Abstract
Introduction and objective:
To evaluate whether significant loss in ipsilateral renal parenchymal volume (IRPV) and renal function occurs during active surveillance (AS) of renal oncocytoma (RO) patients.
Methods:
Renal function (estimated glomerular filtration rate, eGFR) dynamics were retrospectively analyzed in 32 consecutive biopsy-diagnosed RO patients managed with AS at a National Comprehensive Cancer Network institute. Three-dimensional kidney and tumor reconstructions were generated and IRPV was calculated using volumetry software (Myrian, Inc.) for all patients with manually estimated RO growth >+10 cm3.
GFR and IRPV were compared at AS initiation vs. last follow-up using two-sided paired t-tests. Correlation between change in IRPV and change in RO size or GFR was tested using a Spearman coefficient.
Results:
With median follow-up of 37 months, there was no significant change between initial vs. last eGFR (median 71.0 vs. 70.5 mL/min/1.73m2, p=0.50; median change −3.0 mL/min/1.73m2). Among patients (n=17) with RO growth >+10 cm3 during AS (median growth +28.6 cm3, IQR +16.9-+46.5 cm3), IRPV generally remained stable (median change +0.5%, IQR −1.2%-+1.2%), with only 2 cases surpassing 5% loss. No IRPV loss was detected among any patient within the top tertile of RO growth magnitude. RO growth magnitude did not correlate with loss of either IRPV (ρ=−0.30, p=0.24) or eGFR (ρ=−0.16, p=0.40), including among patient subsets with lower initial eGFR. Study limitations include lack of long-term follow-up.
Conclusions:
Volumetry is a promising novel tool to measure kidney and tumor tissue changes during AS. Our study using volumetry indicates that clinically significant loss of IRPV or eGFR is uncommon and unrelated to tumor growth among untreated RO patients with intermediate follow-up. These findings support that AS is in general functionally safe for RO patients, however longer study is needed to determine safety durability, particularly among uncommon ≥cT2 RO variants.
Keywords: Active surveillance, renal oncocytoma, renal function, renal parenchyma volume, 3-D imaging, Myrian
Graphical abstract
1. Introduction
Renal oncocytoma (RO) is a benign neoplasm accounting for 3–7% of resected renal tumors[1], including approximately 20% of those ≤4 cm[2]. Historically, nonsurgical diagnosis of RO versus renal cell carcinoma (RCC) has been challenged by significant morphologic overlap on renal mass biopsy (RMB), necessitating diagnostic invasive extirpation and associated operative risks, including rare mortality[1]. More recently, reliable RO diagnosis using RMB without surgery has evolved due to technical advances and standardized immunohistochemistry biomarker panels, in addition to radiology-based approaches that corroborate the diagnosis including Sestamibi scan and CT contrast enhancement measurement (e.g., tumor:cortex PEER scoring)[3,4].
Active surveillance (AS) provides an oncologically safe management option for RMB-diagnosed RO patients that avoids the morbidity of invasive extirpation or percutaneous ablation while maintaining 100% disease-specific survival[5–10]. However, it is unknown whether deferral of RO treatment can be detrimental via compromise of adjacent renal parenchyma[8,11]. A similar phenomenon is commonly evidenced in renal cell carcinoma (RCC) patients presenting with large locally invasive tumors and little remaining ipsilateral parenchyma, and large RCC size and invasive stage are associated with worse renal function[12–15]. These observations might not be generalizable to RO tumors, which typically remain small and noninvasive[16,17]. Functional outcomes of untreated RO patients have undergone scarce investigation, with one recent study concluding that renal functional loss may be substantial enough to warrant immediate partial nephrectomy[11]. A better understanding of whether RO growth compromises renal function is critical to optimally counsel patients regarding AS vs. treatment.
Software-assisted volumetry provides a novel technique for measuring tissue size more accurately than conventional cross-sectional imaging estimations[18–20]. Volumetry has been validated for renal parenchymal measurement in several independent studies but has not yet been applied to the study of AS patient outcomes, to our knowledge[21–23]. The current study evaluated renal anatomic and functional outcomes during AS management of RO patients. Unique from prior studies, volumetry software was used to measure renal parenchymal volume changes during RO growth, and correlation tests were performed to determine the relationship between RO growth and renal parenchymal or eGFR changes.
2. Methods
2.1. Patients
Study approval was obtained from the Institutional Review Board of Roswell Park Comprehensive Cancer Center (RPCCC), a National Comprehensive Cancer Network institute. Between January 2013-January 2020, all RMB-diagnosed RO patients seen by a single urologist at RPCCC underwent AS, with none undergoing immediate treatment. A departmental renal tumor patient database was retrospectively queried to identify those RO patients with ≥6 months follow-up during AS. RO patients with a CD117(+) tumor immunostain prospectively underwent CT-based tumor:cortex PEER scoring to corroborate the diagnosis of RO rather than chromophobe RCC, as previously validated in CD117(+) oncocytic tumor patients[3].
2.2. Renal function and tumor growth assessment
AS management was performed as previously described[10]. AS monitoring included serum creatinine (SCr) measurement with cross-sectional imaging every 6–12 months[10]. Estimated glomerular filtration rate (eGFR) was calculated from SCr using the Chronic Kidney Disease-Epidemiology Study Equation[24]. Tumor size was recorded prospectively at each clinic visit based on the longest tumor diameter (LTD) in 3 perpendicular dimensions. Tumor volume was manually estimated based on these 3 dimensions using the ellipsoid formula: 0.5236*x*y*z. Tumor growth was calculated as the difference in estimated tumor volume at most recent follow-up vs. AS initiation.
2.3. 3D volumetric analysis
All patients with a manually estimated tumor volume increase of >+10 cm3 underwent computed measurement of tumor volume and ipsilateral renal parenchymal volume (IRPV) using volumetry software (Myrian, Inc.), which delineated renal tumor and parenchyma on all cross-sectional slices after manual outlining on a single cross-sectional slice. Non-parenchymal renal tissue such as the collecting system or renal sinus was automatically excluded. Software-generated 3D models of kidneys and renal tumors were exported in OJB file format into Autodesk® Meshmixer™ software to smoothen tissue surfaces without affecting calculated volumes (supplementary Figure 1).
2.4. Comparisons and Statistics
Patient and tumor characteristics were summarized using the mean, median, and interquartile ranges (IQR) for continuous variables, and frequencies for categorical variables. Associations between initial eGFR and other clinical variables were tested using a Kruskal-Wallis test for categorical variables and Pearson correlation test for continuous variables. Comparison of eGFR, tumor volume or IRPV at initial presentation vs. last follow-up was performed using a two-sided paired t-test. Scatter plots and a Spearman correlation coefficient were used to visualize and measure correlations between: tumor volume change and eGFR change; manually estimated tumor volume change and volumetry-computed tumor volume change; volumetry-computed tumor volume change and IRPV change. Post hoc power analysis was performed using parameters observed in the actual data set. Analyses were conducted in R v4.0.2 at a significance level of 0.05.
3. Results
3.1. RO patient characteristics
A total of 32 RO patients on AS for ≥6 (median 37, mean 36, IQR 21.1–47.0) months were identified, including 6 patients with synchronous unbiopsied tumors (Table 1). CD117 immunostain was positive in 29 (91%) RO patients, all of which had a tumor:cortex PEER score of >0.55 to corroborate RO diagnosis (supplementary Table 1). Median initial RO LTD and volume were 3.1 cm and 11.6 cm3, respectively. Initial eGFR was not associated by univariate analysis (supplementary Table 2) nor correlated (Spearman correlation - supplementary Table 3) with initial RO size. No RO patient progressed to symptoms, ≥cT3 stage, metastasis or delayed intervention during AS.
Table 1:
Baseline clinical features of RO patients managed with AS.
| Total patients, n (%) | n=32 |
|---|---|
| Age, years; median (mean, IQR) | 73.1 (72.3, 64.7 – 79.6) |
| Gender, n (%) | |
| Male | 15 (46.9%) |
| Female | 17 (53.1%) |
| Race, n (%) | |
| Caucasian | 28 (87.5%) |
| African American | 2 (6.3%) |
| Other/Unknown | 2 (6.3%) |
| Charlson Index, median (mean, IQR) | 1.0 (1.5, 0.0 – 2.3) |
| BMI, kgm−2; median (mean, IQR) | 29.1 (31.0, 26.6 – 34.4) |
| Type II Diabetes, n (%) | 8 (25.0%) |
| Hypertension, n (%) | 19 (59.4%) |
| RO Laterality, n (%) | |
| Right | 13 (40.6%) |
| Left | 19 (59.4%) |
| RO LTD, cm; median (mean, IQR) | 3.1 (3.8, 2.3 – 4.3) |
| RO Volume, cm3; median (mean, IQR) | 11.6 (52.3, 4.7 – 35.3) |
| RENAL Nephrometry score; n (%) | |
| Low (4–6) | 7 (21.9%) |
| Medium (7–9) | 21 (65.6%) |
| High (10–12) | 4 (12.5%) |
| Multifocal tumor patients, n (%) | |
| Total | 6 (18.8%) |
| Bilateral | 4 (12.5%) |
| Unilateral | 2 (6.3%) |
| Tumor number per multifocal patient; median (mean, IQR) | 3.5 (3.7, 2.0 – 5.0) |
| Duration of follow-up, months; median (mean, IQR) | 37.0 (36.0, 21.1 – 47.0) |
RO, renal oncocytoma; AS, active surveillance; BMI, Body Mass Index; GFR, glomerular filtration rate; LTD, longest tumor diameter; IQR, interquartile range
3.2. Manually estimated tumor growth during AS
Median manually estimated change in RO tumor volume during AS was +14.1 (mean +21.1) cm3 (Table 2). 17 RO tumors (53%) had >+10 cm3 total growth with a median increase of +28.6 (mean +38.9) cm3, while 15 (47%) RO tumors had minimal-to-no growth. Most (15/17, 88%) growing RO tumors were >4 cm at last follow-up. Among multifocal tumor patients, the median cumulative growth of biopsied plus unbiopsied tumors per patient was +36.1 (mean +49.1) cm3 (supplementary Table 4).
Table 2:
Tumor growth and renal function outcomes in RO patients managed with AS.
| At AS initiation | At last follow up | p-value | |
|---|---|---|---|
| All Patients (N=32) | |||
| Creatinine, mgdl−1; median (mean, IQR) | 1.0 (1.0, 0.8 – 1.1) | 0.9 (1.0, 0.8 – 1.1) | 0.97 |
| eGFR, mL/min/1.73 m2; median (mean, IQR) | 71.0 (71.2, 61.5 – 85.0) | 70.5 (70.0, 60.0 – 82.3) | 0.50 |
| LTD, cm; median (mean, IQR) | 3.1 (3.8, 2.3 – 4.3) | 3.9 (4.4, 2.6 – 5.4) | <0.001 |
| Volume, cm3; median (mean, IQR) | 11.6 (52.3, 4.7 – 35.3) | 20.3 (73.4, 6.3 – 62.0) | < 0.001 |
| Creatinine Change | 0.0 (0.0, −0.1 – 0.1) | ||
| % Creatinine Change | 0.9 (0.4, −8.9 – 9.7) | ||
| eGFR Change | −3.0 (−1.3, −7.3 – 2.5) | ||
| % eGFR Change | 0.0 (0.0, −0.1 – 0.0) | ||
| LTD change, cm; median (mean, IQR) | 0.5 (0.6, 0.1 – 1.1) | ||
| Volume Change, cm3; median (mean, IQR) | 14.1 (21.1, 0.7 – 29.5) | ||
| LTD Growth Rate, cm/year; median (mean, IQR) | 0.2 (0.2, 0.0 – 0.4) | ||
| Volume Growth Rate, cm3/year; median (mean, IQR) | 3.6 (10.9, 0.3 – 10.2) | ||
| Patients with RO growth >+10 cm3 (n=17) | |||
| Creatinine, mgdl−1; median (mean, IQR) | 1.0 (1.0, 0.8 – 1.1) | 0.9 (1.0, 0.8 – 1.1) | 0.43 |
| eGFR, mL/min/1.73 m2; median (mean, IQR) | 71.0 (70.0, 64.0 – 79.0) | 70.0 (69.8, 61.0 – 82.0) | 0.95 |
| LTD, cm; median (mean, IQR) | 3.6 (4.9, 3.1 – 6.2) | 5.3 (6.0, 4.3 – 7.2) | < 0.001 |
| Volume, cm3; median (mean, IQR) | 23.1 (91.3, 14.3 – 116.8) | 59.6 (130.2, 35.2 – 161.5) | < 0.001 |
| Creatinine Change | 0.0 (0.0, −0.1 – 0.1) | ||
| % Creatinine Change | −1.1 (−2.6, −12.7 – 5.1) | ||
| eGFR Change | −2.0 (−0.2, −6.0 – 4.0) | ||
| % eGFR Change | 0.0 (0.0, −0.1 – 0.1) | ||
| LTD change, cm; median (mean, IQR) | 1.1 (1.1, 0.6 – 1.5) | ||
| Volume Change, cm3; median (mean, IQR) | 28.6 (38.9, 16.9 – 46.5) | ||
| LTD Growth Rate, cm/year; median (mean, IQR) | 0.4 (0.4, 0.2 – 0.5) | ||
| Volume Growth Rate, cm3/year; median (mean, IQR) | 8.6 (19.7, 4.3 – 20.8) |
RO, renal oncocytoma; AS, active surveillance; eGFR, estimated glomerular filtration rate; LTD, longest tumor diameter; IQR, interquartile range
3.3. Volumetry-computed tumor and IRPV changes during AS
Initial and final RO tumor volume and IRPV were computed using software-assisted volumetry in all 17 patients with manually estimated RO growth of >+10 cm3 (Table 3, supplementary Table 5, Figure 1). IRPV showed a significant correlation of moderate strength with eGFR (supplementary Figure 2). The magnitude of RO growth per volumetry (median +25.4 cm3, mean +40.6 cm3) was on average equal to 28.3% of the baseline IRPV (Table 3) and correlated strongly with manually estimated RO growth estimations (ρ=0.91, p<0.001; supplementary Figure 3). Despite this RO growth, IRPV remained stable during AS, with a median change of +0.5% (mean +0.6%, IQR −1.2%-+1.2%) relative to the baseline IRPV. Only 2 patients had >5% IRPV loss during AS, in both cases despite only slight RO growth. No IRPV reduction was detected in the 5 patients with greatest RO growth (all >+50 cm3, range +51.8-+134.0 cm3). Among 6 patients with LTD surpassing 6 cm, the greatest IRPV loss was −1.7%. There was no correlation between RO growth and IRPV decline (ρ= −0.30, p=0.24, Figure 2). Post hoc power analysis revealed 98% power for detecting significant IRPV loss of at least −7.5 cm3, or −5%. All 4 multifocal tumor patients who had growth in synchronous contralateral and/or ipsilateral unbiopsied tumors maintained stable renal volumes bilaterally during AS, with no renal unit decreasing more than −2 cm3 or −1.1% despite tumor growth up to +118 cm3 (supplementary Table 5).
Table 3:
Volumetric and functional outcomes of RO patients with >+10 cm3 tumor growth during AS (n=17).
| Study ID # | Δ RO Tumor Volume | Δ IRPV per Volumetry, cm3 (%) | Δ eGFR, mL/min/1.73 m2 (%) | ||
|---|---|---|---|---|---|
| Per Manual Estimation, cm3 | Per Volumetry | ||||
| cm3 | % of IRPV | ||||
| 2 | +32.2 | +27.0 | 22.0% | +9.0 (+7.3%) | −2.0 (−4.7%) |
| 5 | +37.4 | +26.8 | 15.0% | −3.0 (−1.7%) | −8.0 (−11.3%) |
| 10 | +28.6 | +22.1 | 21.7% | +10.0 (+9.8%) | −7.0 (−18.9%) |
| 11 | +18.2 | +14.4 | 9.3% | −14.0 (−9.0%) | −1.0 (−1.1%) |
| 12 | +91.3 | +134.0 | 131.4% | +0.0 (+0.0%) | −3.0 (−4.8%) |
| 13 | +14.7 | +12.7 | 7.6% | +4.0 (+2.4%) | +9.0 (+12.3%) |
| 14 | +32.4 | +40.2 | 27.0% | −1.0 (−0.7%) | +13.0 (+20.3%) |
| 15 | +23.6 | +19.2 | 16.6% | +1.0 (+0.9%) | −3 (−5.0%) |
| 16 | +14.1 | +16.3 | 9.8% | −2.0 (−1.2%) | −9.0 (−10.7%) |
| 18 | +15.8 | +20.8 | 24.6% | +13.7 (+16.2%) | −4.0 (−5.6%) |
| 19 | +103.7 | +94.0 | 57.7% | +2.0 (+1.2%) | +17.0 (+25.8%) |
| 20 | +20.0 | +25.4 | 14.0% | −2.0 (−1.1%) | +4.0 (+7.0%) |
| 24 | +14.0 | +16.1 | 12.8% | −4.0 (−3.2%) | −6.0 (−7.6%) |
| 26 | +16.9 | +12.8 | 10.8% | −15.0 (−12.7%) | −1.0 (−1.4%) |
| 29 | +60.0 | +51.8 | 27.0% | +1.0 (+0.5%) | −24.0 (−27.3%) |
| 30 | +91.6 | +104.0 | 47.1% | +2.0 (+0.9%) | +20.0 (+26.0%) |
| 31 | +46.5 | +53.0 | 26.5% | +1.0 (+0.5%) | +2.0 (+2.2%) |
| Median | +28.6 | +25.4 | 21.7% | +1.0 (+0.5%) | -2.0 (−4.7%) |
| Mean | +38.9 | +40.6 | 28.3 % | +0.2 (+ 0.6%) | -0.2 (−0.3%) |
| IQR | +16.9 – +46.5 | +16.3 – +51.8 | 12.8 – 27.0% | −2.0 – +2.0 (−1.2 – +1.2%) | −6.0 – +4.0 (−7.6 – +7.0%) |
Including ipsilateral unbiopsied synchronous tumors.
RO, renal oncocytoma; LTD, longest tumor diameter; IRPV, ipsilateral renal parenchymal volume; eGFR, estimated glomerular filtration rate
Figure 1. Volumetry-generated 3D kidney reconstructions in RO patients managed with AS.
Representative CT scan slices (column 1: axial reconstruction; column 2: coronal reconstruction) and Myrian volumetry software-generated images (columns 3–4; pink= tumor; purple= renal parenchyma) are shown for 3 representative RO patients at AS initiation (row 1) and at last follow-up (row 2). Column 5 displays volumetry-generated 3D reconstructions after surface smoothening using Autodesk® Meshmixer™ software (see also supplementary Figure 1). (a) patient ID #5; (b) patient ID #29; (c) patient ID #30.
Figure 2. Lack of correlation between volumetry-computed RO growth and IRPV change during AS management.
A scatter plot depicts volumetry-computed (VC) IRPV change vs. VC RO growth among all (n=17) RO patients with tumor growth of >+10 cm3. Each dot represents one RO patient. ρ, Spearman correlation coefficient
3.4. Renal function outcomes during AS
Similar to IRPV dynamics, renal function was overall relatively stable during AS (Table 2). There was no significant difference in eGFR at presentation (median 71.0 mL/min/1.73m2) vs. last follow-up (median 70.5 mL/min/1.73m2), and the median eGFR change per patient was −3.0 mL/min/1.73m2. Stability in eGFR was also observed in the patient subset with growing tumors (median 71.0 vs. 70.0 mL/min/1.73m2; median change −2.0 mL/min/1.73m2). All patients with eGFR loss had minimal or no IRPV reduction (maximum −1.2%) (Table 3). Spearman testing confirmed no correlation between RO size change and eGFR decline (ρ=−0.16, p=0.40; Figure 3a), including in patient subsets with tumor growth or low initial eGFR (Figure 3b-g). Post hoc power analysis revealed 96% power to detect significant eGFR loss of at least −7 mL/min/1.73m2, or −10%.
Figure 3. Lack of correlation between changes in RO volume and eGFR.
Scatter plots depict eGFR change relative to manually estimated (ME) or volumetry-computed (VC) RO tumor volume change for (a) all patients (N=32), (b) the patient subset with ME RO growth of more than 10 cm3 (n=17), (c) the patient subset with VC RO growth of more than 10 cm3 (n=17), (d) the patient subset with initial eGFR< 90 ml/min/1.73 m2 (n=26); (e) the patient subset with initial eGFR< 80 ml/min/1.73 m2 (n=23); (f) the patient subset with initial eGFR< 70 ml/min/1.73 m2 (n=14); (g) the patient subset with initial eGFR< 60 ml/min/1.73 m2 (n=8). Each dot represents one RO patient. ρ, Spearman correlation coefficient
4. Discussion
The current study tested whether clinically significant loss in renal volume and function occurs during AS in unselected consecutive RO patients. A unique highlight was the novel use of volumetry software to measure IRPV changes during AS. With intermediate follow-up, RO growth showed no correlation with IRPV or eGFR changes. IRPV loss during AS was uncommon and only minor when present, with no detectable loss among patients in the top tertile of RO growth. Similarly, renal function remained relatively stable during AS, regardless of baseline renal function or RO growth; and patients with eGFR loss consistently lacked notable IRPV loss, suggesting other causes instead (e.g., medical renal disease). We conclude that renal compromise is generally not incurred by RO growth, and that AS of at least intermediate duration is functionally safe. Long-term follow-up is needed to evaluate safety durability.
To date, AS functional outcomes study has been limited to serum marker evaluation (i.e., SCr, eGFR), which is prone to variability from technical processing, patient muscle mass and other factors[25]. IRPV loss causing ipsilateral dysfunction may not manifest in eGFR loss due to contralateral renal compensation, while medical renal disease can confound the study of tumor effects on eGFR. To address these limitations, we used software-assisted volumetry to directly measure IRPV loss. Recent studies support more accurate and reproducible size assessment with volumetry relative to conventional imaging-based estimations[18–20]. Renal parenchyma volumetry has been validated for split renal function measurement and prediction of renal function after nephrectomy[21–23], but has not been previously described in AS patients to our knowledge. The current study showed excellent (98%) power to detect even minor (5%) loss in IRPV. Furthermore, volumetry computations closely reproduced manually estimated volume changes, even among tumors with only slight growth (+10–20 cm3), underscoring the platform’s sensitivity for small volume changes. Despite this power and sensitivity, only 2 patients with RO growth had detectable IRPV loss of at least 5%; and both had minimal RO growth, supporting that the IRPV loss was unrelated to the tumor. Strong correlation between volumetry-computed and manually estimated tumor volumes supports the potential future usage of volumetry in AS patient management.
AS functional safety in RO patients was recently challenged due to concern that RO growth might be commonly detrimental to renal parenchyma, similar to locally advanced RCC[5,8,11]. Among 71 RO patients, Meagher et al identified a mean decrease in eGFR of −15.3 (± 15.4) during similar AS duration as the current study[11]. This sizeable eGFR reduction was significantly worse than among RO patients electing immediate partial nephrectomy, leading the authors to condone consideration of immediate RO partial nephrectomy to optimize renal function. We believe it unlikely, however, that RO growth was a major driver for their large eGFR reduction since their reported LTD growth during AS (from median 2.6 cm to median 3.0 cm) predicts spheroid volume growth of only +6 cm3 (~2–3% of typical bilateral parenchymal volume), which is too small to explain their observed eGFR loss. Alternative explanations include differences in pre-existing medical renal disease, which is generally more common in AS/observation cohorts than surgical cohorts. In contrast to Meagher et al, we observed relative stability of renal function during RO AS, including in patient subsets with greater tumor growth or worse baseline renal function. Our observed median eGFR change of −3.0 mL/min/1.73 m2 is consistent with the expected magnitude of renal decline over a 3-year interval in a cohort with median age of 73 years[26]. Consistent with our findings, Miller et al observed that eGFR was maintained at 96% of baseline after 3 years of AS management in an oncocytic tumor cohort comprised predominantly of RO patients[7].
Additional concern has been raised that treatment deferral in RO patients might compromise nephron-sparing treatment if delayed intervention is later desired[8]. Neuzillet et al reported a need for total rather than partial nephrectomy in 4 RO patients undergoing delayed intervention due to growth beyond 6 cm. However, this clinical scenario is uncommon since the vast majority of RO remain <6 cm[7,10,11]. Our findings suggest no harm to continued treatment deferral in this scenario, as we observed no symptom development, metastasis or meaningful IRPV loss (maximum −1.7%) with RO tumors surpassing 6 cm. Further functional investigation is needed for uncommon cases with large or invasive (≥cT2) RO tumors.
Mechanisms underlying renal dysfunction during RCC progression involve tumor invasion with replacement of adjacent renal parenchyma[12–15]. Among 1569 nephrectomy patients studied by Dey et al, cT3/T4 stage was associated with significantly worse renal function than cT2 stage despite similar tumor sizes, suggesting adverse functional impact due to invasion, independent of tumor mass[12]. In RO, invasion to ≥T3 stage is rare, as is evidence of complete pseudo capsule invasion[17]. This lack of invasiveness might explain relative preservation of IRPV and renal function during RO growth. Other mechanisms by which renal mass effect may damage adjacent parenchyma include ischemia, peritumoral glomerulosclerosis and interstitial fibrosis[11,15,27,28]. Although the current study did not evaluate peritumoral histology, such injury is alone unlikely to meaningfully impact renal function due to its confinement within a few millimeters of a tumor[28]. Kheames et al showed that nonviable glomeruli adjacent to a renal tumor do not correlate with eGFR, in contrast to nonviable glomeruli away from the tumor, as in medical renal disease[28]. Mechanisms by which a renal tumor might induce more global parenchymal ischemia currently remain theoretical[29].
Our study provides novel support for AS as an optimal management option for benign RO to avoid morbidity of diagnostic surgery[5–8,10]. Among 1202 pathologically confirmed RO surgeries, Neves et al reported a 20.2% rate of in-hospital complications, and 5 (0.4%) patients died within 60 days, underscoring the surgical risk[1]. Non-surgical diagnosis of RO was challenged historically by considerable histologic overlap with oncocytic RCC variants, particularly chromophobe RCC, but has grown reliable due to improved biopsy technique, real-time cytopathologist confirmation of tumor targeting, and standardization of immunohistochemical biomarker panels that include CK7 and the RO/chromophobe-specific biomarker, CD117/KIT, in addition to RCC markers absent in RO and chromophobe RCC (e.g., CAIX, AMACR, vimentin)[3,30]. Moreover, we have prospectively validated the accuracy of a tumor:cortex PEER (peak early enhancement ratio) score using CT contrast enhancement to differentiate CD117(+) RO from CD117(+) chromophobe RCC[3]. In the current study, all CD117(+) RO tumors were corroborated as RO based on PEER scores >0.55. Study limitations include lack of long-term follow-up and inclusion of only few cT2 patients. Although adequate to conclude that loss of renal volume/function is not a common event in untreated RO patients, the limited cohort size prevents determination as to whether function/volume loss might still occur on occasion in these patients, particularly those with larger (cT2) tumors. Because synchronous primary renal tumors were not biopsied, it is unclear whether our 6 multifocal cases included only RO tumors vs. both RO and RCC. Nevertheless, we detected no sizeable loss of IRPV even in multifocal tumor subset analyses. Relative performance between different available volumetry platforms is unclear, and validation of these findings with another volumetry platform would be informative.
5. Conclusions
Given increasing utilization of AS in RO patients, it is necessary to understand whether RO growth can harm the kidney, in order to optimally counsel patients regarding treatment deferral. Volumetry is a promising novel tool to measure kidney and tumor tissue changes during AS. Our study using volumetry reveals that loss of renal parenchyma and function was uncommon in untreated RO patients and unrelated to tumor growth, which supports the functional safety of AS for RO. Long-term study is needed to determine safety durability and whether occasional exceptions occur among large or invasive (≥cT2) RO variants.
Supplementary Material
Supplementary Figure 1: Smoothening visual presentation of 3D kidney reconstructions. Representative example of a 3D kidney reconstruction generated using Myrian software before (left) versus after (right) surface smoothening using Autodesk® Meshmixer™ software (see also Figure 1, column 5).
Supplementary Figure 2. Correlation between Initial eGFR and IRPV. A scatter plot depicts correlation between initial estimated Glomerular Filtration Rate (eGFR) and initial Ipsilateral Renal Parenchymal Volume (IRPV). Each dot represents one RO patient. ρ, Spearman correlation coefficient
Supplementary Figure 3. Correlation between RO volume change based on volumetry computation versus manual estimation. A scatter plot depicts volumetry-computed (VC) RO volume changes compared to manually estimated (ME) RO volume changes. Each dot represents one RO patient. ρ, Spearman correlation coefficient
Highlights.
Volumetry to assess the impact of oncocytoma growth on renal parenchyma is novel
eGFR did not significantly change in oncocytoma patients during active surveillance
In the presence of oncocytoma growth, renal parenchymal volumes remained stable
Oncocytoma growth magnitude did not correlate with losses in renal volume or eGFR
Loss of renal parenchyma or function is uncommon in untreated oncocytoma patients
Acknowledgements/funding:
This research was generously supported by the RPCCC Friends of Urology. Statistical support was provided by the RPCCC and National Cancer Institute (NCI) grant P30CA016056.
Acronyms
- AS
Active surveillance
- CKD-EPI
Chronic Kidney Disease-Epidemiology Study Equation
- GFR
Glomerular filtration rate
- IRPV
Ipsilateral Renal Parenchymal Volume
- LTD
Longest Tumor Diameter
- NCCN
National Comprehensive Cancer Network
- PEER
Peak Early-Phase Enhancement Ratio
- RCC
Renal cell carcinoma
- RMB
Renal Mass Biopsy
- RO
Renal Oncocytoma
- RPCCC
Roswell Park Comprehensive Cancer Center
- SCr
Serum Creatinine
Footnotes
Conflicts of Interest
The authors report no potential conflicts of interest relevant to this study.
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Associated Data
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Supplementary Materials
Supplementary Figure 1: Smoothening visual presentation of 3D kidney reconstructions. Representative example of a 3D kidney reconstruction generated using Myrian software before (left) versus after (right) surface smoothening using Autodesk® Meshmixer™ software (see also Figure 1, column 5).
Supplementary Figure 2. Correlation between Initial eGFR and IRPV. A scatter plot depicts correlation between initial estimated Glomerular Filtration Rate (eGFR) and initial Ipsilateral Renal Parenchymal Volume (IRPV). Each dot represents one RO patient. ρ, Spearman correlation coefficient
Supplementary Figure 3. Correlation between RO volume change based on volumetry computation versus manual estimation. A scatter plot depicts volumetry-computed (VC) RO volume changes compared to manually estimated (ME) RO volume changes. Each dot represents one RO patient. ρ, Spearman correlation coefficient