 29 ( 35.3% ) ; t3 , n = 19 ( 23.2% ) ; and t4 ; n = 26 ( 31.7% ) . all mri examinations were performed on a 1.5-tesla mri scanner ( optima mr360 ; ge healthcare , nj ) using a head and neck coil . the imaging protocol included axial t1-weighted spin - echo images ( repetition time [ tr]/echo time [ te ] , 580/7.8 milliseconds ; slice number , 36 ; 5-mm slice thickness , 1-mm slice gap , number of excitations [ nexs ] , 2 ) and axial t2-weighted spin - echo images with fat suppression ( tr / te , 6289/85 milliseconds ; slice number , 36 ; 5-mm section thickness , 1-mm intersection gap ; nex , 2 ) . in addition , for contrast - enhanced axial and coronal t1-weighted spin - echo image acquisition , the contrast agent gadodiamide ( omniscan ; ge healthcare ) was administrated intravenously at a dose of 0.1 mmol / kg of body weight . ten b values ( 0 , 50 , 80 , 100 , 150 , 200 , 400 , 600 , 800 and 1000 s / mm ) were applied with a single - shot diffusion - weighted spin - echo echo - planar or ss - se - dw - epi sequence . the lookup table of gradient directions was modified to allow multiple b value measurements in 1 series . a local shim box covering the nasopharyngeal region was applied to minimize susceptibility artifacts . in total , 12 axial slices covering the nasopharynx were obtained with a 22-cm field of view , 5-mm slice thickness , 1-mm slice gap , tr of 4225 milliseconds , te of 106 milliseconds , 128  130 matrix , and 4 nex for all b values . all ivim dwi data were transferred to an advantage workstation with functool software ( version aw 4.6 ; ge medical systems ) for postprocessing . intravoxel incoherent motion analysis was performed using cinetool kit , a software package for multiple adc measurements in the functool software package , and fitted on a pixel - by - pixel basis according to the levenberg - marquardt algorithm . briefly , the major procedures of the ivim analysis were as follows . according to the ivim theory described by le bihan and turner , the signal intensities and b values are related as follows : where sb is the signal intensity with diffusion gradient b ; s0 is the signal intensity for a b value of 0 s / mm ; d is the true diffusion coefficient ( square millimeter per second ) indicating the pure diffusion of water molecular ; f is the microvascular volume fraction , representing the fraction of diffusion related to microcirculation perfusion ; and d * is the pseudodiffusion coefficient ( square millimeter per second ) caused by microcirculation perfusion . because d * is roughly 1 order of magnitude greater than d  bd * would be less than 3 at a high b value ( > 200 s / mm ) , and the term f exp ( bd * ) would be less than 0.05 f. in this case , the contribution of d * to the signal ratio sb / s0 can be neglected , and equation 1 was simplified as equation 2 for an estimation of d : hence , for high b values ( 400 , 600 , 800 , and 1000 s / mm ) , sb was first fitted to equation 2 using a linear model , and d was calculated . secondly , fixing d at the value estimated previously and considering measurements from all 9 b values , d * and f were determined from equation 1 by a nonlinear levenberg - marquardt method . finally , the adc was calculated from the traditional adc equation , equation 3 , using data at b values of 0 , 200 , 400 , 600 , 800 , and 1000 s / mm . intravoxel incoherent motion analysis was independently and double - blindly performed by 2 observers ( h.j and l.f , each with 10 years of experience in head and neck radiology ) who were blinded to the pathological results of all nasopharyngeal lesions . first , the axial image section showing the primary tumor at its widest cross - section was firstly determined by using dwi ( b = 800 s / mm ) , t2-weighted and contrast - enhanced t1-weighted images as references . then , 3 regions of interest ( rois ) were manually drawn by each observer for each tumor on axial t2-weighted images at its widest section plus adjacent up and down sections , covering as much of the nasopharyngeal tumor as possible while avoiding the areas of necrosis , air , large vessels , and adjacent anatomical structures ( ie , fat , muscle , bone ) and then subsequently coregistered to ivim dwi images for further analysis . each ivim - based metric value was acquired by each observer , and correspondingly 2 initial data points were generated , each of which was the average of the values obtained from the 3 rois by 1 observer . the eventual metric value for each tumor was the mean value of the 2 initial data points . the values of the ivim - based parameters for each tumor type are expressed as mean ( sd ) . a flow - related parameter was calculated from the product of f and d * , denoted as fd*. the mann - whitney u test was used to compare the values of the ivim - based parameters between the npc and lymphoma groups . receiver operating characteristic ( roc ) curves were generated with respective cutoff values determined to accommodate best diagnostic accuracy according to the youden index . all statistical analyses were performed using spss v19.0 software ( spss inc , chicago , ill ) . this retrospective study was approved by the medical ethics committee of our institution and informed consent was obtained from all patients . we retrospectively analyzed the data of patients with newly diagnosed , pathologically confirmed nasopharyngeal lymphoma or npc at our hospital from december 2014 to april 2015 . the main inclusion criterion was that the patients had successfully undergone conventional mri and ivim dwi of the nasopharynx before treatment . the main exclusion criteria were as follows : ( 1 ) obvious motion or susceptibility artifacts around the skull base and paranasal sinuses on ivim dwi images , which could prevent the ivim analysis , or ( 2 ) difficulty in performing ivim analysis because of a small tumor volume , which leads to poor signal - to - noise on dwi images . in total , 102 patients including 82 with npc ( 80 nonkeratinizing , 2 keratinizing ) and 20 with lymphoma ( 15 b - cell non - hodgkin , 5 t - cell non - hodgkin ) were enrolled in the present study . the mean ( sd ) tumor volumes for lymphoma and npc were 11.884 ( 13.610 ) and 9.795 ( 10.772 ) cm , respectively . for patients with npc , the distribution of the t staging according to the 7th edition of the american joint committee on cancer was as follows : t1 , n = 8 ( 9.8% ) ; t2 , n = 29 ( 35.3% ) ; t3 , n = 19 ( 23.2% ) ; and t4 ; n = 26 ( 31.7% ) . all mri examinations were performed on a 1.5-tesla mri scanner ( optima mr360 ; ge healthcare , nj ) using a head and neck coil . the imaging protocol included axial t1-weighted spin - echo images ( repetition time [ tr]/echo time [ te ] , 580/7.8 milliseconds ; slice number , 36 ; 5-mm slice thickness , 1-mm slice gap , number of excitations [ nexs ] , 2 ) and axial t2-weighted spin - echo images with fat suppression ( tr / te , 6289/85 milliseconds ; slice number , 36 ; 5-mm section thickness , 1-mm intersection gap ; nex , 2 ) . in addition , for contrast - enhanced axial and coronal t1-weighted spin - echo image acquisition , the contrast agent gadodiamide ( omniscan ; ge healthcare ) was administrated intravenously at a dose of 0.1 mmol / kg of body weight . ten b values ( 0 , 50 , 80 , 100 , 150 , 200 , 400 , 600 , 800 and 1000 s / mm ) were applied with a single - shot diffusion - weighted spin - echo echo - planar or ss - se - dw - epi sequence . the lookup table of gradient directions was modified to allow multiple b value measurements in 1 series . a local shim box covering the nasopharyngeal region was applied to minimize susceptibility artifacts . in total , 12 axial slices covering the nasopharynx were obtained with a 22-cm field of view , 5-mm slice thickness , 1-mm slice gap , tr of 4225 milliseconds , te of 106 milliseconds , 128  130 matrix , and 4 nex for all b values . all ivim dwi data were transferred to an advantage workstation with functool software ( version aw 4.6 ; ge medical systems ) for postprocessing . intravoxel incoherent motion analysis was performed using cinetool kit , a software package for multiple adc measurements in the functool software package , and fitted on a pixel - by - pixel basis according to the levenberg - marquardt algorithm . according to the ivim theory described by le bihan and turner , the signal intensities and b values are related as follows : where sb is the signal intensity with diffusion gradient b ; s0 is the signal intensity for a b value of 0 s / mm ; d is the true diffusion coefficient ( square millimeter per second ) indicating the pure diffusion of water molecular ; f is the microvascular volume fraction , representing the fraction of diffusion related to microcirculation perfusion ; and d * is the pseudodiffusion coefficient ( square millimeter per second ) caused by microcirculation perfusion . because d * is roughly 1 order of magnitude greater than d  bd * would be less than 3 at a high b value ( > 200 s / mm ) , and the term f exp ( bd * ) would be less than 0.05 f. in this case , the contribution of d * to the signal ratio sb / s0 can be neglected , and equation 1 was simplified as equation 2 for an estimation of d : hence , for high b values ( 400 , 600 , 800 , and 1000 s / mm ) , sb was first fitted to equation 2 using a linear model , and d was calculated . secondly , fixing d at the value estimated previously and considering measurements from all 9 b values , d * and f were determined from equation 1 by a nonlinear levenberg - marquardt method . finally , the adc was calculated from the traditional adc equation , equation 3 , using data at b values of 0 , 200 , 400 , 600 , 800 , and 1000 s / mm . intravoxel incoherent motion analysis was independently and double - blindly performed by 2 observers ( h.j and l.f , each with 10 years of experience in head and neck radiology ) who were blinded to the pathological results of all nasopharyngeal lesions . first , the axial image section showing the primary tumor at its widest cross - section was firstly determined by using dwi ( b = 800 s / mm ) , t2-weighted and contrast - enhanced t1-weighted images as references . then , 3 regions of interest ( rois ) were manually drawn by each observer for each tumor on axial t2-weighted images at its widest section plus adjacent up and down sections , covering as much of the nasopharyngeal tumor as possible while avoiding the areas of necrosis , air , large vessels , and adjacent anatomical structures ( ie , fat , muscle , bone ) and then subsequently coregistered to ivim dwi images for further analysis . each ivim - based metric value was acquired by each observer , and correspondingly 2 initial data points were generated , each of which was the average of the values obtained from the 3 rois by 1 observer . the eventual metric value for each tumor was the mean value of the 2 initial data points . the values of the ivim - based parameters for each tumor type are expressed as mean ( sd ) . a flow - related parameter was calculated from the product of f and d * , denoted as fd*. the mann - whitney u test was used to compare the values of the ivim - based parameters between the npc and lymphoma groups . receiver operating characteristic ( roc ) curves were generated with respective cutoff values determined to accommodate best diagnostic accuracy according to the youden index . all statistical analyses were performed using spss v19.0 software ( spss inc , chicago , ill ) . the values of the ivim - based parameters for npc and lymphoma are summarized in table 1 . figures 1 and 2 show representative images of npc and lymphoma , respectively . from the roc curve analysis , the respective optimal cutoff values of the ivim - based parameters ( with their respective area under the curve ( auc ) , sensitivity , and specificity ) are shown in table 2 and figure 3 . for differentiation , fd * had the highest auc ( 0.960 ) , d and fd * had the highest specificity ( 100% ) , whereas adc had the highest sensitivity ( 93.90% ) . comparing the ivim - based parameter values between npc and lymphoma using the mann - whitney u test representative images of npc . images 1a to 1e are axial t2-weighted images , adc , d , d * , and f maps , respectively . the adc , d , d * , and f values of the lesion were 0.890  10 , 0.669  10 , 13.426  10 mm / s , and 0.153 , respectively . representative images of a lymphoma . images 2a to 2e are axial t2-weighted images , adc , d , d * , and f maps , respectively . the adc , d , d * and f values of the lesion were 0.734  10 , 0.545  10 , and 5.925  10mm / s , and 0.149 , respectively . optimal cutoff values for differentiation between npc and lymphoma based on roc curve analysis receiver operating characteristic curves for the ivim - based parameter values with their respective areas under the curves . our data showed that npc and lymphoma had distinctive ivim - based diffusion and perfusion characteristics , suggesting that ivim dwi may be potentially useful for detecting the tissue characteristics of nasopharyngeal tumors and differentiating npc from lymphoma . in our study , npc had a higher adc value than lymphoma , which was similar to an earlier study by fong et al but different from a report by ichikawa et al . in the study , the adc value of nasopharyngeal lymphoma ( [ 0.528 { 0.094 }  10 mm / s ) was slightly lower than that of npc ( [ 0.567 { 0.057 }  10 mm / s ) , but the difference lacked statistical significance . this might be because of the small number of nasopharyngeal cases ( 8 npcs and 7 lymphomas ) enrolled in the study . apparent diffusion coefficient , a combination of d and d * , reflects the total diffusion within the tissue , including the pure diffusion and the perfusion - related diffusion of water molecular . therefore , lymphoma exhibited a lower adc value than npc in our study , suggesting a lower level of pure diffusion and/or perfusion - related diffusion in lymphoma . for adc , a cutoff value of 0.761  10 mm / s allows for differentiation between the 2 groups with a moderate auc value of 0.781 , a high sensitivity of 93.90% , and a low specificity of 55.00% , making it an useful imaging marker , which will require further improvement in its diagnostic efficacy . corresponding to the pure motion of water molecular , d depends mainly on the cell density and the composition of the extracellular matrix . d is generally believed to be inversely correlated with the tissue cellularity and the nuclear - to - cytoplasm ratio . therefore , a reduced cellularity or low nuclear - to - cytoplasm ratio may result in an increased diffusivity of water molecular . in addition , necrosis and cystic changes in tissues may also lead to an increase of the diffusivity . in the present study , the significant difference in d value between npc and lymphoma might result from differences in the microstructure between the 2 tumors . compared with npc , lymphoma is believed to be composed of condensed tumor cells with little cytoplasm , scarce amounts of stroma and necrosis . these differences in histological structure probably account for the lower d and adc values observed in lymphoma compared with npc . for d , a cutoff value of 0.660  10 mm / s could discriminate the 2 tumors with a moderate auc value of 0.802 and a low sensitivity of 54.88% but with a very high specificity of 100.00% , suggesting that d may serve as an important imaging marker and that tumoral cellularity may be a key histological characteristic for differentiation between npc and lymphoma . according to the ivim theory , d * is proportional to the average blood velocity and the mean capillary segment length , which indicates that d * is linked to vascularity and perfusion in tissues . it is well - known that npc usually presents abundant vessels and hyperperfusion . by contrast , lymphoma is always associated with poor perfusion , compared with squamous cell carcinomas in the head and neck . a previous study confirmed that lymphoma showed significantly lower perfusion than npc . in our study , lymphoma presented a much lower d * value than npc , indicating that there is lower tumoral vascularity and perfusion in lymphoma than in npc . to differentiate the 2 tumors , the optimal cutoff value for d * was 7.89  10 mm / s , with a moderate sensitivity of 82.93% , a moderate specificity of 85.00% , and the second highest auc of 0.898 among all the ivim - based parameters , demonstrating that d * is a potentially valuable predictor for differentiation . apart from d * , f is another perfusion - related ivim - based parameter corresponding to the fractional volume ( percent ) of capillary blood flowing in each voxel . specifically , f is the ratio of the volume occupied by the mri - detectable water in the capillary networks . in fact , f was found to correlate well with microvessel density and perfusion parameters . however , paradoxical findings of f have been recorded in several other tumors including npc , lung cancer , and prostate cancer . our data showed that npc had a higher f value than lymphoma , but the difference in f value between the 2 tumors was far less significant than those in the other ivim - based parameters . in our study , the difference in f value between npc and lymphoma was slight and just reached a statistical significance , which disagrees with the observation that npc always exhibits more evident hyperperfusion than lymphoma . the possible reasons for these conflicting results might be related to the mri protocols and tissue characteristics under a magnetic field , which need to be verified in further studies . for example , the measurement of f was found to be greatly dependent on the te and the t2 relaxation time . during ivim dwi , a longer te would cause a greater signal decay at low b values , and consequently , the f value would increase . this te dependence effect would probably be significant for ivim dwi on organs exhibiting short t2 time similar to blood , such as npc and lymphoma . in a previous ivim dwi study on the nasopharynx using a relatively long te of 58 milliseconds , the f value for npc was significantly lower than that for enlarged adenoids , inconsistent with the increased perfusion , which is commonly associated with malignant tumors such as npc . in addition , a longer t2 time for the tissue will result in a lower measured value of f. the t2 time was thought to vary greatly among different tumors . however , to our knowledge , few published studies have described the exact t2 time for npc or lymphoma . wang et al found that small foci of necrosis and cystic change were confirmed by pathologic examination but were not detected on mri images in head and neck tumors . simultaneously , it is well - known that necrosis and cystic changes are more common in npc than in lymphoma . therefore , we propose that the t2 time for npc might be longer than that for lymphoma , leading to a smaller difference in f value between npc and lymphoma . this may be similar to the suggestion by wang et al that a higher f value in obstructive pulmonary consolidation than in lung cancer might be due to exudation . another blood flow - related ivim - based parameter , fd * , is equal to the product of f and d*. in brain , fd * was suggested to be directly proportional to the cerebral blood flow , and it could be used to estimate the relative perfusion or blood flow in tissues . parameter fd * is believed to depend on the relationships among the microvascular anatomy , the vascular permeability , and the blood flow dynamics . lee et al found a moderate positive correlation between fd * value and dynamic contrast enhancement mri parameters in cervical cancers . federau et al demonstrated that the fd * value for the visual cortex and white matter increased during visual stimulation . in another study by federau et al , 
 d * and fd * values were significantly larger during systole than during diastole , whereas d and f values were not obviously altered in the brain of healthy human . in our study , there was a prominent difference in fd * value between npc and lymphoma , indicating that the 2 tumors differ markedly from each other in their microcirculatory anatomy and function . based on the roc analysis , the optimal cutoff value for fd * was 1.99  10 mm / s , with a moderate sensitivity of 85.37% and a very high specificity of 100.00% for differentiation . furthermore , fd * had the largest auc value of 0.960 among all the ivim - based parameters , with a 95% confidence interval ( ci ) from 0.902 to 0.989 , and it did not overlap with any other ivim - based parameter , revealing that it might be a potentially valuable predictor for differentiation between npc and lymphoma . unfortunately , fd * and d * had the largest sds among the 5 ivim - based parameters evaluated in our study , which would severely limit their clinical application . the large standard deviation of d * indicates a poor reproducibility associated with the measurement of parameter d * , which has been widely reported . possible reasons for this poor reproducibility include the distortion of dwi , pulsation artifacts from the heart or great vessels without electrocardiograph gating , noisy d * map , and microvessel density scores that also often show large variations across the tumors . therefore , the image quality and signal - to - noise ratio for fd * and d * on ivim dwi should be improved to make the 2 parameters more reliable . second , we did not correlate the ivim - based parameters with histological features , such as tumor cell density , nuclear - to - cytoplasm ratio , and microvessel density . however , the pathological diagnosis of nasopharyngeal tumors is usually based on biopsy specimens , which are always small and obtained from the surface of the lesions . it is well - known that malignant tumors often exhibit histological heterogeneity , namely , the surface region of a tumor is always associated with greater vascularity and less necrosis on a microscopic level in comparison of the central area . therefore , the pathological features of biopsy specimens may not comprehensively reflect those of the entire tumor . thirdly , the ivim analysis in our study was based on drawing an roi covering the entire solid parenchyma of the tumors to survey the mean value . nevertheless , the information gathered from the entire tumor might be more readily applicable to tumor evaluation . our ivim analysis excluded grossly visible necrosis in tumors , whereas cystic or necrotic portions of tumors might significantly affect the measurements of ivim - based parameters . further studies using regional hot - spot analysis , intratumor pixel - by - pixel analysis , and analysis of the cystic or necrotic portions might be meaningful for comprehensively characterizing different tumors . in conclusion , our preliminary study shows that npc exhibits different ivim - based imaging features from lymphoma . intravoxel incoherent motion dwi is potentially useful for differentiation between the 2 nasopharyngeal tumors , which often present a clinical diagnostic dilemma . considering that fd * and d * are usually more variable
objectivethe aim of the study was to investigate the utility of intravoxel incoherent motion ( ivim ) diffusion - weighted magnetic resonance imaging ( dwi ) for differentiating nasopharyngeal carcinoma ( npc ) from lymphoma.methodsintravoxel incoherent motion  based parameters including the apparent diffusion coefficient ( adc ) , pure diffusion coefficient ( d ) , pseudodiffusion coefficient ( d * ) , perfusion fraction ( f ) , and fd * ( the product of d * and f ) were retrospectively compared between 102 patients ( 82 with npc , 20 with lymphoma ) who received pretreatment ivim dwi.resultscompared with lymphoma , npc exhibited higher adc , d , d * , fd * values ( p < 0.001 ) and f value ( p = 0.047 ) . 
 the optimal cutoff values ( area under the curve , sensitivity , and specificity , respectively ) for distinguishing the 2 tumors were as follows : adc value of 0.761  103 mm2/s ( 0.781 , 93.90% , 55.00% ) ; d , 0.66  103 mm2/s ( 0.802 , 54.88% , 100.00% ) ; d * , 7.89  103 mm2/s ( 0.898 , 82.93% , 85.00% ) ; f , 0.29 ( 0.644 , 41.46% , 95.00% ) ; and fd * , 1.99  103 mm2/s ( 0.960 , 85.37% , 100.00%).conclusionsnasopharyngeal carcinoma exhibits different ivim - based imaging features from lymphoma . 
 intravoxel incoherent motion dwi is useful for differentiating lymphoma from npc .