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Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience
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Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience Patrick O. Richard a, Michael A.S. Jewett a, Jaimin R. Bhatt a, John R. Kachura b, Andrew J. Evans c, Alexandre R. Zlotta a,d, Thomas Hermanns a, Tristan Juvet a, Antonio Finelli a,* a
Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto,
Toronto, Ontario, Canada; b Department of Medical Imaging, Toronto General Hospital, University Health Network and the University of Toronto, Toronto, Ontario, Canada; c Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, University Health Network and the University of Toronto, Toronto, Ontario, Canada; d Division of Urology, Department of Surgery, Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, Canada
Article info
Abstract
Article history: Accepted April 1, 2015
Background: Renal tumor biopsy (RTB) for the characterization of small renal masses (SRMs) has not been widely adopted despite reported safety and accuracy. Without pretreatment biopsy, patients with benign tumors are frequently overtreated. Objective: To assess the diagnostic rate of RTBs, to determine their concordance with surgical pathology, and to assess their impact on management. Design, setting, and participants: This is a single-institution retrospective study of 529 patients with biopsied solid SRMs 4 cm in diameter. RTBs were performed to aid in clinical management. Outcome measurements and statistical analysis: Diagnostic and concordance rates were presented using proportions. Factors that contributed to a diagnostic biopsy were identified using a multivariable logistic regression. Results and limitations: The first biopsy was diagnostic in 90% (n = 476) of cases. Of the nondiagnostic biopsies, 24 patients underwent a second biopsy of which 83% were diagnostic. When both were combined, RTBs yielded an overall diagnostic rate of 94%. Following RTB, treatment could have been avoided in at least 26% of cases because the lesion was benign. Tumor size and exophytic location were significantly associated with biopsy outcome. RTB histology and nuclear grade were highly concordant with final pathology (93% and 94%, respectively). Adverse events were low (8.5%) and were all selflimited with the exception of one. Although excellent concordance between RTB and final pathology was observed, only a subset of patients underwent surgery following biopsy. Thus it is possible that some patients were misdiagnosed. Conclusions: RTB of SRMs provided a high rate of diagnostic accuracy, and more than a quarter were benign. Routine RTB for SRMs informs treatment decisions and diminishes unnecessary intervention. Our results support its systematic use and suggest that a change in clinical paradigm should be considered. Patient summary: Renal tumor biopsy (RTB) for pretreatment identification of the pathology of small renal masses (SRMs) is safe and reliable and decreases unnecessary treatment. Routine RTB should be considered in all patients with an indeterminate SRM for which treatment is being considered. # 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Renal cell carcinoma Renal tumor biopsies Small renal mass
* Corresponding author. Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, 610 University Avenue, Room 3-130, Toronto, Ontario, Canada, M5G 2M9. Tel. +1 416 946 2851; Fax: +1 416 946 6590. E-mail address: antonio.fi[email protected] (A. Finelli). http://dx.doi.org/10.1016/j.eururo.2015.04.004 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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1.
Introduction
a contour abnormality of the renal capsule. The tumor histology was reviewed and correlated to surgical pathology if available. Tumor
The incidence of kidney cancer is increasing, primarily due to an increase in the detection of small renal masses (SRMs) that are often early stage renal cell carcinomas (RCCs) [1]. This is thought to be in large part related to the greater use of abdominal imaging [2]. Surgical treatment of stage pT1a RCC produces excellent cancer-specific survival rates [3]. Most are incidentally detected as SRMs that are usually solid enhancing masses on imaging and concerning for malignancy [2]. There are currently no clinical or radiographic features that accurately predict histologic diagnosis. Hence surgical series have shown that 20–30% of SRMs are benign on final pathology. Moreover, SRMs found to be malignant are usually of lower nuclear grade than their larger counterparts [4]. Renal tumor biopsies (RTBs) have been proposed as a safe and useful tool for the pretreatment identification of benign tumors. The goal of RTB is to avoid the potential morbidity associated with overtreatment of SRMs [5–8]. Despite their potential benefits, RTBs have not been widely adopted in the management of SRMs [9]. The lag in uptake is likely due to concerns regarding the lack of sufficient tissue for diagnosis, discordance with final pathology, safety, and, most importantly, the lack of perceived impact on clinical management. Several, albeit generally small, studies suggest that these concerns were exaggerated [5–8]. However, large series that demonstrate the benefits of RTB are currently lacking. In this study, we described the largest single-institution experience with RTB of SRMs, explored factors associated with diagnostic success, and assessed the impact of RTB on clinical management.
histology was classified according to the World Health Organization [10]. Tumors in which the subtype was not reported were defined as RCC, unspecified. Fuhrman grade was recorded for clear cell RCC (ccRCC) histology only. If two grades were assigned to a specimen, only the higher Fuhrman grade was recorded. A biopsy was deemed nondiagnostic if there was insufficient material for histology assessment or if nonrenal or unremarkable parenchymal tissue was biopsied.
2.3.
Biopsy procedure
All RTBs were performed by 1 of the 20 IRs and carried out under imaging guidance. Most RTBs (90%) (Table 1) were performed using a 17-gauge coaxial sheath and an 18-gauge core needle. The number of cores taken at the time of the RTB was left to the discretion of the operator. Postprocedure imaging was routinely performed prior to discharge to rule out a complication.
2.4.
Pathologic evaluation
All pathologic specimens were processed according to standard institutional pathologic procedures. Specific immunohistochemical and advanced diagnostic studies were carried out at the discretion of the pathologist. All biopsies were read by one of four dedicated genitourinary pathologists.
2.5.
Objectives
The primary objectives were to establish the rates of diagnostic biopsy following the first or second RTB (if performed) and to determine the factors associated with an initial diagnostic RTB. Secondary objectives included assessing whether the diagnostic rate improved over time, measuring the safety of RTBs, and describing the impact of RTB on the management of SRMs. Last, we evaluated the concordance between the RTB pathology and the surgical pathology in patients who underwent
2.
Methods
surgery.
2.1.
Patient selection
2.6.
Statistical analysis
This retrospective single-center study was approved by the institutional
Continuous variables were reported as medians (interquartile range
review board. Subjects who underwent an RTB for a radiologically
[IQR]); categorical variables were described with proportions. The
indeterminate SRM between January 2001 and December 2013 were
baseline characteristics of the patients who had a diagnostic and
identified through a prospectively maintained database. A chart review
nondiagnostic RTB were compared using the Wilcoxon rank-sum test for
was completed to abstract periprocedural complications and to exclude
continuous variables and the chi-square or Fisher exact test for
predominantly cystic lesions as well as RTBs that were not performed
proportions. Univariable and multivariable logistic regressions models
with the objective of aiding treatment planning. A total of 705 RTBs performed in patients with lesions 4 cm were
were generated to test for an association among patient (age, gender, BMI, ASA score), lesion (laterality, location, size, exophytic appearance),
identified. Of these, 152 (21.6%) were excluded because they were
procedure-related characteristics (year of biopsy, number of previous
performed at the time of radiofrequency ablation (RFA; n = 108),
RTBs performed by the IR, type of image guidance), and the odds of
were performed at an outside institution (n = 11), or consisted of
obtaining a diagnostic biopsy at the time of the initial RTB. The
complex cystic lesions (n = 33).
multivariable model was fit with variables significant at p < 0.20 level on univariable analysis. The fit of the model was assessed using the
2.2.
Data
Hosmer-Lemeshow test and the C statistic. Residuals were assessed using a casewise diagnostics method. The odds ratios (ORs) are
We abstracted the patient demographic characteristics (age, gender,
presented with their 95% confidence intervals (CIs). The Cochran-
body mass index [BMI], American Society of Anesthesiology [ASA]
Armitage test for trend was used to test whether the diagnostic rate of
classification [grade 2–3 vs 1]), lesion characteristics (laterality, location,
the RTBs increased over the years. Proportions were used to report the
size, exophytic appearance, histology, Fuhrman grade), and procedural
safety of RTB and to report the histologic and Fuhrman grade
characteristics (year of biopsy, number of previous RTBs performed by
concordance between RTB pathology and definitive surgical pathology.
the interventional radiologist [IR], type of image guidance, number of
All data were recorded, and statistical analyses were conducted using
biopsy cores, periprocedural morbidity, and type of subsequent
SAS v.9.3 (SAS Institute Inc., Cary, NC, USA). All tests were two sided, and
intervention). An exophytic lesion was defined as a lesion that caused
p values <0.05 were considered statistically significant.
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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Table 1 – Patient, procedural, and lesion characteristics of the initial diagnostic and nondiagnostic renal tumor biopsies Variables
Age, yr, median (IQR) Gender, n (%) Male Female BMI, kg/m2, median (IQR) ASA score, n (%) 1 2 3 Unknown Kidney biopsied, n (%) Right side Left side Transplanted kidney Lesion location, n (%) Lower pole Middle pole Upper pole Tumor size, cm, median (IQR) Exophytic appearance, n (%) Yes No Unknown Previous no. of biopsies performed per provider at time of biopsy, median (IQR) Type of imaging used, n (%) Ultrasound Computed tomography scan Unknown Biopsy cores, n (%) 1–2 3–4 5 Unknown Size of biopsy needle, n (%) 18G Other Unknown
Overall (n = 529) 64 (54–73)
Diagnostic biopsies (n = 476) 65 (54–73)
Nondiagnostic biopsies (n = 53) 60 (52–69)
319 (60.3) 210 (39.7) 27.3 (24.3–31.1)
285 (89.3) 191 (91.0) 27.4 (24.3–31.1)
34 (10.7) 19 (9.0) 26.1 (24.2–29.1)
355 129 13 32
322 112 12 30
33 17 1 2
(67.1) (24.4) (2.5) (6.0)
(90.7) (86.8) (92.3) (93.8)
p value
0.045 0.55
0.50 0.44
(9.3) (13.2) (7.7) (6.2) 0.88
289 (54.6) 238 (45.0) 2 (0.4)
261 (90.3) 214 (89.9) 1 (50.0)
28 (9.7) 24 (10.1) 1 (50.0)
185 (35.0) 195 (36.9) 149 (28.1) 2.5 (1.8–3.2)
163 (88.1) 179 (91.8) 134 (89.9) 2.5 (1.9–3.4)
22 (11.9) 16 (8.2) 15 (10.1) 2.0 (1.5–2.7)
405 114 10 16
375 91 10 17
30 23 0 15
0.49
(76.6) (21.6) (1.9) (7–30)
(92.6) (79.8) (100) (7–30)
(7.4) (20.2) (0) (7–31)
<0.001 <0.001
0.98 0.03
388 (73.4) 115 (21.7) 26 (4.9)
355 (91.5) 97 (84.3) 24 (92.3)
33 (8.5) 18 (15.7) 2 (7.7)
100 211 203 15
92 192 177 15
8 19 26 0
0.31 (18.9) (39.9) (38.4) (2.8)
(92.0) (91.0) (87.2) (100)
(8.0) (9.0) (12.8) (0) 1.00
475 (89.8) 11 (2.1) 43 (8.1)
428 (90.1) 10 (90.9) 38 (88.4)
47 (9.9) 1 (9.1) 5 (11.6)
ASA = American Society of Anesthesiologists; BMI = body mass index; IQR = interquartile range.
3.
Results
A total of 529 biopsied SRMs in 509 patients were included in the analysis. The initial biopsy was diagnostic in 90% (n = 476). Of these, 26% (n = 123) were of benign histology. The patient, procedure, and lesion characteristics of initial diagnostic and nondiagnostic biopsies are compared in Table 1. Of the 53 nondiagnostic RTBs, a rebiopsy was performed in 24 masses (45%) and was diagnostic in 83% (n = 20) of them (Fig. 1). Therefore, the overall diagnostic rate when the first and second RTBs were combined was 94% (n = 496). Of these, 26% (n = 131) were benign. Most of the malignant lesions were low–Fuhrman grade ccRCC (Table 2). Although the diagnostic rates improved over time, the difference was nonsignificant (p = 0.06) (Table 3). On univariable analysis, age, tumor size, exophytic tumor location, and type of imaging used were significantly associated with the biopsy outcome. However, on multivariable analysis, larger tumor size (OR: 1.71; 95% CI, 1.17–2.50) and an exophytic location (OR: 2.91; 95% CI, 1.56–5.44) were
the only factors associated with an initial diagnostic biopsy (Table 4). The postprocedure complication status was available in 492 patients (97%). Among these, a total of 48 adverse events were reported in 42 patients (8.5%). Most of the adverse events (75%) were perirenal hematomas discovered on postprocedure imaging or bleeding through the coaxial sheath. According to the Clavien-Dindo classification [11], the complications were all grade 1 with the exception of one patient who required percutaneous angioembolization (grade 3b). After a median follow-up time of 28 mo (IQR: 11–53), no needle tract seeding had been reported (Table 5). Following RTB, 175 patients underwent surgery. Surgical pathology was unavailable in three cases (1.7%). Pathology revealed the presence of necrosis in only one case where surgery was performed following a complication after RFA. Therefore, interpretable surgical pathology was available in 171 cases. Four nephrectomies were performed following nondiagnostic biopsies, and all demonstrated malignancy. Three surgeries were performed following RTB showing a benign histology. Two of the biopsy results were confirmed on
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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Nondiagnostic biopsies (n = 53)
RFA (n = 4)
Surveillance (n = 25)
Repeat biopsy (n = 18)
Nephrectomy (n = 3)
Rebiopsy pending (n = 3)
Outcome Outcome
Repeat biopsy (n = 6)
Malignant (n = 2) Benign (n = 2)
Malignant (n = 9) Benign (n = 5) Nondiagnostic (n = 4)
Outcome Malignant (n = 3)
Outcome Malignant (n = 3) Benign (n = 3)
Fig. 1 – Outcome of the initially nondiagnostic biopsies. RFA = radiofrequency ablation.
final pathology, and one final pathology revealed normal renal parenchyma with an adjacent fat-poor angiomyolipoma in a patient with a benign spindle-cell tumor on RTB histology. There was agreement between biopsy and surgical histology in 93% of the cases (155 of 167). The discordant cases are presented in Supplementary Table 1. RTB correctly
identified ccRCC, chromophobe, and papillary RCC compared with surgical pathology in 99% (101 of 102), 100% (15 of 15), and 91% (32 of 35) of cases, respectively (Supplementary Fig. 1). With regard to the patients who were operated and diagnosed with ccRCC on both RTB and surgical pathology, Fuhrman grade was concordant in 63%
Table 2 – Histology of benign and malignant tumor obtained through biopsy (n = 496) Benign masses (n = 131)
Malignant masses (n = 365)
Type
n (%)
Type
n (%)
Oncocytic renal neoplasm, suggesting oncocytoma
80 (61.1)
Fat-poor AML
36 (27.5)
Metanephric adenoma Leiomyoma Other – –
3 (2.3) 2 (1.5) 10 (7.6) – –
Clear cell RCC Fuhrman grade I Fuhrman grade II Fuhrman grade III Fuhrman grade IV Unspecified Papillary RCC Type 1 Type 2 Unspecified Chromophobe RCC RCC (unspecified subtype) Xp11 translocation RCC Mucinous tubular and spindle cell carcinoma RCC (unclassified) Mixed clear cell and papillary RCC Other Metastasis from other primary
214 (58.6) 100 (46.7) 94 (43.9) 16 (7.5) 1 (0.5) 3 (1.4) 95 (26.0) 65 (68.4) 14 (14.7) 16 (16.8) 26 (7.1) 5 (1.4) 1 (0.3) 1 (0.3) 11 (3.0) 1 (9.1) 12 (3.3) 9 (75.0)
–
–
AML = angiomyolipoma; RCC = renal cell carcinoma.
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Table 3 – Outcome of the initially performed renal tumor biopsy and median size of lesions biopsied over the years Year 2001–2006 2007 2008 2009 2010 2011 2012 2013 Total *
Total, n (%) 54 53 43 85 59 65 90 80 529
(100) (100) (100) (100) (100) (100) (100) (100) (100)
Diagnostic n (%) 44 48 37 78 54 61 84 70 476
Nondiagnostic (%)
(81.5) (90.6) (86.0) (91.8) (91.8) (93.8) (93.3) (87.5) (90.0)
10 5 6 7 5 4 6 10 53
(18.5) (9.4) (14.0) (8.2) (8.2) (6.2) (6.7) (12.5) (10.0)
p value
Lesion size, cm, overall*
0.06
2.5 2.7 2.3 2.7 2.4 2.3 2.6 2.3 2.5
(2.0–3.2) (1.8–3.5) (1.7–3.2) (2.0–3.4) (1.8–3.0) (1.8–3.2) (1.9–3.4) (1.5–3.2) (1.8–3.2)
p value 0.30
Median (interquartile range).
Table 4 – Univariable and multivariable analysis of factors associated with a diagnostic biopsy at the time of the initial renal tumor biopsy (n = 529) Variables
Patients characteristics Age, yr (per 1-yr increase) Gender (Female vs male) BMI, km/m2 (per 1 km/m2 increase) ASA score (2–3 vs 1) Lesion characteristics Kidney biopsied (right vs left) Lesion location Middle vs lower pole Upper vs lower pole Tumor size, cm, per 1-cm increase Exophytic appearance, yes vs no Procedurals characteristics Previous no. of biopsies performed per provider at the time of biopsy (per 1-biopsy increase) Type of imaging used, ultrasound vs CT Year of biopsy, per 1-yr increase
Multivariate*,y
Univariate Odds ratio
95% CI
p value
Odds ratio
95% CI
p value
1.02 1.20
1.00–1.04 0.66–2.17
0.04 0.55
1.02
0.99–1.04
0.16
1.04 0.71
0.96–1.12 0.38–1.30
0.38 0.26
1.05
0.60–1.86
0.88
1.51 1.20 1.88 3.16
0.77–2.97 0.60–2.42 1.32–2.68 1.75–5.70
0.23 0.60 <0.001 <0.001
1.71 2.91
1.17–2.50 1.56–5.44
0.006 <0.001
1.00
0.98–1.01
0.48
2.00 1.08
1.08–3.70 0.97–1.20
0.03 0.16
1.71 1.08
0.88–3.31 0.96–1.22
0.11 0.21
ASA = American Society of Anesthesiologists [classification]; BMI = body mass index; CI = confidence interval; CT = computed tomography. Hosmer-Lemeshow goodness-of-fit test: 0.68. y C statistics: 0.72. *
of cases (64 of 101) (Supplementary Table 2). RTB undergraded most of the discordant cases (n = 34 of 37). When grades were pooled into low (1 or 2) and high grades (3 or 4), the biopsy accuracy was 94% (95 of 101). When pooled, six cases had discordant grades, all of which were of lower grade on the RTB compared with definitive pathology.
Table 5 – Adverse events reported following renal tumor biopsies (n = 509 patients) Type Perirenal hematoma Conservative Percutaneous angioembolization Skin hematoma Venous bleeding through coaxial sheath Self-limited Hemostatic agents used Self-limited gross hematuria Nausea/Vomiting Persistent pain Dizziness
Of the masses that were not initially treated surgically, 230 were managed by active surveillance (AS), 94 with thermal ablation therapy, 15 were referred to an oncologist for systemic therapies (nine for metastasis from non-RCC primaries), 10 were awaiting a decision, and 8 had been lost to follow-up before any treatment decision was made. The histology of lesions managed by AS is illustrated in Supplementary Figure 2. Of these patients, four eventually received definitive treatment because of tumor growth (surgery in three and RFA in one).
n (%) 24 23 1 1 12 5 7 5 1 3 2
(4.7) (95.8) (4.2) (0.2) (2.4) (41.7) (58.3) (1.0) (0.2) (0.6) (0.4)
4.
Discussion
Despite a growing body of evidence, the merits and safety of pretreatment biopsy continue to be debated. This study focused on RTB of SRMs as an aid to treatment decision making. To the best of our knowledge, it is the largest single-institution cohort published on SRM biopsy. We have demonstrated a 90% diagnostic rate with an initial biopsy and an 83% diagnostic rate after a rebiopsy for initially nondiagnostic RTB. Thus RTBs led to a diagnosis in 94% of
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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patients with SRMs when the outcomes from the first and second biopsy were combined. Our results are consistent with the higher end of previously reported diagnostic rates varying from 70% to 91% for SRMs in smaller series [5,8,12–18]. Although diagnostic rates increased over time, the improvement was statistically nonsignificant. In the present study, larger SRMs and exophytic location were significantly associated with increased odds of obtaining a diagnostic biopsy. The odds of obtaining a diagnostic biopsy were almost threefold higher with an exophytic mass compared with a completely endophytic one. Tumor size as a predictor of diagnostic biopsies was previously reported [5,8,17,18]. Neither IR experience nor patient BMI was related to a diagnostic RTB. These results have also shown that histologic subtypes diagnosed with RTB had a high concordance (94%) with surgical pathology. Such rates were stated in a 2012 review article to be between 86% and 98% [19]. As previously reported [19–21], RTB seems to be less accurate in determining Fuhrman grade with a tendency to undergrade compared with the final surgical pathology. Fuhrman grades have been often pooled into low (1 and 2) and high (3 and 4) to improve the prognostic value of grade in ccRCC [22]. The prognostic utility of such pooling in SRMs is unknown, but if it were to be applied, substantial agreement would be observed (94%). Furthermore, studies have shown that ccRCC masses <3 cm are low grade in >90% of cases [23]. The controversy regarding grade heterogeneity in SRMs is pertinent to programs where initial AS is offered and should be acknowledged as a shortcoming of the technique. As we learn more of the natural history of SRMs managed by AS [24] and the greater likelihood of older and infirm patients dying from other causes [25], RTB to determine pretreatment histology may become more relevant to treatment decisions. It is generally believed that low-grade ccRCC, papillary type 1, and chromophobe tumors carry more favorable prognoses [26]. Thus if AS was offered as initial treatment for low-grade malignancies, definitive therapy could be avoided in even more individuals following RTBs. As previously reported [19], this study confirms the safety of RTBs with significant complications occurring in <1% of cases. Although needle tract seeding remains a concern, none of the patients biopsied experienced such an event. Moreover, since the use of coaxial biopsy techniques, no such cases have been reported in the literature [19]. This study is not devoid of limitations. First, it is possible that noncaptured variables may have affected the biopsy success rates, such as the lesion’s echogenicity, anterior versus posterior location, and amount of adipose tissue. Likewise, given the fact that periprocedural complications were captured retrospectively, it is likely that complications were underestimated. The small number of patients who underwent a rebiopsy following an initial nondiagnostic RTB also limited our ability to assess the value of rebiopsy. Nonetheless, given the relatively high diagnostic rate after a repeat biopsy (83%) and the high benign rate among these (40%), it seems worthwhile. Finally, although we have demonstrated a good correlation between biopsy and final pathology, the fact remains that
only a subset of patients underwent surgery. For example, it is possible that a subset of patients labeled as harboring a benign oncocytic renal neoplasm are in fact actually harboring a chromophobe RCC or a mixed tumor. Due to this concern, we routinely follow these patients with regular imaging despite the presence of a favorable RTB pathology. In experienced hands, RTB is associated with a high diagnostic yield, high pathologic correlation with definitive surgical pathology, and low morbidity. Moreover, based on the biopsy results, treatment was avoided or could have been avoided in at least 25% of patients because of benign histology by RTB. In addition to preventing unnecessary interventions, studies have also shown RTBs to be cost effective [27]. RTBs may also help better define candidates for AS. As such, RTBs may help avoid unnecessary treatment and its related morbidity. Renal surgery is associated with morbidity including but not limited to hemorrhage (<10%), urine leak (<3%), acute renal insufficiency (<2%), flank bulge or hernia (approximately 5%), and a low but nonetheless real risk of perioperative mortality (<1%) [28,29]. As such, in our opinion, it seems very difficult to continue justifying performing potentially morbid surgery for SRMs based only on imaging findings because RTB is safe and has a diagnostic yield in >90% of cases. 5.
Conclusions
Although the evidence in favor of routine RTB to characterize SRMs is compelling, critics have continued to argue against the practice because of the previously enumerated concerns. Our results demonstrate that each of these concerns is exaggerated. In view of our results, it seems difficult to continue to justify a timid uptake of routine SRM biopsies and the use of this information to implement treatment strategies. Indeed RCC is one of the very few tumors where indications for surgery are based on imaging only. Given the current evidence, it is our strong belief that it is now time to shift the clinical paradigm. We believe that RTB should be considered the initial step in the management of patients with radiographically indeterminate SRMs in whom a therapeutic approach is being considered. In an era where overdiagnosis and overtreatment of favorable cancers is gaining worldwide attention, routine RTB for SRM should lead to diminished intervention. Furthermore, with biomarker discovery RTB could ultimately facilitate the personalization of care. The abstract was presented at the Annual Urological Association meeting, (May 16–21, 2014) and the annual Canadian Urological Association meeting (June 28–July 1, 2014). Author contributions: Antonio Finelli had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Finelli, Jewett, Kachura, Evans, Zlotta. Acquisition of data: Richard, Bhatt, Juvet, Hermanns, Finelli. Analysis and interpretation of data: Richard, Finelli, Jewett, Evans. Drafting of the manuscript: Richard, Jewett, Bhatt, Kachura, Evans, Hermanns, Juvet, Zlotta, Finelli.
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Critical revision of the manuscript for important intellectual content:
7
[10] Eble E, Sauter G, Epstein J, et al. WHO pathology and genetics of the
Richard, Jewett, Bhatt, Evans, Hermanns, Zlotta, Finelli.
urinary system and male genital organs. Lyon, France: IARC Press;
Statistical analysis: Richard, Finelli.
2004.
Obtaining funding: None. Administrative, technical, or material support: Finelli. Supervision: Jewett, Finelli. Other (specify): None.
[11] Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. [12] Salem S, Ponsky LE, Abouassaly R, et al. Image-guided biopsy of small renal masses in the era of ablative therapies. Int J Urol
Financial disclosures: Antonio Finelli certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michael A.S. Jewett is an employee of Impact Genetics, Inc., owns stock in Theralase, Inc; receives honoraria and funding and also is a consultant for Myriad Genetics, Pfizer, Janssen, and Viventia. He also receives honoraria and is a consultant for Novartis. He holds patents for Bard. Andrew J. Evans is a consultant for GE/Omnyx digital pathology. Alexandre R. Zlotta receives honoraria and funding from Sanofi and is a consultant for Queen’s CPD. The remaining authors have nothing to disclose. Funding/Support and role of the sponsor: None.
2013;20:580–4. [13] Millet I, Curros F, Serre I, et al. Can renal biopsy accurately predict histological subtype and Fuhrman grade of renal cell carcinoma? J Urol 2012;188:1690–4. [14] Veltri A, Garetto I, Tosetti I, et al. Diagnostic accuracy and clinical impact of imaging-guided needle biopsy of renal masses. Retrospective analysis on 150 cases. Eur Radiol 2011;32:393–401. [15] Neuzillet Y, Lechevallier E, Andre M, et al. Accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0 cm) renal masses. J Urol 2004; 171:1802–5. [16] Shannon BA, Cohen RJ, de Bruto H, et al. The value of preoperative needle core biopsy for diagnosing benign lesions among small, incidentally detected renal masses. J Urol 2008;180:1257–61. [17] Barwari K, Beemster PW, Hew MN, et al. Are there parameters that
Acknowledgment: The authors acknowledge Karthikeyan Manickava-
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Department of Biostatistics, Princess Margaret Cancer Centre, for her valuable statistical advice.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.04.004.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Kidney Cancer Editorial by XXX on pp. x–y of this issue
Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience Patrick O. Richard a, Michael A.S. Jewett a, Jaimin R. Bhatt a, John R. Kachura b, Andrew J. Evans c, Alexandre R. Zlotta a,d, Thomas Hermanns a, Tristan Juvet a, Antonio Finelli a,* a
Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto,
Toronto, Ontario, Canada; b Department of Medical Imaging, Toronto General Hospital, University Health Network and the University of Toronto, Toronto, Ontario, Canada; c Department of Laboratory Medicine and Pathobiology, Toronto General Hospital, University Health Network and the University of Toronto, Toronto, Ontario, Canada; d Division of Urology, Department of Surgery, Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, Canada
Article info
Abstract
Article history: Accepted April 1, 2015
Background: Renal tumor biopsy (RTB) for the characterization of small renal masses (SRMs) has not been widely adopted despite reported safety and accuracy. Without pretreatment biopsy, patients with benign tumors are frequently overtreated. Objective: To assess the diagnostic rate of RTBs, to determine their concordance with surgical pathology, and to assess their impact on management. Design, setting, and participants: This is a single-institution retrospective study of 529 patients with biopsied solid SRMs 4 cm in diameter. RTBs were performed to aid in clinical management. Outcome measurements and statistical analysis: Diagnostic and concordance rates were presented using proportions. Factors that contributed to a diagnostic biopsy were identified using a multivariable logistic regression. Results and limitations: The first biopsy was diagnostic in 90% (n = 476) of cases. Of the nondiagnostic biopsies, 24 patients underwent a second biopsy of which 83% were diagnostic. When both were combined, RTBs yielded an overall diagnostic rate of 94%. Following RTB, treatment could have been avoided in at least 26% of cases because the lesion was benign. Tumor size and exophytic location were significantly associated with biopsy outcome. RTB histology and nuclear grade were highly concordant with final pathology (93% and 94%, respectively). Adverse events were low (8.5%) and were all selflimited with the exception of one. Although excellent concordance between RTB and final pathology was observed, only a subset of patients underwent surgery following biopsy. Thus it is possible that some patients were misdiagnosed. Conclusions: RTB of SRMs provided a high rate of diagnostic accuracy, and more than a quarter were benign. Routine RTB for SRMs informs treatment decisions and diminishes unnecessary intervention. Our results support its systematic use and suggest that a change in clinical paradigm should be considered. Patient summary: Renal tumor biopsy (RTB) for pretreatment identification of the pathology of small renal masses (SRMs) is safe and reliable and decreases unnecessary treatment. Routine RTB should be considered in all patients with an indeterminate SRM for which treatment is being considered. # 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Renal cell carcinoma Renal tumor biopsies Small renal mass
* Corresponding author. Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, 610 University Avenue, Room 3-130, Toronto, Ontario, Canada, M5G 2M9. Tel. +1 416 946 2851; Fax: +1 416 946 6590. E-mail address: antonio.fi[email protected] (A. Finelli). http://dx.doi.org/10.1016/j.eururo.2015.04.004 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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1.
Introduction
a contour abnormality of the renal capsule. The tumor histology was reviewed and correlated to surgical pathology if available. Tumor
The incidence of kidney cancer is increasing, primarily due to an increase in the detection of small renal masses (SRMs) that are often early stage renal cell carcinomas (RCCs) [1]. This is thought to be in large part related to the greater use of abdominal imaging [2]. Surgical treatment of stage pT1a RCC produces excellent cancer-specific survival rates [3]. Most are incidentally detected as SRMs that are usually solid enhancing masses on imaging and concerning for malignancy [2]. There are currently no clinical or radiographic features that accurately predict histologic diagnosis. Hence surgical series have shown that 20–30% of SRMs are benign on final pathology. Moreover, SRMs found to be malignant are usually of lower nuclear grade than their larger counterparts [4]. Renal tumor biopsies (RTBs) have been proposed as a safe and useful tool for the pretreatment identification of benign tumors. The goal of RTB is to avoid the potential morbidity associated with overtreatment of SRMs [5–8]. Despite their potential benefits, RTBs have not been widely adopted in the management of SRMs [9]. The lag in uptake is likely due to concerns regarding the lack of sufficient tissue for diagnosis, discordance with final pathology, safety, and, most importantly, the lack of perceived impact on clinical management. Several, albeit generally small, studies suggest that these concerns were exaggerated [5–8]. However, large series that demonstrate the benefits of RTB are currently lacking. In this study, we described the largest single-institution experience with RTB of SRMs, explored factors associated with diagnostic success, and assessed the impact of RTB on clinical management.
histology was classified according to the World Health Organization [10]. Tumors in which the subtype was not reported were defined as RCC, unspecified. Fuhrman grade was recorded for clear cell RCC (ccRCC) histology only. If two grades were assigned to a specimen, only the higher Fuhrman grade was recorded. A biopsy was deemed nondiagnostic if there was insufficient material for histology assessment or if nonrenal or unremarkable parenchymal tissue was biopsied.
2.3.
Biopsy procedure
All RTBs were performed by 1 of the 20 IRs and carried out under imaging guidance. Most RTBs (90%) (Table 1) were performed using a 17-gauge coaxial sheath and an 18-gauge core needle. The number of cores taken at the time of the RTB was left to the discretion of the operator. Postprocedure imaging was routinely performed prior to discharge to rule out a complication.
2.4.
Pathologic evaluation
All pathologic specimens were processed according to standard institutional pathologic procedures. Specific immunohistochemical and advanced diagnostic studies were carried out at the discretion of the pathologist. All biopsies were read by one of four dedicated genitourinary pathologists.
2.5.
Objectives
The primary objectives were to establish the rates of diagnostic biopsy following the first or second RTB (if performed) and to determine the factors associated with an initial diagnostic RTB. Secondary objectives included assessing whether the diagnostic rate improved over time, measuring the safety of RTBs, and describing the impact of RTB on the management of SRMs. Last, we evaluated the concordance between the RTB pathology and the surgical pathology in patients who underwent
2.
Methods
surgery.
2.1.
Patient selection
2.6.
Statistical analysis
This retrospective single-center study was approved by the institutional
Continuous variables were reported as medians (interquartile range
review board. Subjects who underwent an RTB for a radiologically
[IQR]); categorical variables were described with proportions. The
indeterminate SRM between January 2001 and December 2013 were
baseline characteristics of the patients who had a diagnostic and
identified through a prospectively maintained database. A chart review
nondiagnostic RTB were compared using the Wilcoxon rank-sum test for
was completed to abstract periprocedural complications and to exclude
continuous variables and the chi-square or Fisher exact test for
predominantly cystic lesions as well as RTBs that were not performed
proportions. Univariable and multivariable logistic regressions models
with the objective of aiding treatment planning. A total of 705 RTBs performed in patients with lesions 4 cm were
were generated to test for an association among patient (age, gender, BMI, ASA score), lesion (laterality, location, size, exophytic appearance),
identified. Of these, 152 (21.6%) were excluded because they were
procedure-related characteristics (year of biopsy, number of previous
performed at the time of radiofrequency ablation (RFA; n = 108),
RTBs performed by the IR, type of image guidance), and the odds of
were performed at an outside institution (n = 11), or consisted of
obtaining a diagnostic biopsy at the time of the initial RTB. The
complex cystic lesions (n = 33).
multivariable model was fit with variables significant at p < 0.20 level on univariable analysis. The fit of the model was assessed using the
2.2.
Data
Hosmer-Lemeshow test and the C statistic. Residuals were assessed using a casewise diagnostics method. The odds ratios (ORs) are
We abstracted the patient demographic characteristics (age, gender,
presented with their 95% confidence intervals (CIs). The Cochran-
body mass index [BMI], American Society of Anesthesiology [ASA]
Armitage test for trend was used to test whether the diagnostic rate of
classification [grade 2–3 vs 1]), lesion characteristics (laterality, location,
the RTBs increased over the years. Proportions were used to report the
size, exophytic appearance, histology, Fuhrman grade), and procedural
safety of RTB and to report the histologic and Fuhrman grade
characteristics (year of biopsy, number of previous RTBs performed by
concordance between RTB pathology and definitive surgical pathology.
the interventional radiologist [IR], type of image guidance, number of
All data were recorded, and statistical analyses were conducted using
biopsy cores, periprocedural morbidity, and type of subsequent
SAS v.9.3 (SAS Institute Inc., Cary, NC, USA). All tests were two sided, and
intervention). An exophytic lesion was defined as a lesion that caused
p values <0.05 were considered statistically significant.
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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Table 1 – Patient, procedural, and lesion characteristics of the initial diagnostic and nondiagnostic renal tumor biopsies Variables
Age, yr, median (IQR) Gender, n (%) Male Female BMI, kg/m2, median (IQR) ASA score, n (%) 1 2 3 Unknown Kidney biopsied, n (%) Right side Left side Transplanted kidney Lesion location, n (%) Lower pole Middle pole Upper pole Tumor size, cm, median (IQR) Exophytic appearance, n (%) Yes No Unknown Previous no. of biopsies performed per provider at time of biopsy, median (IQR) Type of imaging used, n (%) Ultrasound Computed tomography scan Unknown Biopsy cores, n (%) 1–2 3–4 5 Unknown Size of biopsy needle, n (%) 18G Other Unknown
Overall (n = 529) 64 (54–73)
Diagnostic biopsies (n = 476) 65 (54–73)
Nondiagnostic biopsies (n = 53) 60 (52–69)
319 (60.3) 210 (39.7) 27.3 (24.3–31.1)
285 (89.3) 191 (91.0) 27.4 (24.3–31.1)
34 (10.7) 19 (9.0) 26.1 (24.2–29.1)
355 129 13 32
322 112 12 30
33 17 1 2
(67.1) (24.4) (2.5) (6.0)
(90.7) (86.8) (92.3) (93.8)
p value
0.045 0.55
0.50 0.44
(9.3) (13.2) (7.7) (6.2) 0.88
289 (54.6) 238 (45.0) 2 (0.4)
261 (90.3) 214 (89.9) 1 (50.0)
28 (9.7) 24 (10.1) 1 (50.0)
185 (35.0) 195 (36.9) 149 (28.1) 2.5 (1.8–3.2)
163 (88.1) 179 (91.8) 134 (89.9) 2.5 (1.9–3.4)
22 (11.9) 16 (8.2) 15 (10.1) 2.0 (1.5–2.7)
405 114 10 16
375 91 10 17
30 23 0 15
0.49
(76.6) (21.6) (1.9) (7–30)
(92.6) (79.8) (100) (7–30)
(7.4) (20.2) (0) (7–31)
<0.001 <0.001
0.98 0.03
388 (73.4) 115 (21.7) 26 (4.9)
355 (91.5) 97 (84.3) 24 (92.3)
33 (8.5) 18 (15.7) 2 (7.7)
100 211 203 15
92 192 177 15
8 19 26 0
0.31 (18.9) (39.9) (38.4) (2.8)
(92.0) (91.0) (87.2) (100)
(8.0) (9.0) (12.8) (0) 1.00
475 (89.8) 11 (2.1) 43 (8.1)
428 (90.1) 10 (90.9) 38 (88.4)
47 (9.9) 1 (9.1) 5 (11.6)
ASA = American Society of Anesthesiologists; BMI = body mass index; IQR = interquartile range.
3.
Results
A total of 529 biopsied SRMs in 509 patients were included in the analysis. The initial biopsy was diagnostic in 90% (n = 476). Of these, 26% (n = 123) were of benign histology. The patient, procedure, and lesion characteristics of initial diagnostic and nondiagnostic biopsies are compared in Table 1. Of the 53 nondiagnostic RTBs, a rebiopsy was performed in 24 masses (45%) and was diagnostic in 83% (n = 20) of them (Fig. 1). Therefore, the overall diagnostic rate when the first and second RTBs were combined was 94% (n = 496). Of these, 26% (n = 131) were benign. Most of the malignant lesions were low–Fuhrman grade ccRCC (Table 2). Although the diagnostic rates improved over time, the difference was nonsignificant (p = 0.06) (Table 3). On univariable analysis, age, tumor size, exophytic tumor location, and type of imaging used were significantly associated with the biopsy outcome. However, on multivariable analysis, larger tumor size (OR: 1.71; 95% CI, 1.17–2.50) and an exophytic location (OR: 2.91; 95% CI, 1.56–5.44) were
the only factors associated with an initial diagnostic biopsy (Table 4). The postprocedure complication status was available in 492 patients (97%). Among these, a total of 48 adverse events were reported in 42 patients (8.5%). Most of the adverse events (75%) were perirenal hematomas discovered on postprocedure imaging or bleeding through the coaxial sheath. According to the Clavien-Dindo classification [11], the complications were all grade 1 with the exception of one patient who required percutaneous angioembolization (grade 3b). After a median follow-up time of 28 mo (IQR: 11–53), no needle tract seeding had been reported (Table 5). Following RTB, 175 patients underwent surgery. Surgical pathology was unavailable in three cases (1.7%). Pathology revealed the presence of necrosis in only one case where surgery was performed following a complication after RFA. Therefore, interpretable surgical pathology was available in 171 cases. Four nephrectomies were performed following nondiagnostic biopsies, and all demonstrated malignancy. Three surgeries were performed following RTB showing a benign histology. Two of the biopsy results were confirmed on
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Nondiagnostic biopsies (n = 53)
RFA (n = 4)
Surveillance (n = 25)
Repeat biopsy (n = 18)
Nephrectomy (n = 3)
Rebiopsy pending (n = 3)
Outcome Outcome
Repeat biopsy (n = 6)
Malignant (n = 2) Benign (n = 2)
Malignant (n = 9) Benign (n = 5) Nondiagnostic (n = 4)
Outcome Malignant (n = 3)
Outcome Malignant (n = 3) Benign (n = 3)
Fig. 1 – Outcome of the initially nondiagnostic biopsies. RFA = radiofrequency ablation.
final pathology, and one final pathology revealed normal renal parenchyma with an adjacent fat-poor angiomyolipoma in a patient with a benign spindle-cell tumor on RTB histology. There was agreement between biopsy and surgical histology in 93% of the cases (155 of 167). The discordant cases are presented in Supplementary Table 1. RTB correctly
identified ccRCC, chromophobe, and papillary RCC compared with surgical pathology in 99% (101 of 102), 100% (15 of 15), and 91% (32 of 35) of cases, respectively (Supplementary Fig. 1). With regard to the patients who were operated and diagnosed with ccRCC on both RTB and surgical pathology, Fuhrman grade was concordant in 63%
Table 2 – Histology of benign and malignant tumor obtained through biopsy (n = 496) Benign masses (n = 131)
Malignant masses (n = 365)
Type
n (%)
Type
n (%)
Oncocytic renal neoplasm, suggesting oncocytoma
80 (61.1)
Fat-poor AML
36 (27.5)
Metanephric adenoma Leiomyoma Other – –
3 (2.3) 2 (1.5) 10 (7.6) – –
Clear cell RCC Fuhrman grade I Fuhrman grade II Fuhrman grade III Fuhrman grade IV Unspecified Papillary RCC Type 1 Type 2 Unspecified Chromophobe RCC RCC (unspecified subtype) Xp11 translocation RCC Mucinous tubular and spindle cell carcinoma RCC (unclassified) Mixed clear cell and papillary RCC Other Metastasis from other primary
214 (58.6) 100 (46.7) 94 (43.9) 16 (7.5) 1 (0.5) 3 (1.4) 95 (26.0) 65 (68.4) 14 (14.7) 16 (16.8) 26 (7.1) 5 (1.4) 1 (0.3) 1 (0.3) 11 (3.0) 1 (9.1) 12 (3.3) 9 (75.0)
–
–
AML = angiomyolipoma; RCC = renal cell carcinoma.
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Table 3 – Outcome of the initially performed renal tumor biopsy and median size of lesions biopsied over the years Year 2001–2006 2007 2008 2009 2010 2011 2012 2013 Total *
Total, n (%) 54 53 43 85 59 65 90 80 529
(100) (100) (100) (100) (100) (100) (100) (100) (100)
Diagnostic n (%) 44 48 37 78 54 61 84 70 476
Nondiagnostic (%)
(81.5) (90.6) (86.0) (91.8) (91.8) (93.8) (93.3) (87.5) (90.0)
10 5 6 7 5 4 6 10 53
(18.5) (9.4) (14.0) (8.2) (8.2) (6.2) (6.7) (12.5) (10.0)
p value
Lesion size, cm, overall*
0.06
2.5 2.7 2.3 2.7 2.4 2.3 2.6 2.3 2.5
(2.0–3.2) (1.8–3.5) (1.7–3.2) (2.0–3.4) (1.8–3.0) (1.8–3.2) (1.9–3.4) (1.5–3.2) (1.8–3.2)
p value 0.30
Median (interquartile range).
Table 4 – Univariable and multivariable analysis of factors associated with a diagnostic biopsy at the time of the initial renal tumor biopsy (n = 529) Variables
Patients characteristics Age, yr (per 1-yr increase) Gender (Female vs male) BMI, km/m2 (per 1 km/m2 increase) ASA score (2–3 vs 1) Lesion characteristics Kidney biopsied (right vs left) Lesion location Middle vs lower pole Upper vs lower pole Tumor size, cm, per 1-cm increase Exophytic appearance, yes vs no Procedurals characteristics Previous no. of biopsies performed per provider at the time of biopsy (per 1-biopsy increase) Type of imaging used, ultrasound vs CT Year of biopsy, per 1-yr increase
Multivariate*,y
Univariate Odds ratio
95% CI
p value
Odds ratio
95% CI
p value
1.02 1.20
1.00–1.04 0.66–2.17
0.04 0.55
1.02
0.99–1.04
0.16
1.04 0.71
0.96–1.12 0.38–1.30
0.38 0.26
1.05
0.60–1.86
0.88
1.51 1.20 1.88 3.16
0.77–2.97 0.60–2.42 1.32–2.68 1.75–5.70
0.23 0.60 <0.001 <0.001
1.71 2.91
1.17–2.50 1.56–5.44
0.006 <0.001
1.00
0.98–1.01
0.48
2.00 1.08
1.08–3.70 0.97–1.20
0.03 0.16
1.71 1.08
0.88–3.31 0.96–1.22
0.11 0.21
ASA = American Society of Anesthesiologists [classification]; BMI = body mass index; CI = confidence interval; CT = computed tomography. Hosmer-Lemeshow goodness-of-fit test: 0.68. y C statistics: 0.72. *
of cases (64 of 101) (Supplementary Table 2). RTB undergraded most of the discordant cases (n = 34 of 37). When grades were pooled into low (1 or 2) and high grades (3 or 4), the biopsy accuracy was 94% (95 of 101). When pooled, six cases had discordant grades, all of which were of lower grade on the RTB compared with definitive pathology.
Table 5 – Adverse events reported following renal tumor biopsies (n = 509 patients) Type Perirenal hematoma Conservative Percutaneous angioembolization Skin hematoma Venous bleeding through coaxial sheath Self-limited Hemostatic agents used Self-limited gross hematuria Nausea/Vomiting Persistent pain Dizziness
Of the masses that were not initially treated surgically, 230 were managed by active surveillance (AS), 94 with thermal ablation therapy, 15 were referred to an oncologist for systemic therapies (nine for metastasis from non-RCC primaries), 10 were awaiting a decision, and 8 had been lost to follow-up before any treatment decision was made. The histology of lesions managed by AS is illustrated in Supplementary Figure 2. Of these patients, four eventually received definitive treatment because of tumor growth (surgery in three and RFA in one).
n (%) 24 23 1 1 12 5 7 5 1 3 2
(4.7) (95.8) (4.2) (0.2) (2.4) (41.7) (58.3) (1.0) (0.2) (0.6) (0.4)
4.
Discussion
Despite a growing body of evidence, the merits and safety of pretreatment biopsy continue to be debated. This study focused on RTB of SRMs as an aid to treatment decision making. To the best of our knowledge, it is the largest single-institution cohort published on SRM biopsy. We have demonstrated a 90% diagnostic rate with an initial biopsy and an 83% diagnostic rate after a rebiopsy for initially nondiagnostic RTB. Thus RTBs led to a diagnosis in 94% of
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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patients with SRMs when the outcomes from the first and second biopsy were combined. Our results are consistent with the higher end of previously reported diagnostic rates varying from 70% to 91% for SRMs in smaller series [5,8,12–18]. Although diagnostic rates increased over time, the improvement was statistically nonsignificant. In the present study, larger SRMs and exophytic location were significantly associated with increased odds of obtaining a diagnostic biopsy. The odds of obtaining a diagnostic biopsy were almost threefold higher with an exophytic mass compared with a completely endophytic one. Tumor size as a predictor of diagnostic biopsies was previously reported [5,8,17,18]. Neither IR experience nor patient BMI was related to a diagnostic RTB. These results have also shown that histologic subtypes diagnosed with RTB had a high concordance (94%) with surgical pathology. Such rates were stated in a 2012 review article to be between 86% and 98% [19]. As previously reported [19–21], RTB seems to be less accurate in determining Fuhrman grade with a tendency to undergrade compared with the final surgical pathology. Fuhrman grades have been often pooled into low (1 and 2) and high (3 and 4) to improve the prognostic value of grade in ccRCC [22]. The prognostic utility of such pooling in SRMs is unknown, but if it were to be applied, substantial agreement would be observed (94%). Furthermore, studies have shown that ccRCC masses <3 cm are low grade in >90% of cases [23]. The controversy regarding grade heterogeneity in SRMs is pertinent to programs where initial AS is offered and should be acknowledged as a shortcoming of the technique. As we learn more of the natural history of SRMs managed by AS [24] and the greater likelihood of older and infirm patients dying from other causes [25], RTB to determine pretreatment histology may become more relevant to treatment decisions. It is generally believed that low-grade ccRCC, papillary type 1, and chromophobe tumors carry more favorable prognoses [26]. Thus if AS was offered as initial treatment for low-grade malignancies, definitive therapy could be avoided in even more individuals following RTBs. As previously reported [19], this study confirms the safety of RTBs with significant complications occurring in <1% of cases. Although needle tract seeding remains a concern, none of the patients biopsied experienced such an event. Moreover, since the use of coaxial biopsy techniques, no such cases have been reported in the literature [19]. This study is not devoid of limitations. First, it is possible that noncaptured variables may have affected the biopsy success rates, such as the lesion’s echogenicity, anterior versus posterior location, and amount of adipose tissue. Likewise, given the fact that periprocedural complications were captured retrospectively, it is likely that complications were underestimated. The small number of patients who underwent a rebiopsy following an initial nondiagnostic RTB also limited our ability to assess the value of rebiopsy. Nonetheless, given the relatively high diagnostic rate after a repeat biopsy (83%) and the high benign rate among these (40%), it seems worthwhile. Finally, although we have demonstrated a good correlation between biopsy and final pathology, the fact remains that
only a subset of patients underwent surgery. For example, it is possible that a subset of patients labeled as harboring a benign oncocytic renal neoplasm are in fact actually harboring a chromophobe RCC or a mixed tumor. Due to this concern, we routinely follow these patients with regular imaging despite the presence of a favorable RTB pathology. In experienced hands, RTB is associated with a high diagnostic yield, high pathologic correlation with definitive surgical pathology, and low morbidity. Moreover, based on the biopsy results, treatment was avoided or could have been avoided in at least 25% of patients because of benign histology by RTB. In addition to preventing unnecessary interventions, studies have also shown RTBs to be cost effective [27]. RTBs may also help better define candidates for AS. As such, RTBs may help avoid unnecessary treatment and its related morbidity. Renal surgery is associated with morbidity including but not limited to hemorrhage (<10%), urine leak (<3%), acute renal insufficiency (<2%), flank bulge or hernia (approximately 5%), and a low but nonetheless real risk of perioperative mortality (<1%) [28,29]. As such, in our opinion, it seems very difficult to continue justifying performing potentially morbid surgery for SRMs based only on imaging findings because RTB is safe and has a diagnostic yield in >90% of cases. 5.
Conclusions
Although the evidence in favor of routine RTB to characterize SRMs is compelling, critics have continued to argue against the practice because of the previously enumerated concerns. Our results demonstrate that each of these concerns is exaggerated. In view of our results, it seems difficult to continue to justify a timid uptake of routine SRM biopsies and the use of this information to implement treatment strategies. Indeed RCC is one of the very few tumors where indications for surgery are based on imaging only. Given the current evidence, it is our strong belief that it is now time to shift the clinical paradigm. We believe that RTB should be considered the initial step in the management of patients with radiographically indeterminate SRMs in whom a therapeutic approach is being considered. In an era where overdiagnosis and overtreatment of favorable cancers is gaining worldwide attention, routine RTB for SRM should lead to diminished intervention. Furthermore, with biomarker discovery RTB could ultimately facilitate the personalization of care. The abstract was presented at the Annual Urological Association meeting, (May 16–21, 2014) and the annual Canadian Urological Association meeting (June 28–July 1, 2014). Author contributions: Antonio Finelli had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Finelli, Jewett, Kachura, Evans, Zlotta. Acquisition of data: Richard, Bhatt, Juvet, Hermanns, Finelli. Analysis and interpretation of data: Richard, Finelli, Jewett, Evans. Drafting of the manuscript: Richard, Jewett, Bhatt, Kachura, Evans, Hermanns, Juvet, Zlotta, Finelli.
Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004
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Critical revision of the manuscript for important intellectual content:
7
[10] Eble E, Sauter G, Epstein J, et al. WHO pathology and genetics of the
Richard, Jewett, Bhatt, Evans, Hermanns, Zlotta, Finelli.
urinary system and male genital organs. Lyon, France: IARC Press;
Statistical analysis: Richard, Finelli.
2004.
Obtaining funding: None. Administrative, technical, or material support: Finelli. Supervision: Jewett, Finelli. Other (specify): None.
[11] Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. [12] Salem S, Ponsky LE, Abouassaly R, et al. Image-guided biopsy of small renal masses in the era of ablative therapies. Int J Urol
Financial disclosures: Antonio Finelli certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michael A.S. Jewett is an employee of Impact Genetics, Inc., owns stock in Theralase, Inc; receives honoraria and funding and also is a consultant for Myriad Genetics, Pfizer, Janssen, and Viventia. He also receives honoraria and is a consultant for Novartis. He holds patents for Bard. Andrew J. Evans is a consultant for GE/Omnyx digital pathology. Alexandre R. Zlotta receives honoraria and funding from Sanofi and is a consultant for Queen’s CPD. The remaining authors have nothing to disclose. Funding/Support and role of the sponsor: None.
2013;20:580–4. [13] Millet I, Curros F, Serre I, et al. Can renal biopsy accurately predict histological subtype and Fuhrman grade of renal cell carcinoma? J Urol 2012;188:1690–4. [14] Veltri A, Garetto I, Tosetti I, et al. Diagnostic accuracy and clinical impact of imaging-guided needle biopsy of renal masses. Retrospective analysis on 150 cases. Eur Radiol 2011;32:393–401. [15] Neuzillet Y, Lechevallier E, Andre M, et al. Accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0 cm) renal masses. J Urol 2004; 171:1802–5. [16] Shannon BA, Cohen RJ, de Bruto H, et al. The value of preoperative needle core biopsy for diagnosing benign lesions among small, incidentally detected renal masses. J Urol 2008;180:1257–61. [17] Barwari K, Beemster PW, Hew MN, et al. Are there parameters that
Acknowledgment: The authors acknowledge Karthikeyan Manickava-
predict a nondiagnostic biopsy outcome taken during laparoscopic-
chagam, Division of Urology, Princess Margaret Cancer Centre, for his
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help with the acquisition of data and Lisa Le, senior statistician,
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Department of Biostatistics, Princess Margaret Cancer Centre, for her valuable statistical advice.
[18] Davis IC, Heilburn ME, Tangtiang K, et al. Computed tomographyguided renal tumor biopsies: tumor imaging features affecting sample adequacy. J Comp Assis Tomogr 2013;37:171–5.
Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.04.004.
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Please cite this article in press as: Richard PO, et al. Renal Tumor Biopsy for Small Renal Masses: A Single-center 13-year Experience. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.04.004