Small (< 4 cm) Renal Mass: Differentiation of Oncocytoma From Renal Cell Carcinoma on Biphasic Contrast-Enhanced CT

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1 Geitouriary Imagig Origial Research Sasaguri et al. Differetiatig Ococytoma From RCC o Cotrast-Ehaced CT Geitouriary Imagig Origial Research Kohei Sasaguri 1,2 Naoki Takahashi 1 Daiel Gomez-Cardoa 1 Shuai Leg 1 Grat D. Schmit 1 Rickey E. Carter 3 radley C. Leibovich 4 kira Kawashima 1 Sasaguri K, Takahashi N, Gomez-Cardoa D, et al. Keywords: CT, differetial diagosis, kidey, real cell carcioma, real ococytoma DOI:1214/JR Received October 9, 2014; accepted after revisio February 26, Departmet of Radiology, Mayo Cliic, 200 First St SW, Rochester, MN ddress correspodece to N. Takahashi (Takahashi.Naoki@mayo.edu). 2 Preset address: Departmet of Radiology, Faculty of Medicie, Saga Uiversity, Saga, Japa. 3 Departmet of Health Scieces Research, Mayo Cliic, Rochester, MN. 4 Departmet of Urology, Mayo Cliic, Rochester, MN. This article is available for credit. JR 2015; 205: X/15/ merica Roetge Ray Society Small (< 4 cm) Real Mass: Differetiatio of Ococytoma From Real Cell Carcioma o iphasic Cotrast-Ehaced CT OJECTIVE. The purpose of this study was to evaluate whether small (< 4 cm) ococytomas ca be differetiated from real cell carciomas (RCCs) o biphasic cotrast-ehaced CT. MTERILS ND METHODS. Forty-three patiets with 53 ococytomas ad 123 patiets with 128 RCCs (24 papillary subtype ad 104 clear cell ad other subtypes) who uderwet biphasic cotrast-ehaced CT were icluded i the study. Patiet demographics ad CT tumor characteristics were evaluated i each case. multiomial logistic regressio model was the costructed for differetiatig ococytoma from clear cell ad other subtype RCCs, ococytoma from papillary RCCs, ad clear cell ad other subtype RCCs from papillary RCCs. The probability of each group was calculated from the model. Diagostic performace amog three pairwise diagoses ad betwee ococytoma ad ay RCC (clear cell ad other subtypes ad papillary) were assessed by UC values. RESULTS. Patiet age, tumor CT atteuatio values ad skewess (i.e., histogram aalysis of CT values) i both the corticomedullary ad ephrographic phases, ad subjective tumor heterogeeity were statistically sigificat variables i the multiomial logistic regressio aalysis. The logistic regressio model usig the variables yielded UCs of 2, 5, 1, ad 4 for differetiatig ococytomas from clear cell ad other subtype RCCs, ococytomas from papillary RCCs, clear cell ad other subtype RCCs from papillary RCCs, ad ococytomas from ay RCC (clear cell ad other subtypes ad papillary), respectively. CONCLUSION. combiatio of imagig features o biphasic CT, icludig tumor CT atteuatio values ad tumor texture (heterogeeity ad skewess), ca help differetiate ococytoma from RCC. T wety percet to 30% of solid real tumors smaller tha 4 cm are beig, ad of these beig lesios, more tha half are ococytomas [1, 2]. I view of the beig course ad excellet progosis of patiets with real ococytomas, active surveillace has bee icreasigly adopted as a treatmet strategy [3, 4]. Thus, it would be helpful to have a CT algorithm that could help to more cofidetly differetiate ococytoma from real cell carcioma (RCC). Classically described imagig fidigs of ococytoma (i.e., well-differetiated margis; homogeeous ehacemet without hemorrhage, calcificatio, or ecrosis; ad cetral stellate scar) are ot cosidered diagostic because of cosiderable overlap with RCC [5, 6]. I recet studies, segmetal ehacemet iversio o biphasic MDCT has bee reported as a fidig specific for real ococytoma [7, 8]. However other ivestigators have reported this fidig to be ifrequet ad ot characteristic of ococytoma [9, 10]. The purpose of this study was to determie whether small ococytomas ca be differetiated from RCCs by evaluatig a combiatio of tumor imagig characteristics o biphasic cotrast-ehaced CT. lthough o sigle imagig feature has bee idetified to cofidetly differetiate ococytoma from RCC, we hypothesized that diagostic accuracy could be improved by combiig multiple imagig features. Materials ad Methods Patiets This retrospective study was approved by our istitutioal review board ad is compliat with the HIP. ll patiets had previously coseted to the use of their medical records for research purposes. flowchart of patiet selectio is show i Figure 1. etwee Jauary 2003 ad Jauary 2011, 961 RCCs ad 168 ococytomas JR:205, November

2 Sasaguri et al. were diagosed histologically after surgical removal of primary real tumors smaller tha 4 cm i diameter at our istitutio. Durig the same period, 269 RCCs ad 67 ococytomas were diagosed by core eedle biopsy before percutaeous ablatio therapy for real tumors smaller tha 4 cm i diameter. Twety-three tumors diagosed as ococytic eoplasm by biopsy (ot diagostic of RCC or ococytoma) were excluded. Of these, all ococytomas ad oe half of RCCs were icluded i the study. We the selected patiets who uderwet multiphase cotrast-ehaced CT, icludig both corticomedullary ad ephrographic phases. Predomiatly cystic masses without a measurable solid compoet (i.e., septatios or mural odule smaller tha a few millimeters) were excluded (four RCCs). mog the remaiig patiets, ie had multiple ococytomas ad four had multiple RCCs; i these cases, up to three of the largest masses for each patiet were icluded i the evaluatio. The fial cohort icluded 43 patiets with 53 ococytomas (23 me ad 20 wome; mea age, 66.8 years) ad 123 patiets with 128 RCCs (82 me ad 41 wome; mea age, 61.9 years). Fourtee ococytomas ad 35 RCCs were diagosed by biopsy. Subtypes of RCC icluded 92 clear cell RCCs, 24 papillary RCCs, ad 12 other subtypes of RCC (three chromophobe RCCs, two combied clear cell ad papillary RCCs, ad seve RCCs of ucertai type). CT Protocol ll patiets uderwet multiphase cotrast-ehaced CT icludig both corticomedullary ad geeralized ephrographic phases. Our stadard CT real scaig protocol icludes tube voltage of 120 kvp, tube curret of m (depedig o patiet size), pitch of 84, slice thickess of 5.0 mm, IV ijectio of 140 ml of oioic cotrast material (iohexol, Omipaque 300, GE Healthcare) at a ijectio rate of 3 ml/s, ad scaig delays of 45 secods for the corticomedullary phase ad 90 secods for the ephrographic phase. Twety-eight patiets who uderwet CT at outside istitutios lacked records of amout ad ijectio rate of iodiaed cotrast material ad scaig delay time. dequacy of the phases (corticomedullary or ephrographic) was determied subjectively for these patiets. The corticomedullary phase was judged as adequate whe the real cortex ehaced brightly ad was easily differetiated from the miimally ehacig real medulla. The ephrographic phase was judged as adequate whe the real parechyma ehaced homogeeously but little or o cotrast material was excreted ito the collectig system. Slice thickess o these outside examiatios was variable ad raged from 1.3 to 6.5 mm (mea, 3.8 mm). CT Image alysis CT images were reviewed o a workstatio (dvatage for Widows versio 4.6, GE Healthcare). We recorded pertiet real tumor imagig features refereced i previous articles [11 14]. ll these features were assessed o the trasverse images. Reviewers were blided to the pathologic diagosis. Subjective Radiologic Features Cetral scar, agular iterface sig, pseudocapsule, cystic compoet, calcificatio, segmetal ehacemet iversio, degree of exophytic growth of the tumor, ad subjective heterogeeity of the tumor were retrospectively ad idepedetly assessed by two radiologists (with 8 ad 13 years of experiece i abdomial imagig). The locatio of each mass was give to the reviewers to avoid cofusio i patiets with more tha oe real mass. cetral scar was defied as a cetral stellate hypodesity i corticomedullary phase with or without progressive ehacemet i ephrographic phase. agular iterface sig was cosidered to be preset whe the tumor showed exophytic growth with a agular-shaped itraparechymal compoet ad a rouded exophytic compoet. Segmetal ehacemet iversio was determied to be preset whe the real tumor had two differetly ehacig segmets o corticomedullary phase images, with reversal of this ehacemet patter o the subsequet ephrographic phase images. pseudocapsule was defied as a high- or low-atteuatio rim surroudig the tumor. These subjective features were assessed as biary variables. The fial assessmet for discordat cases was made by cosesus review. The degree of exophytic growth of the tumor was graded by percetage of tumor outside the expected cotour of real parechyma (0 100% at 10% icremets). Subjective heterogeeity was rated usig a 3-poit gradig scale (1, homogeeous; 2, mildly heterogeeous; ad 3, markedly heterogeeous); the readers determied this gradig from either the corticomedullary or ephrographic phase images, whichever showed the most tumor heterogeeity. The degree of exophytic tumor growth ad subjective heterogeeity grade by the two readers were averaged for statistical aalysis. Objective Radiologic Features Objective features icluded maximal tumor diameter, CT atteuatio value of the tumor (Housfield uits) i both the corticomedullary ad ephrographic phases, ad quatitative tumor texture parameters measured by pixel distributio histogram of CT values, icludig etropy (irregularity of pixel distributio), skewess (skewess of pixel distributio), ad kurtosis (peakedess of pixel distributio) i both the corticomedullary ad ephrographic phase [15, 16] (equatios used to calculate etropy, skewess, ad kurtosis are show i ppedix 1). These parameters were measured by a sigle radiologist usig CT images i DICOM format exported to a PC. CT tumor atteuatio values ad texture parameters were calculated usig a Matlab (MathWorks) based software package developed i-house. Image-based deoisig was performed before calculatig the tumor texture [17]. The largest possible ellipsoid ROI was placed o the tumor for the largest crosssectioal area to calculate CT atteuatio ad tumor texture parameters, with careful attetio to avoid partial volume averagig from the adjacet ormal real parechyma ad periephric fat (Fig. 2). CT atteuatio value of the real cortex was measured i each phase. Stadard of Referece The stadard of referece was pathologic examiatio (official pathology report) for all tumors. Statistical alysis Uivariate aalysis was performed to compare patiet demographic data ad tumor radiologic features betwee the ococytomas ad RCCs. Clear cell RCCs ad papillary RCCs were aalyzed separately because they have distictly differet CT fidigs; other subtype RCCs were grouped alog with clear cell RCCs. Comparisos betwee the categoric data were tested usig the chi-square or Fisher exact probability test. Comparisos betwee the cotiuous data were tested usig the idepedet t test if ormal distributio was achieved; otherwise, the oparametric Ma- Whitey U test was used. I additio, the correlatio betwee subjective tumor heterogeeity ad etropy (objective tumor heterogeeity) was assessed with the Spearma rak correlatio coefficiet, usig the higher etropy value from either the corticomedullary or ephrographic phase. The oparametric Ma-Whitey U test was used to evaluate for a correlatio betwee tumor skewess ad subjective iteral tumor features (segmetal ehacemet iversio ad cetral scar). multiomial logistic regressio model was costructed for differetiatig ococytoma, clear cell ad other subtype RCCs, ad papillary RCCs. I this aalysis, the samplig fractio was cosidered whe weightig the observatios. Samplig weights were set by the prevalece of the lesio type i the etire case series divided by the prevalece of the lesio type i the sample i which imagig characteristics were studied. This allowed oversamplig of the less-commo lesio types ad provided a meas to correctly estimate positive predictive probabilities for each tumor group. Give this weightig schedule ad the feature vec JR:205, November 2015

3 Differetiatig Ococytoma From RCC o Cotrast-Ehaced CT TLE 1: Summary of Variables ad Uivariate alyses p Variables Ococytoma Clear Cell ad Other Subtype RCC Papillary RCC tor cotaiig primarily lesio-level attributes, tumors were treated as statistically idepedet durig modelig. The modelig was iitially performed such that all idepedet variables were etered as covariates. Stepwise selectio was the used util oly variables with p values for the likelihood ratio test less tha 0.05 were retaied i the fial model. Fourfold cross-validatio was used to costruct the models. Three of the four sets were used to costruct each model, ad the remaiig set was used for validatio. The model givig the best validatio statistic was chose as the fial model. This fial fitted ad cross-validated model was the used to calculate probabilities for each lesio type: ococytoma, clear cell ad other subtype RCCs, ad papillary RCCs. These probabilities were adjusted for the tumor prevalece i the etire cohort (235 ococytomas ad 1230 RCCs). Diagostic performace of the model to differetiate ococytoma from ay RCC (clear cell ad other subtypes ad papillary), as well as the ability to differetiate each pair of tumor groups (ococytoma vs clear cell ad other subtype RCCs, ococytoma vs papillary RCC, ad clear cell ad other subtype RCCs vs papillary RCC) was evaluated usig ROC curves. To elaborate the effect of iclusio of patiets who uderwet CT at outside istitutios, patiet demographics, tumor histologic features, ad CT atteuatio of real cortex were compared betwee those patiets who uderwet CT at our istitutio ad those who did so at outside istitutio. Statistical aalyses were performed usig statistical software (JMP versio 10.0, SS Istitute), ad p < 0.05 was cosidered to be statistically sigificat. Ococytoma vs Clear Cell ad Other Subtypes Ococytoma vs Papillary Clear Cell ad Other Subtypes vs Papillary Demographic data ge (y) 67 ± ± ± a 0.08 Sex, male-to-female ratio 30:23 68:36 19: Subjective CT features, % (o./total) Cetral scar 11.3 (6/53) 9.6 (10/104) 0 (0/24) Segmetal ehacemet iversio 13.2 (7/53) 3.8 (4/104) 0 (0/24) 0.04 a 1 gular iterface sig 5.7 (3/53) 1.9 (2/104) 0 (0/24) 1 Cystic compoet 3.8 (2/53) 9.6 (10/104) 0 (0/24) 1 Calcificatio 0 (0/53) 1.9 (2/104) 0 (0/24) 1 1 Pseudocapsule 17.0 (9/53) 32.7 (34/104) 8.3 (2/24) 0.04 a 0.02 a Exophytic growth (%) b 44 ± ± ± 26 Subjective heterogeeity b 1.9 ± 2.2 ± 1.1 ± 0.08 < a < a Objective CT features Size (mm) 22 ± 8 26 ± ± a 0.06 CT atteuatio value i corticomedullary phase (HU) 136 ± ± ± a < a < a CT atteuatio value i ephrographic phase (HU) 126 ± ± ± 15 < a < a < a Etropy i corticomedullary phase 6.3 ± 6.5 ± 5.7 ± 0.07 < a < a Etropy i ephrographic phase 6.1 ± 6.2 ± 5.7 ± < a < a Skewess i corticomedullary phase 4 ± 1 2 ± ± a 0.03 a Skewess i ephrographic phase 2 ± 2 0 ± ± 0.06 Kurtosis i corticomedullary phase 3.7 ± ± 3.2 ± 0.05 Kurtosis i ephrographic phase 3.2 ± 3.1 ± 3.2 ± Note Except where oted otherwise, data are mea ± SD. RCC = real cell carcioma. a The compariso was statistically sigificat. b veraged score of two radiologists. Results Uivariate alysis The results of uivariate aalyses are summarized i Table 1. Tumor segmetal ehacemet iversio, pseudocapsule, subjective ad objective heterogeeity (etropy), CT atteuatio values i both the corticomedullary ad ephrographic phases, ad skewess i corticomedullary phase were statistically sigificat betwee at least oe pair of the three groups. Segmetal ehacemet iversio was observed i seve of 53 (13.2%) ococytomas, four of 104 (3.8%) clear cell ad other subtype RCCs, ad zero of 24 (0.0%) papillary RCCs. Pseudocapsule was observed i 34 of 104 (32.7%) clear cell ad other subtypes, ie of 53 (17.0%) ococytomas, ad two of 24 (8.3%) papillary RCCs. Ococytomas showed slightly higher CT atteuatio values i the corticomedullary phase compared with clear cell ad other subtype RCCs, ad this differece icreased further i the ephrographic phase. Papillary RCCs showed distictly lower ehacemet tha did the other tumor groups. Ococytomas teded to be slightly more homogeeous tha JR:205, November

4 Sasaguri et al. TLE 2: Results of Multiomial Logistic Regressio alysis Ococytoma vs Clear Cell ad Other Subtype RCC Ococytoma vs Papillary RCC Clear Cell ad Other Subtype RCC vs Papillary RCC Rage of Parameters (1/3 of Rage) Coefficiet OR a (95% CI) Rage of Parameter (1/3 of Rage) Coefficiet OR a (95% CI) Rage of Parameters (1/3 of Rage) Coefficiet OR a (95% CI) Variable Costat ge (y) (20) ( ) (20) (6 6.2) (16) (9 1.4) CT atteuatio values i (92) ( ) (76) (0 115) (92) (0 1029) corticomedullary phase (HU) CT atteuatio values i (61) ( ) (62) (4 2282) (60) ( ) ephrographic phase (HU) Skewess i 2.64 to 1.63 (1.4) ( ) 1.53 to 1.63 (1.1) 1 3 ( ) 2.64 to 0 (1.2) (2 30) corticomedullary phase Skewess i ephrographic 1.20 to 3 (8) ( ) 1.20 to 3 (8) (9 23) 1.03 to 2 (8) (5 4.7) phase Subjective heterogeeity 1 3 (1) 6 (5 0) 1 3 (1) (3 5.5) 1 3 (1) ( ) Note RCC = real cell carcioma. a Odds ratio (OR) is reported for chage i oe third of the parameter rage istead of per uit chage so that relative cotributio of each parameter ca be estimated. clear cell ad other subtype RCCs o both subjective assessmet ad objective heterogeeity evaluatio (etropy). Papillary RCCs were statistically sigificatly more homogeeous tha the other tumor groups, ad subjective tumor heterogeeity ad etropy were strog predictors of tumor type (correlatio coefficiet, 4). Skewess i the corticomedullary phase was statistically sigificatly lower i tumors with a cetral scar tha those without a cetral scar (p = 0.047), but skewess i ephrographic phase was ot statistically sigificatly differet (p = 9). Skewess was also ot statistically sigificatly differet betwee tumors with or without segmetal ehacemet iversio i either phase (p = 1 i corticomedullary phase; p = 6 i ephrographic phase). Multivariate alysis The results of multiomial aalyses are summarized i Table 2. Tumor CT atteuatio values ad skewess (histogram aalysis of CT values) i both the corticomedullary ad ephrographic phases, subjective tumor heterogeeity, ad patiet age were statistically sigificat variables i the multiomial logistic regressio aalysis. Whe oe third of each parameter rage was used to compare relative cotributio for each of these tumor characteristics, CT atteuatio values i the ephrographic phase had the largest chage i log-odds for differetiatig ococytomas from clear cell ad other subtype RCCs ad ococytomas from papillary RCCs, skewess i the corticomedullary phase was the secod most importat factor for differetiatig ococytomas from clear cell ad other subtype RCCs. CT atteuatio value i the corticomedullary phase was the secod most importat factor for differetiatio ococytomas from papillary RCCs. Fial probabilities of each group calculated from the model with prevalece adjustmet are show o terary plots (Fig. 3). UCs for differetiatig ococytomas from clear cell ad other subtype RCCs, ococytomas from papillary RCCs, ad clear cell ad other subtype RCCs from papillary RCCs were 2, 5, ad 1, respectively. The UC for differetiatig ococytomas from ay RCC (clear cell ad other subtype RCCs ad papillary RCC) was 4. Sesitivity, specificity, ad prevalece-adjusted positive predictive value at represetative cutoff values of probability of ococytoma are show i Table 3. Case examples are show i Figures 4 6. Compariso etwee Patiets Who Uderwet CT at Our Istitutio ad at Outside Istitutios Oe hudred thirty-eight patiets with 152 real masses uderwet CT at our istitutio, whereas 28 patiets with 29 real masses uderwet CT at outside istitutios. There were o statistically sigificat differeces betwee mea patiet age (63.3 vs 61.1 years old; p = ), male-to-female ratio (100:52 vs 17:12; p = ), ad real mass pathologic profiles (48 ococytomas, 84 clear cell ad other subtype RCCs, ad 20 papillary RCCs vs 5 ococytomas, 20 clear cell ad other subtype RCCs, ad 4 papillary RCCs; p = ), whereas ehacemet of the real cortex was statistically sigificatly higher i patiets who uderwet CT i our istitutio versus outside istitutios (184 ± 56 HU vs 156 ± 46 HU o corticomedullary phase, p = 0.01; ad 172 ± 38 HU vs 150 ± 36 HU o ephrographic phase, p < 0.01). Discussio Several studies have described CT features of real ococytomas (i.e., well-differetiated margis; homogeeous ehacemet without hemorrhage, calcificatio, or ecrosis; ad the presece of a cetral stellate scar). However, these features are ot cosidered diagostic of real ococytomas because there is cosiderable overlap with RCCs [11, 13]. Kim et al. [7] idetified tumor segmetal ehacemet iversio o biphasic MDCT to be both a sesitive ad specific idicator of real ococytoma, ad a study by Woo et al. [18] reported this fidig to be preset i 17 of 33 (51.5%) ococytomas. However, other ivestigators have reported segmetal ehacemet iversio to be a ifrequetly idetified characteristic of ococytomas (0 12.5%) [9, 10] JR:205, November 2015

5 Differetiatig Ococytoma From RCC o Cotrast-Ehaced CT TLE 3: Diagostic Performace i Differetiatio of Ococytoma From Clear Cell ad Other Subtype Real Cell Carcioma (RCC) ad Papillary RCC Probability of Ococytoma (%) Sesitivity (%) Specificity (%) PPV (%) a > (33/53) [ ] 89.1 (114/128) [ ] 52.2 > (24/53) [ ] 93.0 (119/128) [ ] 55.3 > (20/53) [ ] 96.9 (124/128) [ ] 69.9 > (15/53) [ ] 97.7 (125/128) [ ] 7 Note Data are percetage (o. of cases/totals) [95% CI]. PPV = positive predictive value. a PPV was adjusted to the prevalece of origial cohort (235 ococytomas ad 1230 RCCs). I our study, segmetal ehacemet iversio was statistically sigificatly more commo i ococytomas (13.2%) tha RCCs (3.1%), but it was ot a statistically sigificat parameter i the multiomial logistic regressio aalysis. Oe of the reasos for the discrepacy i the prevalece of this fidig might be attributed to the differece i CT protocol [18]. I our study, the sca delays for the corticomedullary ad ephrographic phases were 45 secods ad 90 secods i most cases, whereas secods ad secods were used i the studies by Kim et al. [7] ad Woo et al. [18]. Our shorter iterval betwee the first ad secod phase of cotrast ehacemet may ot have allowed eough time for the tumor ehacemet patter to reverse. mog other subjective radiologic features (cetral scar, agular iterface sig, pseudocapsule, cystic compoet, calcificatio, subjective heterogeeity, ad exophytic growth), oly subjective heterogeeity was a statistically sigificat factor i the multiomial logistic regressio aalysis. The degree ad patter of ehacemet o multiphase cotrast-ehaced CT were the most importat parameters for differetiatig ococytomas from RCCs i our study. Several studies have focused o real tumor ehacemet patters [11, 12, 19 21]. I a study icludig oly tumors smaller tha 4 cm [20], the peak ehacemet more commoly occurred i the ephrographic phase i ococytomas, whereas it occurred more commoly i the corticomedullary phase i clear cell RCCs. study usig multiphasic cotrast-ehaced MRI also showed a similar ehacemet patter [21]. I the study by Youg et al. [22], both ococytomas ad clear cell RCCs showed peak ehacemet i the corticomedullary phase, but the degree of deehacemet i the ephrographic phase was smaller for ococytomas tha for clear cell RCCs. These results idicate that a smaller degree of deehacemet i the ephrographic phase may be a feature of ococytomas. Ideed, our study showed that ococytomas had lesser deehacemet, ad the higher CT atteuatio values i the ephrographic phase icreased the probability of a diagosis of ococytoma i the logistic regressio model. Our study showed that ococytomas ehaced more i both the corticomedullary ad ephrographic phases tha did clear cell ad other subtype RCCs, whereas clear cell RCCs ehaced more tha ococytomas did i the study by Youg et al. We speculate that the differece i the way the ROIs were draw betwee the two studies may have cotributed to this disparity. Youg et al. placed a relatively small ROI o the most avidly ehacig part of the lesio, whereas we placed the largest possible ROI o the tumor because we thought this method would be more reproducible. Differeces i CT atteuatio values betwee the two measuremet methods were likely larger i clear cell RCCs because of the high prevalece of low-atteuatio regios (i.e., degeeratio or ecrosis) see i this tumor group. Our study showed that papillary RCCs had distictly lower ehacemet i both the corticomedullary ad ephrographic phases tha did clear cell RCCs ad ococytomas, ad this is compatible with fidigs from prior studies [20, 22]. Subjective tumor heterogeeity has bee show to be a importat parameter for real tumor characterizatio [5, 6, 10 12, 19]. I our aalysis, papillary RCCs were the most homogeeous tumor. Ococytomas teded to be more homogeeous tha clear cell ad other subtype RCCs, although this fidig was ot statistically sigificat i the uivariate aalysis. I additio to subjective assessmet, we performed a quatitative tumor texture aalysis, icludig evaluatio of etropy, skewess, ad kurtosis. Texture aalysis is a image processig algorithm that ca be used to quatify texture by assessig the pixel distributio of CT values withi the tumor [15, 16]. Recet studies suggest that texture aalysis may serve as a importat imagig biomarker to predict progosis i patiets with cacer [15, 16, 23, 24] ad may be useful for tumor differetiatio [25, 26]. To our kowledge, however, this is the first study to use texture aalysis to differetiate real tumors o CT. Tumor etropy (objective heterogeeity) showed the same tedecy as subjective heterogeeity for tumor characterizatio, but this was ot a statistically sigificat variable i the multiomial logistic regressio aalysis. Tumor skewess i both the corticomedullary ad ephrographic phase was a statistically sigificat parameter i the multiomial logistic regressio aalysis. Skewess quatifies the symmetry of the pixel distributio histogram with respect to the mea CT values withi the ROI ad is ot iflueced by the absolute CT atteuatio values. Tumors with more low-ct-value pixels tha high-ctvalue pixels with respect to the mea have skewess values above zero ad vice versa. I our study, skewess i the corticomedullary phase was statistically sigificatly lower i tumors with a cetral scar. We speculate that the low-atteuatio cetral scar may create a log tail of lower-ct-value pixels withi the tumor. However, this speculatio does ot fully explai this differece i skewess. The diagostic performace of the proposed model is ot sufficiet to make the defiitive diagosis of ococytoma by itself. For example, the prevalece-adjusted predictive value was 52.2% to achieve a sesitivity of 62.3%, whereas the pretest predictive value was 16.0% (235/1465). Our proposed CT diagostic model could be icorporated i the diagostic algorithm ad could determie who should udergo biopsy before surgery or ablatio ad who could be followed (watchful waitig) without biopsy. There are a umber of limitatios to our study. First, the study was retrospective, ad a prospective validatio study was ot performed. Secod, CT techiques were variable, particularly those performed at outside istitutios. These icluded differeces i slice thickess, amout ad ijectio rate of iodiated cotrast material, ad sca delay. The ehacemet of real cortex was statistically sigificatly lower i patiets who uderwet CT at outside istitutios ( 13 15% i corticomedullary ad ephrographic phases). However, cosiderig that the umber of JR:205, November

6 Sasaguri et al. patiets evaluated at outside istitutios was small ad that there was o statistically sigificat differece i the distributio of real mass histologic profiles, we decided to iclude these patiets. Third, although tumor skewess i both the corticomedullary ad ephrographic phases by texture aalysis was idetified as a statistically sigificat parameter for differetiatig ococytomas from RCCs i our study, this fidig is difficult to completely explai, ad future studies will be ecessary to cofirm its importace for characterizig real masses. Fourth, ococytic tumors (ot diagostic of RCC or ococytoma) at biopsy were excluded from the study. I coclusio, a combiatio of multiple imagig features o biphasic cotrast-ehaced CT, icludig atteuatio values ad texture (heterogeeity ad skewess) of the tumor, ca help differetiate small (< 4 cm) ococytomas from RCCs. Refereces 1. Frak I, lute ML, Cheville JC, Lohse CM, Weaver L, Zicke H. Solid real tumors: a aalysis of pathological features related to tumor size. J Urol 2003; 170: Remzi M, Ozsoy M, Kligler HC, et al. re small real tumors harmless? alysis of histopathological features accordig to tumors 4 cm or less i diameter. J Urol 2006; 176: Kurup N, Thompso RH, Leibovich C, et al. Real ococytoma growth rates before itervetio. JU It 2012; 110: Kawaguchi S, Ferades K, Fielli, Robiette M, Flesher N, Jewett M. Most real ococytomas appear to grow: observatios of tumor kietics with active surveillace. J Urol 2011; 186: Qui MJ, Hartma DS, Friedma C, et al. Real ococytoma: ew observatios. Radiology 1984; 153: Davidso J, Hayes WS, Hartma DS, McCarthy WF, Davis CJ Jr. Real ococytoma ad carcioma: failure of differetiatio with CT. Radiology 1993; 186: Kim JI, Cho JY, Moo KC, Lee HJ, Kim SH. Segmetal ehacemet iversio at biphasic multidetector CT: characteristic fidig of small real ococytoma. Radiology 2009; 252: Woo S, Cho JY, Kim SH, Kim SY. Compariso of segmetal ehacemet iversio o biphasic MDCT betwee small real ococytomas ad chromophobe real cell carciomas. JR 2013; 201: McGaha JP, Lamba R, Fisher J, et al. Is segmetal ehacemet iversio o ehaced biphasic MDCT a reliable sig for the oivasive diagosis of real ococytomas? JR 2011; 197:[web] W674 W O Malley ME, Tra P, Habidge, Rogalla P. Small real ococytomas: is segmetal ehacemet iversio a characteristic fidig at biphasic MDCT? JR 2012; 199: Millet I, Doyo FC, Hoa D, et al. Characterizatio of small solid real lesios: ca beig ad maligat tumors be differetiated with CT? JR 2011; 197: Zhag J, Lefkowitz R, Ishill NM, et al. Solid real cortical tumors: differetiatio with CT. Radiology 2007; 244: Choudhary S, Rajesh, Mayer NJ, Mulcahy K, Haroo. Real ococytoma: CT features caot reliably distiguish ococytoma from other real eoplasms. Cli Radiol 2009; 64: Verma SK, Mitchell DG, Yag R, et al. 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7 PPENDIX 1: Equatios for Calculatig Etropy, Skewess, ad Kurtosis Differetiatig Ococytoma From RCC o Cotrast-Ehaced CT Etropy quatifies the homogeeity of the CT value histogram ad is calculated as follows: j max Etropy = p(j) log 2 p( j), (1) j = j mi where p(i) is the probability of image pixels havig a CT value of i, with i ragig from the miimal CT value (i mi ) to the maximal CT value (i max ) Patiets with real mass less tha 4 cm (surgery, 1214; biopsy, 457) betwee Jauary 2003 ad Jauary Patiets with ococytomas (surgery, 168; biopsy, 67) 43 Patiets with 53 ococytoma Icluded patiets who uderwet biphasic CT Skewess quatifies the asymmetry of the CT value histogram relative to the ormal distributio ad is calculated as follows: 1 (x j x) 3 j = 1 Skewess = 1 { (x j x) } 2 j = 1 3 2, (2) where, x is the mea of the CT value of all pixels, ad is the umber of pixels withi the ROI. histogram with a loger tail o the left side (lower CT value) teds to have a egative skewess value, whereas a histogram with a loger tail o the right side (higher CT value) teds have a positive skewess value Patiets with RCCs (surgery, 961; biopsy, Patiets with 128 RCCs (92 clear cell, 24 papillary, 3 chromophobe, 9 others) No. of Pixels Patiets excluded 91 giomyolipomas 75 Nodiagostic 23 Ococytic eoplasms 17 Others Half of patiets with RCCs ( = 615) were excluded at radom 4 Patiets excluded: cystic RCCs CT tteuatio Value (HU) Kurtosis quatifies the peakedess of the CT value histogram relative to the ormal distributio ad is calculated as follows: 1 (x j x) 4 j = 1 Kurtosis = 1 { (x j x) } 2 j = 1, (3) 2 where x j is the CT value of each pixel, x is the mea of the CT value of all pixels, ad is the umber of pixels withi the ROI. histogram with a distict peak ear the mea teds to have a high kurtosis value, whereas a histogram with flat top ear the mea teds to have a low kurtosis value. ormal distributio has a kurtosis value of 3. Fig. 1 Flowchart shows iclusio ad exclusio criteria adopted for our study. RCC = real cell carcioma. Fig. 2 Examples of ROI placemet ad histogram of CT values., 59-year-old woma with clear cell real cell carcioma. Largest possible roud ROI (circle) was placed over real mass., Example of histogram of CT values withi ROI, which results i etropy of 6.79, skewess of 1.24, ad kurtosis of JR:205, November

8 Sasaguri et al. Probability of Clear Cell ad Other Subtype RCC Probability of Ococytoma Probability of Clear Cell ad Other Subtype RCC Probability of Ococytoma Probability of Papillary RCC Probability of Papillary RCC C Probability of Clear Cell ad Other Subtype RCC Probability of Ococytoma Fig. 3 Terary plots of probabilities of ococytoma, clear cell ad other subtypes of real cell carcioma (RCC), ad papillary RCC. Data poits close to left lower apex, top apex, ad right lower apex are likely ococytomas, clear cell ad other subtype RCCs, ad papillary RCCs, respectively., Plots of ococytoma cases ( = 53). With cutoff value of probability of ococytoma > 50% (gray area), 20 of 53 ococytomas were correctly diagosed. May false-egative cases had high probability of clear cell ad other subtype RCC., Plots of clear cell ad other subtype RCC cases ( = 104). With cutoff value of probability of ococytoma < 50% (gray area), 100 of 104 cases of clear cell ad other subtype RCC were classified as RCC, but four cases were misclassified as ococytoma (false-positive). C, Plots of papillary RCC cases ( = 24). ll Papillary RCCs had probability of ococytoma of < 20% (gray area). Probability of Papillary RCC Fig year-old woma with ococytoma. ad, Trasverse cotrast-ehaced CT images show 3.2-cm mass i left kidey. Variables for logistic regressio models were age 66 years ad CT atteuatio values of 153 HU i corticomedullary phase () ad 179 HU i ephrographic phase (). Mea subjective heterogeeity score was 2.5 (average of two readers), skewess i corticomedullary phase was 8, ad skewess i ephrographic phase was 7. Calculated probability of ococytoma was 79%, ad lesio was correctly diagosed as ococytoma JR:205, November 2015

9 Differetiatig Ococytoma From RCC o Cotrast-Ehaced CT FOR YOUR INFORMTION Fig year-old woma with clear cell real cell carcioma (RCC). ad, Trasverse cotrast-ehaced CT images show 3.8-cm mass i left kidey. Variables for logistic regressio models iclude age 78 years ad CT atteuatio values of HU i corticomedullary phase () ad 66.9 HU i ephrographic phase (). Mea subjective heterogeeity score was 3, skewess i corticomedullary phase was 0.088, ad skewess i ephrographic phase was 9. Model correctly classified tumor as clear cell ad other subtype RCC (calculated probability of clear cell ad other subtype RCC, 94%). Fig year-old ma with ococytoma. ad, Trasverse cotrast-ehaced CT images show 3.3-cm mass i left kidey. Variables for logistic regressio models were age 62 years ad CT atteuatio values of HU i corticomedullary phase () ad HU i i ephrographic phase (). Mea subjective heterogeeity score was 2.5 (average of two readers), skewess i corticomedullary phase was 89, ad skewess i ephrographic phase was Calculated probability of ococytoma was 8%, ad lesio was icorrectly diagosed as real cell carcioma. This article is available for CME ad Self-ssessmet (S-CME) credit that satisfies Part II requiremets for maiteace of certificatio (MOC). To access the examiatio for this article, follow the prompts associated with the olie versio of the article. JR:205, November