Benign Renal Oncocytoma and Chromophobe Renal Cell Carcinoma Jay Amin1,Boxu2, Shervin Badkhshan1, Terrance T

Home , Kidney cancer, Oncocytoma, Renal cell carcinoma, Renal oncocytoma

Published OnlineFirst May 11, 2018; DOI: 10.1158/1078-0432.CCR-18-0252

Personalized Medicine and Imaging Clinical Cancer Research Identiﬁcation and Validation of Radiographic Enhancement for Reliable Differentiation of CD117(þ) Benign Renal Oncocytoma and Chromophobe Renal Cell Carcinoma Jay Amin1,BoXu2, Shervin Badkhshan1, Terrance T. Creighton1, Daniel Abbotoy1, Christine Murekeyisoni1, Kristopher M. Attwood3, Thomas Schwaab1,4,5, Craig Hendler6, Michael Petroziello6, Charles L. Roche6, and Eric C. Kauffman1,5,7

Abstract

Purpose: The diagnostic differential for CD117/KIT(þ) onco- ment ratio (PEER) using multiphase CT. Among 54 PEER- cytic renal tumor biopsies is limited to benign renal oncocytoma evaluable tumors in the retrospective cohort [19 CD117(þ), versus chromophobe renal cell carcinoma (ChRCC); however, 13 CD117(), 22 CD117-untested], PEER classified each cor- further differentiation is often challenging and requires surgical rectly as renal oncocytoma (PEER >0.50) or ChRCC (PEER resection. We investigated clinical variables that might improve 0.50), except for four misclassified CD117()ChRCCvar- preoperative differentiation of CD117(þ) renal oncocytoma ver- iants. Prospective study of PEER confirmed 100% accuracy of sus ChRCC to avoid the need for benign tumor resection. renal oncocytoma/ChRCC classification among 22/22 addi- Experimental Design: A total of 124 nephrectomy patients tional CD117(þ) tumors. Prospective interobserver reproduc- from a single institute with 133 renal oncocytoma or ChRCC ibility was excellent for PEER scoring (intraclass correlation tumors were studied. Patients from 2003 to 2012 comprised a coefficient, ICC ¼ 0.97) and perfect for renal oncocytoma/ retrospective cohort to identify clinical/radiographic variables ChRCC assignment (ICC ¼ 1.0). associated with renal oncocytoma versus ChRCC. Prospective Conclusions: In the largest clinical comparison of renal onco- validation was performed among consecutive renal oncocy- cytoma versus ChRCC to our knowledge, we identified and toma/ChRCC tumors resected from 2013 to 2017. prospectively validated a reproducible radiographic measure that Results: Tumor size and younger age were associated with differentiates CD117(þ) renal oncocytoma from ChRCC with ChRCC, and multifocality with renal oncocytoma; however, the potentially 100% accuracy. PEER may allow reliable biopsy-based most reliable variable for ChRCC versus renal oncocytoma diagnosis of CD117(þ) renal oncocytoma, avoiding the need for differentiation was the tumor:cortex peak early-phase enhance- diagnostic nephrectomy. Clin Cancer Res; 1–10. 2018 AACR.

Introduction amenable to partial nephrectomy. However, partial nephrectomy is associated with overall and high-grade complication rates of Historically, renal tumors have been treated as renal cell car- 25% to 30% and 10% to 15%, respectively, in addition to a small cinoma (RCC) until proven otherwise by surgical resection using decline in renal function and an estimated healthcare cost of partial or radical nephrectomy. Yet, at least 10% of resected renal $24,000 per resection (>$30,000 if complicated; refs. 3–7). On masses are benign (1, 2). The majority of resected benign tumors the basis of >60,000 new kidney tumor diagnoses in the United are asymptomatic renal oncocytomas with typically small size States annually (8) of which >90% are RCC (9), and a 5% incidence (range 3–7%) of renal oncocytoma among resected renal cell tumors (10, 11), renal oncocytoma resection can be 1Department of Urology, Roswell Park Cancer Institute, Buffalo, New York. 2Department of Pathology and Laboratory Medicine, Roswell Park Cancer estimated to incur an annual health care cost in the United States Institute, Buffalo, New York. 3Department of Biostatistics and Bioinformatics, of nearly 100 million dollars. Reliable preoperative renal onco- Roswell Park Cancer Institute, Buffalo, New York. 4Department of Immunology, cytoma diagnosis would allow signiﬁcant reductions in surgical Roswell Park Cancer Institute, Buffalo, New York. 5Department of Urology, State resections, patient morbidity, and healthcare costs. University of New York at Buffalo, Buffalo, New York. 6Department of Diagnostic 7 Currently, preoperative differentiation of renal oncocytoma Radiology, Roswell Park Cancer Institute, Buffalo, New York. Department of from RCC is aided by renal tumor biopsy, which has a high Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York. diagnostic rate, a low incidence of predominantly low-grade Note: Supplementary data for this article are available at Clinical Cancer complications, and a miniscule (<1:10,000) estimated risk of Research Online (http://clincancerres.aacrjournals.org/). tumor seeding in contemporary studies (12–17). Yet, biopsy is Corresponding Author: Eric C. Kauffman, Roswell Park Cancer Institute, Elm and still commonly deferred because RCC cannot be deﬁnitively ruled Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8498; Fax: 716-845-3300; out when the biopsy favors renal oncocytoma (18). The most E-mail: [email protected] common diagnostic challenge in this regard is the differentiation doi: 10.1158/1078-0432.CCR-18-0252 of renal oncocytoma from chromophobe RCC (ChRCC; 2018 American Association for Cancer Research. refs. 18–21). Renal oncocytoma and ChRCC share classic

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study to also consider the impact of CD117 positivity. We Translational Relevance hypothesized that certain clinical and/or radiographic features Current inability to reliably differentiate benign renal onco- might allow reliable preoperative differentiation of these two cytomas from renal cell carcinoma (RCC) using needle core renal tumor subtypes, particularly among classic CD117(þ) biopsy remains the primary reason behind routine surgical tumors for which the ChRCC/renal oncocytoma question on resection of these benign tumors, which is associated with biopsy is most relevant. Using both a retrospective discovery frequent perioperative morbidity and an estimated annual cohort and prospective validation cohort, we identified a simple health care cost approaching 100 million dollars in the United CT enhancement measure that differentiated renal oncocytoma States alone. Historically, the greatest challenge for preoper- from ChRCC with 100% accuracy and perfect interobserver ative renal oncocytoma diagnosis using biopsy has been reproducibility whenever CD117 was expressed; occasional inac- the difficult differentiation of this benign tumor from the curacy was limited strictly to CD117() tumor variants. This chromophobe RCC (ChRCC) subtype due to significant generalizable approach may facilitate renal oncocytoma versus histologic and molecular overlap, including common expres- ChRCC diagnosis among CD117(þ) oncocytic tumor biopsies sion of the CD117 biomarker. Here we retrospectively iden- and negate the need for CD117(þ) renal oncocytoma resection to tified and prospectively validated a simple radiographic rule out malignancy. measurement ("PEER") that achieved 100% (41/41 cases) accuracy in differentiating CD117(þ) renal oncocytoma from CD117(þ) ChRCC. In the setting of a CD117(þ) renal tumor Materials and Methods biopsy, a high PEER value may reliably confirm renal onco- Retrospective patient cohort cytoma diagnosis without the need for surgical resection, Institutional review board approval at Roswell Park Cancer allowing significant reductions in patient morbidity and Institute, a National Comprehensive Cancer Network institute, health care costs. was obtained for this study. A prospectively maintained nephrectomy database was queried to identify all patients who underwent partial or radical nephrectomy for pathologically confirmed renal oncocytoma or ChRCC between August 2003 and December oncocytic histology and also a remarkably similar molecular 2012. One patient with four hybrid renal oncocytoma-ChRCC biomarker profile (19, 20, 22, 23). In addition, eosinophilia that tumors was excluded from analyses due to indeterminate malig- is characteristic of renal oncocytoma can be mimicked by ChRCC, nant versus benign pathology (30, 31). CD117 and CK7 immu- which has predominant eosinophilia in 40% of cases and at least nostain results were obtained from pathology reports, and clas- some eosinophilic foci in most remaining cases (20). Both tumor sified as positive for moderate-to-strong/diffuse membranous subtypes are relatively indolent and appropriate for active sur- stain, or as negative for absent or weak/focal (<10%) stain veillance management. However, whereas renal oncocytoma is (25). Hematoxylin- and eosin-stained slides from a subset of benign, ChRCC has occasional metastatic potential and resection ChRCC tumors were scored retrospectively for eosinophilia tissue is warranted for select patients (24). percentage (0%–100%) and eosinophilia intensity (0–3þ)bya Biopsy differentiation of renal tumor subtypes has been aided genitourinary pathologist (B. Xu). by contemporary immunohistochemical biomarker panels. Most (70%) but not all renal oncocytoma and ChRCC tumors express Radiographic tumor measurements the protein biomarker, CD117/KIT, which is absent in other RCC Preoperative cross-sectional radiographic imaging for each subtypes and therefore narrows the differential diagnosis to renal tumor in the retrospective cohort was evaluated by two members oncocytoma versus ChRCC (23). Similarly, both renal oncocy- of a committee comprised of three radiologists (C. Hendler, toma and ChRCC lack classic biomarkers (e.g., CAIX, vimentin, M. Petroziello, and C.L. Roche) and one urologic oncologist with AMACR) of clear cell RCC (CcRCC) and/or papillary RCC (PRCC; kidney cancer specialization (E.C. Kauffman) while blinded to refs. 22, 23). Accordingly, although the diagnostic differential for tumor histologic subtype. Scans were acquired from several an oncocytic renal tumor includes many renal cell tumor subtypes different radiology facilities and no standardized imaging (18), contemporary immunostain panels incorporating CD117 protocol was used. CT signal intensity (Hounsfield units, HU) and other biomarkers reliably differentiate renal oncocytoma and of each tumor was measured in an early (arterial/cortical or ChRCC from other oncocytic RCC variants, including CcRCC and venous/nephrogenic) contrast phase and a delayed/excretory PRCC. When the diagnostic differential has been narrowed to contrast phase for the peak enhancing portion of each tumor renal oncocytoma versus ChRCC, the CK7 protein biomarker is using a 1.0-cm diameter region-of-interest (ROI) circle; or a commonly used to support ChRCC diagnosis. However, CK7 is 1.0-cm 0.5-cm elliptical ROI for small heterogeneous tumors occasionally inaccurate in this role (22, 25, 26), and more reliable to avoid hypoenhancing portions. When multiple early CT phases approaches are needed (21). Radiographic approaches, such as CT were available for a patient, the earliest phase was used. Signal contrast enhancement measurement, have not yet shown utility in intensity of renal cortex adjacent to the tumor was measured aiding preoperative renal oncocytoma diagnosis. However, most using an elliptical ROI without specified dimensions. Tumor prior radiographic studies have focused on the differentiation of heterogeneity was estimated using a subjective 3-point scale renal oncocytoma from RCC subtypes collectively, overlooking (1, homogenous; 2, mild heterogeneity; 3, high heterogeneity). the specific comparison of renal oncocytoma with the ChRCC subtype and the potential impact of occasional CD117() Prospective validation variants (27–29). Clinical/radiographic variables that were significantly associ- Here we report the largest study to our knowledge comparing ated with renal oncocytoma or ChRCC in the retrospective anal- clinical features of renal oncocytoma and ChRCC, and the first ysis were evaluated prospectively between January 2013 and

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February 2017. All resected tumors from this period were stained ability to classify 40 additional tumors (20 renal oncocytoma, 20 prospectively for CD117 and CK7. Preoperative radiographic ChRCC) from 37 consecutive nephrectomy patients with renal imaging for each resected tumor was evaluated independently oncocytoma or ChRCC. A total of 28/40 (14 renal oncocytoma, by three observers (E.C. Kaufmann, M. Petroziello, C.L. Roche), 14 ChRCC) tumors had preoperative multiphase CT scans avail- who assigned ChRCC or renal oncocytoma classification based on able for PEER measurement, 22 of which were CD117(þ) and six radiographic assessment while blinded to the actual tumor sub- of which were CD117(). All 22 CD117(þ) tumors were correctly type histology. classified using a PEER threshold value of 0.50 by each of the three independent reviewers, whereas 3/6 CD117() tumors were Statistical analyses misclassified by each reviewer using this approach (Fig. 3A Patient and tumor characteristics were reported using the and B). Interobserver reliability was excellent for PEER scoring mean/range for continuous variables, and frequencies/relative (ICC ¼ 0.97), and perfect for renal oncocytoma versus ChRCC frequencies for categorical variables. Comparisons were made classification (ICC ¼ 1.0; Fig. 3A). Multifocality correctly classified using the Wilcoxon rank-sum and Fisher exact tests for continuous 6/6 CD117( þ) tumors as renal oncocytoma, age <50 years cor- and categorical variables, respectively. Inter-rater reliability was rectly classified 4/5 CD117(þ) tumors as ChRCC, size <2cm assessed using the intraclass correlation coefficient (ICC), where correctly classified 4/5 CD117(þ) tumors as renal oncocytoma, 0.90 is considered a priori as sufficient demonstration of reliabil- and size >7 cm correctly classified 4/5 CD117(þ) tumors ity. All analyses were completed in SAS v9.4 at a significance level as ChRCC. of 0.05. In a combined analysis of the prospective and retrospective cohorts, PEER classified renal oncocytoma versus ChRCC correctly in 63/63 (100%) tumors without evidence of CD117() Results staining, including 41/41 cases confirmed to be CD117(þ) Retrospective evaluation (Table 2; Fig. 3C). In contrast, the CK7 biomarker occasionally A total of 87 patients (93 tumors) comprised the retrospective misclassified CD117(þ) tumors, including 17% of CD117(þ) cohort, which included 53 renal oncocytoma patients (59 tumors) ChRCC tumors (Table 2; Supplementary Fig. S3). Neither PEER and 34 ChRCC patients (34 tumors). Renal oncocytoma and nor CK7 performed well among CD117() variants (Table 2). ChRCC patients were similar for most preoperative features Although CD117(þ) renal oncocytoma and CD117(þ) ChRCC (Table 1). Younger age (<50 years) was significantly associated tumors were reliably separated by PEER using either the with ChRCC (80% specific), but only 24% sensitive for this arterial/cortical or venous/nephrogenic phase, the former phase subtype (Table 1A). Multifocality was significantly associated allowed greater separation (Fig. 3D). Among CD117(þ) ChRCC with renal oncocytoma (100% specific), but only 27% sensitive tumors evaluated by PEER, eosinophilia of moderate-to-strong for this subtype (Table 1B). Smaller tumor sizes were enriched for intensity was present diffusely (80% of tissue) in close to one renal oncocytoma, whereas larger tumor sizes and higher nephro- third of cases and at least focally in most cases; however, eosin- metry scores were enriched for ChRCC (Table 1B). ophilia tended to be more prevalent among CD117() tumors The variable most reliably associated with renal oncocytoma (Supplementary Table S1). PEER values of four tumors from the versus ChRCC diagnosis was the CT peak signal intensity within a excluded hybrid patient ranged from 0.44 to 0.47, each of which tumor, particularly when expressed as a tumor:cortex ratio was CD117(þ). (Table 1B). Differences in tumor:cortex peak signal intensity between renal oncocytoma and ChRCC were greater when measured using net enhancement (i.e., contrast phase signal intensity Discussion minus noncontrast phase signal intensity; Fig. 1; Supplementary Currently, most benign renal oncocytoma tumor patients Fig. S1A) compared with absolute signal intensity using the continue to undergo unnecessary partial or radical nephrec- contrast phase only (Supplementary Fig. S1B and S1C); and when tomy because biopsy alone is inadequate to definitively rule measured using an early (arterial/cortical or venous/nephrogenic) out cancer. Improved preoperative diagnosis of benign renal contrast phase (Fig. 1; Supplementary Fig. S1B) compared with a oncocytoma tumors would avoid a need for diagnostic renal delayed/excretory contrast phase (Supplementary Fig. S1A and oncocytoma resection and thereby allow significant reductions S1C). Combining these observations, we identified the most in patient morbidity and healthcare costs (3–7). The greatest discriminating radiographic measurement to be the peak early- challenge for nonsurgical diagnosis of renal oncocytoma has phase enhancement ratio (PEER) of the tumor:cortex (Fig. 1). All been the difficult differentiation of renal oncocytoma from renal oncocytoma tumors were relatively hyperenhancing with ChRCC on percutaneous needle-core biopsy, due to significant a tumor:cortex PEER >0.50 (Figs. 1 and 2A–D). In contrast, all overlap in histology and biomarker profile, including common but four ChRCC tumors were relatively hypoenhancing with expression of CD117 (19–23). Although both tumor types a tumor:cortex PEER <0.50 (Figs. 1 and 2E–H). Intriguingly, confer excellent candidacy for active surveillance management, all four ChRCC tumors with a tumor:cortex PEER >0.50 were the latter has occasional lethal potential and warrants resection CD117() variants (Fig. 1; Supplementary Fig. S2). Thus, a in select patients. tumor:cortex PEER threshold value of 0.50 reliably separated This study investigated clinical variables which might facilitate renal oncocytoma (PEER >0.50) from ChRCC (PEER <0.50) for nonoperative diagnostic differentiation of renal oncocytoma all tumors that were either CD117(þ) or CD117-untested (Fig. 1). from ChRCC, including the potential impact of CD117 expression status. In the largest clinical comparison of ChRCC versus Prospective validation renal oncocytoma to our knowledge, we retrospectively identified Variables of age, tumor size, multifocality, and tumor:cortex a simple CT enhancement measure (tumor:cortex PEER) that PEER were next evaluated prospectively over a 4-year period for differentiated renal oncocytoma from ChRCC whenever

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Table 1. Clinicopathologic features of the retrospective cohort ChRCC RO P A. Patient features Total patients, n (%) 34 (39%) 53 (61%) Age, mean (range) 61.2 (28–84) 66.2 (35–89) 0.16 <50, n (%) 8 (24%) 2 (4%) 0.012 Gender, n (%) Male 20 (59%) 37 (70%) 0.36 Female 14 (41%) 16 (30%) Race, n (%) White 32 (94%) 49 (92%) 1.00 Black 1 (3%) 3 (6%) Other 1 (3%) 1 (2%) BMI, n (%) 30 16 (47%) 32 (62%) 0.27 35 10 (29%) 10 (19%) 0.31 Smoking history Never smoker, n (%) 23 (68%) 27 (51%) 0.18 Any smoking, n (%) 11 (32%) 26 (49%) Pack years, mean (range) 24.9 (1–100) 25.6 (5–50) 0.31 Serum creatinine, mean (range) 1.0 (0–1.9) 1.1 (0.8–2.4) 0.37 Charlson index, mean (range) 2.5 (0–8) 2.5 (0–11) 0.98

B. Tumor features Total tumors, n (%) 34 (37%) 59 (63%) Laterality, n (%) Left 22 (65%) 35 (59%) 0.66 Right 12 (35%) 24 (41%) Multifocality, n (%) 0 (0%) 16 (27%) <0.001 Synchronous RCC 0 (0%) 3 (19%) Synchronous RO 0 (0%) 11 (69%) Synchronous AML 0 (0%) 2 (12%) Tumor diameter, cm Mean (range) 6.4 (1.8–20.0) 3.4 (0.9–12.0) <0.001 4, n (%) 13 (38%) 44 (75%) <0.001 4.1–7, n (%) 11 (32%) 12 (20%) >7, n (%) 10 (29%) 3 (5%) RENAL score Total, mean (range) 8.3 (5–11) 7.3 (4–11) 0.022 R, mean (range) 1.9 (1–3) 1.3 (1–3) 0.001 E, mean (range) 1.6 (1–3) 1.7 (1–3) 0.47 N, mean (range) 2.6 (1–3) 2.2 (1–3) 0.022 A, n (%) Anterior 13 (38%) 27 (46%) 0.65 Posterior 11 (32%) 14 (24%) Neither 10 (29%) 18 (31%) L, mean (range) 2.2 (1–3) 2.2 (1–3) 0.76 Endophytic %, mean (range) 51.1 (5–100) 56.2 (10–100) 0.40 Kidney pole, n (%) Upper 7 (21%) 13 (22%) 0.77 Middle 16 (47%) 31 (53%) Lower 9 (26%) 14 (24%) N/A 2 (6%) 1 (2%) Stellate scar, n (%) Yes 2 (6%) 5 (8%) 1.00 No 26 (76%) 46 (78%) Unknown 6 (18%) 8 (14%) Heterogeneity score, mean (range) 2.0 (1–3) 1.9 (1–3) 0.62 CT signal intensity (HU), mean (range) Tumor Early phase 99.1 (53.5–186) 133.4 (70–250) 0.002 Neta early phase 63.7 (17.5–162) 110.4 (48–225) <0.001 Delayed phase 74.6 (39–146) 94.9 (41–180) 0.043 Neta delayed phase 42.7 (16–122) 70.5 (15.5–155) 0.009 Tumor:cortex Early phase 0.63 (0.32–1.00) 0.80 (0.55–1.04) 0.001 Neta early phase 0.45 (0.18–0.96) 0.77 (0.50–1.00) <0.001 Delayed phase 0.53 (0.36–0.86) 0.70 (0.48–0.93) <0.001 Neta delayed phase 0.39 (0.16–0.80) 0.62 (0.23–0.95) <0.001 aNet difference between contrast and noncontrast CT phases.

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CD117(þ) with 100% accuracy. All renal oncocytoma tumors in the retrospective cohort had hyperenhancement (PEER >0.50) regardless of CD117 positivity, whereas ChRCC tumors typically had hypoenhancement (PEER <0.50) except for a minority of cases which, to our surprise, were all CD117() variants. To validate this finding, all resected renal oncocytoma or ChRCC tumors in the past 4 years at our institution were evaluated prospectively by CD117/CK7 expression and PEER, as measured by three independent reviewers blinded to whether each tumor was renal oncocytoma or ChRCC. All CD117(þ) tumors in this prospective cohort were correctly classified as renal oncocytoma or ChRCC by each reviewer using PEER; and as in the retrospective cohort, only CD117() ChRCC variants were misclassified. In combined retrospective and prospective cohort analyses, PEER classified renal oncocytoma versus ChRCC correctly when not CD117() in 63/63 (100%) evaluable cases, including 41/41 confirmed CD117(þ) cases. These findings indicate PEER is an accurate tool for differentiating CD117(þ) renal oncocytoma from ChRCC. Currently, the CD117 biomarker is used in contemporary pathology to narrow the diagnostic differential of an oncocytic renal tumor to either renal oncocytoma or ChRCC (22, 23). Histomorphology is the gold-standard for renal oncocytoma Figure 1. versus ChRCC differentiation but may be inadequately repre- Tumor:cortex PEER values in renal oncocytoma (RO) versus ChRCC tumors sented in small biopsy tissues. Furthermore, eosinophilia present of retrospective cohort patients according to CD117 expression. The contrast CT peak signal intensity (HU) of each tumor calculated as to some degree in most ChRCC tumors and predominant in

(tumorcontrast tumornoncontrast)/(cortexcontrast cortexnoncontrast) is plotted 40% of cases (20), can mimic classic renal oncocytoma according to RO versus ChRCC histology and stratiﬁed by CD117 immunostain eosinophilia when captured on biopsy. In this scenario, the CK7 result. An early contrast phase includes either an arterial/cortical phase or clinical biomarker can be helpful to support ChRCC diagnosis; venous/nephrogenic phase. however, some ChRCC variants lack CK7 expression (22, 25, 26).

Figure 2. Representative early-phase contrast CT images of CD117(þ) renal oncocytoma/ChRCC tumors. A–D, Four representative CD117(þ) renal oncocytoma tumors with tumor hyperenhancement that is similar to the enhancement level of the adjacent cortex (tumor:cortex PEER scores ¼ 0.96, 0.92, 0.93, 0.71, respectively). E–H, Four representative CD117(þ) ChRCC tumors with hypoenhancement relative to the adjacent cortex (tumor:cortex PEER scores ¼ 0.28, 0.27, 0.32, 0.27, respectively). Dotted circles and ellipses (ROI) denote the peak enhancing areas of the tumors and representative regions of renal cortex, respectively, used for tumor:cortex PEER calculation.

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Figure 3. Prospective validation of tumor:cortex PEER score for assignment of renal oncocytoma (RO) versus ChRCC histology. A, Comparison of PEER scores from three independent physician reviewers for 28 consecutive RO/ChRCC tumors in the prospective cohort, indicating high interobserver agreement (ICC ¼ 0.97) and perfect agreement for the assigned histology (ICC ¼ 1.0). B, The mean tumor:cortex PEER score for each tumor in the prospective cohort is plotted according to CD117 expression. C, PEER scores for all tumors in the combined retrospective and prospective cohorts are plotted according to CD117 expression. D, PEER scores from part C after exclusion of tumors measured using a venous/nephrogenic rather than arterial/cortical contrast phase show improved separation of CD117(þ) renal oncocytoma and CD117(þ) ChRCC tumors.

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Table 2. Overall accuracy of PEER and CK7 for ChRCC/RO classiﬁcation in the combined retrospective and prospective cohorts ChRCC RO Total CD117 level PEER (%) CK7 (%) PEER (%) CK7 (%) PEER (%) CK7 (%) Not tested 5/5 (100) 2/2 (100) 17/17 (100) 4/4 (100) 22/22 (100) 6/6 (100) Positive 15/15 (100) 15/18 (83) 26/26 (100) 28/28 (100) 41/41 (100) 43/46 (93) Negative 3/10 (30) 7/10 (70) 9/9 (100) 7/10 (70) 12/19 (63) 14/20 (70) Abbreviation: RO, renal oncocytoma.

Accordingly, definitive renal oncocytoma diagnosis cannot be less relevance to the clinical challenge of ChRCC versus renal confirmed on the basis of CK7 absence alone in a biopsy, and oncocytoma, because the diagnostic differential of a CD117() is often deferred to surgical resection pathology (20, 22, 26). In oncocytic tumor biopsy is not limited to these two subtypes this study, PEER outperformed CK7, which misclassified 17% of and includes several other RCC subtypes as well (18). Only when CD117(þ) ChRCC cases as renal oncocytoma, consistent with an oncocytic tumor is CD117(þ) does the renal oncocytoma prior reports (22, 25, 26). Although neither PEER nor CK7 was versus ChRCC distinction become critical, and in this scenario very accurate among CD117() tumors, this scenario has PEER achieves high if not perfect accuracy.

Figure 4. Management algorithm for an oncocytic renal tumor biopsy patient using CD117 immunostain and tumor:cortex PEER. An oncocytic renal tumor biopsy should undergo CD117 and CK7 immunostain; multiple biopsy cores should be obtained to differentiate diffuse versus focal expression. If CD117(), the differential is large and includes CcRCC and PRCC, in addition to less common RCC subtypes, and resection is favored if tumor size and patient health are appropriate. If CD117(þ), the differential is limited to ChRCC and RO, and a tumor:cortex PEER score can be measured using CT imaging that includes an early contrast phase and an unenhanced phase. For tumor:cortex PEER 0.50, the CD117(þ) tumor is predicted to be ChRCC and can be resected or surveyed depending on tumor size and patient health/life expectancy. , Active surveillance may be appropriate in select patients with small tumors and/or limited life expectancy. , A PEER score of 0.51 to 0.55 was not observed in this study for any CD117(þ) tumor; a hypothetical CD117(þ) tumor with PEER score falling within this range based on a venous/nephrogenic phase should undergo repeat CT imaging with a true arterial/cortical phase, which may yield a higher PEER value if the tumor is renal oncocytoma. If PEER remains between 0.51 and 0.55 using an arterial/cortical phase, consider CK7 immunostain result and other clinical features (patient age, tumor size/focality) or defer to diagnostic resection.

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Figure 4 illustrates a proposed algorithm that combines PEER relevant to the contemporary diagnostic challenge of a CD117(þ) with CD117 immunostain in the management of oncocytic renal oncocytic tumor biopsy (28). Furthermore, no study comparing tumor biopsy patients. PEER does not negate the need for biopsy radiographic features of renal oncocytoma and ChRCC has con- in preoperative renal oncocytoma diagnosis, but may improve sidered CD117 expression. Bird and colleagues studied CT biopsy accuracy so that diagnostic resection can be avoided for enhancement in various renal cell tumor types, which included CD117(þ) renal oncocytoma tumors, which account for most 12 renal oncocytoma and 5 ChRCC (29). Renal oncocytoma renal oncocytoma cases. For CD117() renal oncocytoma enhancement was three times higher than ChRCC enhancement, tumors, PEER does not facilitate diagnosis and other novel with greatest difference in the arterial phase, as in this study. Gorin diagnostic approaches are needed to avoid surgery. In our pro- and colleagues has reported that a sestamibi scan has high spective series, CD117() tumors accounted for 21% of all renal sensitivity for renal oncocytoma but cannot reliably rule out oncocytoma/ChRCC cases, which is consistent with reported ChRCC, which occasionally gives a positive result (38). Canvasser incidences (23). and colleagues reported recently an algorithm using MRI signal Additional study is needed to validate the management algo- intensity to predict CcRCC histology (39). A total of 9 ChRCC and rithm in Figure 4 and confirm the added value of PEER in the 7 renal oncocytoma tumors of unspecified CD117 status were clinic. Goals of this future research should include verification of studied and showed overlap in MRI enhancement. the optimal PEER cut-off value for ChRCC versus renal oncocy- Novel molecular biomarkers may help differentiate renal onco- toma differentiation. The cut-off PEER value of 0.50 in our cytoma and ChRCC on biopsy, but have not yet translated prospective cohort was arbitrarily selected on the basis of our clinically (21, 40–44). Kauffman et al. reported CD82/KAI1 as retrospective observations; however, a cut-off PEER value of 0.55 a sensitive ChRCC marker that is typically absent in renal onco- too would have achieved 100% diagnostic accuracy in both the cytoma, a finding validated subsequently by Truong and collea- retrospective and prospective cohorts. Because PEER measure- gues (42, 45). Additional promising biomarker candidates to ments never fell within the 0.51–55 range for any CD117(þ) distinguish renal oncocytoma and ChRCC include S100A1 and tumor in this study, additional investigation is needed to deter- cyclin D1 (46, 47), whereas other potential biomarkers involve mine whether this scenario ever occurs; and if so, whether such more complicated definitions of positivity or molecular tumors are renal oncocytoma (in which case a 0.50 cut-off would approaches (40, 41, 43, 44). In contrast, a PEER ratio can be be optimal) or ChRCC (in which case a cut-off of 0.55 would be determined rapidly and cheaply using routine multiphase CT optimal). In the interim, for a hypothetical CD117(þ) tumor with imaging, which has already been obtained for many patients PEER value of 0.51–0.55 based only on a venous/nephrogenic prior to the CD117(þ) oncocytic tumor biopsy. A strength of phase, a repeat CT scan with an arterial/cortical phase should be this study is that CT scans were from different facilities without considered because this phase augmented slightly the separation protocol standardization. Although the cortical phase gave of renal oncocytoma versus ChRCC tumors in this study when the best separation of renal oncocytoma from ChRCC when CD117(þ) (Figs. 3D and 4). CD117(þ), either the cortical or nephrogenic phase was 100% An association between CD117 positivity and radiographic accurate. Hence, the specific CT protocol and precise timing of enhancement level is not previously reported to our knowledge. the early contrast phase does not appear to be critical, which Our discovery that CD117 absence correlates with frequent should facilitate generalized PEER usage. ChRCC hyperenhancement is unexpected on the basis of known A historical concern with active surveillance of biopsy-favored CD117 function. CD117 is a tyrosine kinase membrane receptor renal oncocytoma is that the tumor might simultaneously harbor for the ligand, stem cell factor (SCF), and positively regulates a ChRCC, as in rare hybrid oncocytic tumors (HOCT; ref. 48). diversity of cell processes, including proliferation, differentiation, However, to our knowledge, HOCT metastatic behavior has never migration, and angiogenesis (32, 33). CD117 interacts with been confirmed, raising the assertion by some investigators that several cell signaling pathways implicated in cancer development, these hybrid tumors might be benign (30). Consistent with this such as those of PI3K/Akt, Src family kinases, and Ras-Erk (34). possibility, Pote and colleagues recently concluded that HOCT is The role of CD117 in ChRCC/renal oncocytoma tumorigenesis, genetically more similar to renal oncocytoma than ChRCC and however, is unknown. Given its known function in increasing may therefore be a renal oncocytoma variant (31). Regardless, microvessel density and angiogenesis (33), absence of CD117 given its indolent clinical behavior and lack of known metastatic expression might be expected to decrease vascularity/enhance- potential, the rare possibility of HOCT should not justify routine ment, which is opposite to observations in this study. CD117 is a resection of tumors with renal oncocytoma diagnosis favored on differentiation marker for the nephron distal renal tubule (35), biopsy, because HOCT too is appropriate for surveillance (49). from which renal oncocytoma and ChRCC tumors are believed to In addition to PEER outcomes, we found that younger age and originate, and it is possible that its loss in ChRCC tumors might larger tumor size enriched for ChRCC, while multifocality and reflect dedifferentiation to a hypervascular and potentially more smaller tumor size enriched for renal oncocytoma. Although an aggressive variant. Also worthy of note is our observation that age cutoff of <50 years had high specificity for ChRCC, the optimal CD117() tumors have a high rate of predominant eosinophilia. age cutoff to discern these two subtypes needs to be better defined Together, these findings suggest the existence of a ChRCC biologic in larger studies with statistical analyses designed to identify this variant characterized by CD117 negativity, frequent atypical cutoff. The association of ChRCC with young age is consistent hypervascularity, and common eosinophilia. Study is currently with recent observations from Daugherty and colleagues, who ongoing to characterize the clinicopathologic features and prog- noted ChRCC tumors to be the most common nonclear RCC nostic significance of these CD117() ChRCC variants. subtype in young white females (50). In contrast to PEER, how- Prior studies that compared clinical features of renal oncocy- ever, each of these other variables (age, size, focality) was poorly toma and RCC have generally overlooked the direct renal onco- sensitive for either renal oncocytoma or ChRCC in the current cytoma versus ChRCC comparison (1, 36, 37), which is most study; and with the exception of multifocality, none was 100%

OF8 Clin Cancer Res; 2018 Clinical Cancer Research

Differentiation of CD117(þ) Oncocytoma and ChRCC Using PEER

specific. Nevertheless, these variables might be clinically helpful would not have changed the 100% accuracy of PEER among to corroborate PEER findings among CD117(þ) tumors with a CD117(þ)tumors. PEER value near the 0.50 threshold (Fig. 4). Caution must be A historical challenge to reliable preoperative renal oncocy- exercised with multifocal tumors, because renal oncocytoma toma diagnosis using biopsy has been differentiation from diagnosis for one tumor does not exclude malignancy in another ChRCC, which shares common CD117 biomarker expression (48). Additional biopsy should be considered for any synchro- with renal oncocytoma, but warrants resection in select cases nous tumor with radiographic features (e.g., PEER, size, growth due to occasional lethal potential. We identified and prospec- rate) that are discordant from the biopsied renal oncocytoma tively validated a reproducible and easily generalizable tumor. radiographic measure (tumor:cortex PEER) that uses standard Consistently high PEER values for renal oncocytoma, regardless multiphase CT imaging to differentiate CD117(þ)renal of CD117 positivity, suggest that a tumor:cortex PEER <0.50 oncocytoma from CD117(þ) ChRCC with potentially 100% might rule out renal oncocytoma without the need for biopsy. accuracy. Age, tumor size, focality, and CK7 immunostain may Fat-poor angiomyolipoma (AML) represents the other main corroborate renal oncocytoma/ChRCC diagnosis but are alone benign renal tumor besides renal oncocytoma that often under- not 100% reliable. In contrast, a high PEER value may reliably goes unnecessary diagnostic resection; although unlike renal confirm renal oncocytoma diagnosis whenever an oncocytic oncocytoma, AML diagnosis by percutaneous biopsy is uncom- renal tumor biopsy is CD117(þ), and thereby allow diagnostic plicated. Interestingly, AML is characterized by hypervascularity resection to be avoided. The number of patients in this study that might be expected to yield uniformly high PEER values, with known CD117(þ) tumors that were evaluable with similar to renal oncocytoma. Future studies are therefore PEER was limited (41 cases), and external validation in larger warranted to determine the accuracy of a low tumor:cortex PEER cohorts will be helpful to confirm the clinical value of PEER value to rule out any common benign histology (i.e., renal for CD117(þ) renal oncocytoma diagnosis. oncocytoma and fat-poor AML) without the need for biopsy. A limitation of this study is that CD117 staining was deter- Disclosure of Potential Conflicts of Interest mined with surgically resected tumors, whereas PEER is pro- No potential conflicts of interest were disclosed. posed to guide clinical management based on the CD117 status of biopsy tissues (Fig. 4). Additional investigation is there- Authors' Contributions fi fore needed to con rm concordance between CD117 staining Conception and design: J. Amin, E.C. Kauffman on biopsy tissue and resected specimens. In the interim, a Development of methodology: J. Amin, S. Badkhshan, C. Hendler, CD117(þ) stain result based on only a single biopsy core E.C. Kauffman should be interpreted with caution because this result may not Acquisition of data (provided animals, acquired and managed patients, rule out a CD117() tumor with focal positivity. To avoid provided facilities, etc.): J. Amin, B. Xu, S. Badkhshan, T.T. Creighton, this scenario, multiple tumor biopsies are recommended to C. Murekeyisoni, T. Schwaab, C. Hendler, C.L. Roche, E.C. Kauffman Analysis and interpretation of data (e.g., statistical analysis, biostatistics, ensure adequate tumor sampling that reliably differentiates computational analysis): J. Amin, B. Xu, S. Badkhshan, C. Murekeyisoni, focal versus diffuse CD117 expression. K.M. Attwood, C. Hendler, M. Petroziello, C.L. Roche, E.C. Kauffman Additional study limitations include a single institute setting Writing, review, and/or revision of the manuscript: J. Amin, B. Xu, and lack of external validation. Although the study is the largest C. Murekeyisoni, C.L. Roche, E.C. Kauffman clinical comparison of ChRCC and renal oncocytoma to our Administrative, technical, or material support (i.e., reporting or organizing knowledge, the cohort is nevertheless limited in size, and many data, constructing databases): J. Amin, S. Badkhshan, D. Abbotoy, C. Murekeyisoni, patients were lacking preoperative multiphase CT scans neces- Study supervision: E.C. Kauffman sary to measure PEER. Furthermore, MRI enhancement was not evaluated in this study due to a limited number of available Acknowledgments cases at our institute and warrants future investigation. Finally, Statistical support for this study was provided by NCI grant P30CA016056. many tumors in the retrospective cohort were not tested for CD117 expression; however, all CD117-untested tumors were Received January 22, 2018; revised March 23, 2018; accepted May 7, 2018; classified correctly by PEER, so revealing their CD117 status published first May 11, 2018.

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OF10 Clin Cancer Res; 2018 Clinical Cancer Research

Identification and Validation of Radiographic Enhancement for Reliable Differentiation of CD117(+) Benign Renal Oncocytoma and Chromophobe Renal Cell Carcinoma

Jay Amin, Bo Xu, Shervin Badkhshan, et al.

Clin Cancer Res Published OnlineFirst May 11, 2018.

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