Small renal mass biopsy how, what and when: report from an international consensus panel

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1 Review Small renal mass biopsy how, what and when: report from an international consensus panel Matvey Tsivian 1, Edward N. Rampersaud Jr 1, Maria del Pilar Laguna Pes 2, Steven Joniau 3, Raymond J. Leveillee 4, William B. Shingleton 5, Monish Aron 6, Charles Y. Kim 7, Angelo M. DeMarzo 8, Mihir M. Desai 6, James D. Meler 9, James F. Donovan 10, Hans Christoph Klingler 11, David R. Sopko 7, John F. Madden 12, Michael Marberger 11, Michael N. Ferrandino 1 and Thomas J. Polascik 1 1 Division of Urology, Department of Surgery, Duke University Medical Center, Durham, NC, USA, 2 Department of Urology, AMC University Hospital, Amsterdam, The Netherlands, 3 Department of Urology, UZ Leuven, Leuven, Belgium, 4 Department of Urology, University of Miami, Miami, FL, 5 Section of Urology, Department of Surgery, Georgia Health Sciences University, Augusta, GA, 6 Department of Urology, University of Southern California, Los Angeles, CA, 7 Department of Radiology, Duke University Medical Center, Durham, NC, 8 Department of Pathology, Johns Hopkins University Medical Center, Baltimore, MD, 9 Department of Radiology, Baylor University Medical Center, Dallas, TX, 10 Division of Urology, Department of Surgery, University of Cincinnati, Cincinnati, OH, USA, 11 Department of Urology, Medical University of Vienna, Vienna, Austria, and 12 Department of Pathology, Duke University Medical Center, Durham, NC, USA To discuss the use of renal mass biopsy (RMB) for small renal masses (SRMs), formulate technical aspects, outline potential pitfalls and provide recommendations for the practicing clinician. The meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics. A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point. A consensus was established and lack of agreement to topics or specific items was noted at this point. Recommended biopsy technique: at least two cores, sampling different tumour regions with ultrasonography being the preferred method of image guidance. Pathological interpretation: non-diagnostic samples should refer to insufficient material, inconclusive and normal renal parenchyma. For non-diagnostic samples, a repeat biopsy is recommended. Fine-needle aspiration may provide additional information but cannot substitute for core biopsy. Indications for RMB: biopsy is recommended in most cases except in patients with imaging or clinical characteristics indicative of pathology (syndromes, imaging characteristics) and cases whereby conservative management is not contemplated. RMB is recommended for active surveillance but not for watchful-waiting candidates. We report the results of an international consensus meeting on the use of RMB for SRMs, defining the technique, pathological interpretation and indications. Keywords small renal mass, biopsy, ablation, renal cell carcinoma (RCC), renal mass biopsy, consensus Introduction Currently, management options for the small renal mass (SRM) are represented by a wide spectrum of strategies, from extirpative surgery, through minimally invasive ablative techniques to conservative management with active surveillance (AS). The choice of one strategy over another is largely guided by assessing the balance between patient factors (including life expectancy, comorbidities, etc.), surgical expertise and the biological potential of the renal mass. With the advent of conservative management strategies and the ultimate goal of individualised medicine, governed by the array of different management options available, clinical decisionmaking often requires additional prognostic information about the tumour that can be provided by renal mass biopsy (RMB). The present consensus panel convened to discuss the use of RMB for SRMs, formulate technical aspects, outline potential BJU Int 2014; 113: wileyonlinelibrary.com BJU International 2013 BJU International doi: /bju Published by John Wiley & Sons Ltd.

2 Small renal mass biopsy pitfalls and provide recommendations for the practicing clinician about the use of RMB in this setting. Methods The consensus meeting was held on 6 June 2012, at the start of the 5th International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer (Durham, NC, USA, The panel was tasked with focusing on the role of biopsy in the management of SRMs. An international multidisciplinary panel was selected based on the individuals expertise in the diagnosis and management of kidney cancer. Meeting topics and items were preselected and discussed in detail by one of the three groups of the consensus panel members, with each of the three groups comprised of experts within the fields of urological surgery, urological pathology, and genitourinary radiology. The group meetings were followed by a presentation of the recommendations by each one of the three groups representatives and a general discussion by the entire panel. The topics and items to be discussed were available for the panel members in advance, leaving an opportunity for the necessary preparations, including supporting literature and highlights of findings to be presented for the general discussion. No specific selection criteria were used to retrieve the literature, as high-level evidence on the topic is scarce. Rather, for this consensus panel, we relied on the expertise of the members to highlight high quality supporting literature. The list of topics is detailed in Table 1. The meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics. A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point. A consensus was established and lack of agreement to topics or specific items was noted at this point. Albeit the SRM is typically defined as ct1a (i.e. <4 cm), for the purposes of the present consensus meeting no strict size limit was applied and the term small renal mass refers more broadly to renal masses amenable to multiple management approaches as deemed by the clinician. The content of the consensus is readily applicable to ct1a renal masses, but it can be extended beyond this size in select clinical scenarios. All contributors to the consensus process have read and approved the present manuscript and concur with the essential content of this article. Table 2 Recommendations for technical standards of RMB. Technical aspect Number of cores Needle size Sampling pattern Biopsy of cystic lesions Anatomically challenging scenarios Imaging guidance method Tumour size limit Biopsy approach Biopsy complications Recommendation by consensus At least two cores 18 G or larger Different tumour regions Central and peripheral in larger tumours In individual, carefully selected cases On a case-by-case basis Based on availability and expertise US preferred No size limit Smaller lesions may have lower yield Based on anatomical characteristics More data is needed Favourable morbidity profile Severe complications rare Tumour seeding exceedingly rare Table 1 Detailed topics and specific items set to be discussed by the panel. Table 3 Summary of consensus statements on topic regarding pathological interpretation of biopsy samples. Topic Items Topic Brief statement Definition of the optimal technique for RMB Accuracy and reliability of pathological interpretation of the biopsy Indications for RMB Tissue sampling: number of cores, needle size, peripheral vs central sampling, targeting imaging feature of the mass (i.e. in Bosniak III lesions) Biopsy approach: supra- vs subcostal, image guidance (CT/MRI/US) Feasibility: cystic lesions, very small lesions (<2 cm), hilar/central lesions, vascular anomalies, anatomical variants. Complications of RMB: risk of seeding, bleeding, other complications. Identifying malignancy: sufficient samples, accuracy compared with final pathology, ability to define histotypes Grading on biopsy: feasibility of grading, two- tier vs four-tier grading system, grading non-clear cell histology Oncocytic lesions: oncocytoma vs chromophobe RCC Biopsy for ablative techniques: before vs at the time of intervention Selective vs routine biopsy in consideration of treatment options RMB for AS Non-diagnostic samples Verification of sample adequacy Non-diagnostic biopsy FNA Term should include insufficient material, inconclusive and normal renal parenchyma. Visual inspection of harvested tissue Recommend repeat biopsy Suggested interval: 3 months Cannot substitute core biopsy When added to RMB may provide additional information Very high, approaches 100% Accuracy in identifying malignancy Accuracy in histotyping Very high, >90% Pitfalls: inadequate sampling, hybrid tumours, oncocytic lesions Accuracy in grading Pitfalls in oncocytic neoplasms Challenging diagnoses Moderate, may be higher with simplified grading systems Rarely a diagnostic dilemma; most resolve with additional staining. Recommend review by expert uropathologist BJU International 2013 BJU International 855

3 Review Table 4 Consensus statements on indications for RMB. Topic Biopsy in the setting of ablation Before vs after cryoablation RMB in consideration of management options RMB not indicated Patients with other primary Patients with prior renal lesion Patients with multiple synchronous tumours Candidates for AS Watchful waiting Results The Optimal Technique for RMB Brief statement Obtaining a biopsy is essential Favour biopsy before ablation RMB recommended, except patients with clear indication of pathological diagnosis (syndromes, imaging appearance) Syndromes with monomorphic pathology Imaging characteristics of specific pathology Conservative management is not an option. RMB recommended RMB recommended RMB of all lesions recommended, if feasible Recommended Not recommended Fine-needle aspiration (FNA) vs core biopsy There are currently two methods for obtaining biopsy tissue, FNA and core biopsy. With FNA multiple passes through the tumour obtain aspirated cellular elements, and, theoretically, provide a more extensive sampling of the tumour. With core biopsy on the other hand, a limited number of solid tissue samples are obtained. These tissue samples allow for assessment of tissue architecture but could be potentially affected by sampling errors. FNA has been shown to be inferior to core biopsy in diagnostic yield. However, adding FNA to core biopsy has been suggested to increase the diagnostic accuracy of RMB [1]. Also, novel processing methods have been proposed to increase the diagnostic accuracy of FNA, effectively transforming it into a microbiopsy [2]. The panel agrees that FNA should not be performed in lieu of core biopsy. However, performing FNA in addition to core biopsies may increase the diagnostic yield. Further studies are needed to determine the role of FNA. Needle size Most centres use 18-G needles for RMB. Several studies investigated the effect of needle size on the diagnostic yield. In a direct ex vivo comparison between 14-, 18- and 20-G needle biopsies, smaller (20 G) needles had the highest rates of insufficient tissue for diagnosis; 14- and 18-G needles offered comparable results [3]. Similarly, Hruby et al. [4] assessed 11 biopsy devices with needle sizes varying between 20 and 12 G in an animal model. Their findings suggest that 20-G needles had significantly lower performance, in terms of tissue yield measured as core length, compared with their larger counterparts; the authors found no significant difference in core length among the larger calibre devices (12 18 G). Consistent with these results, another study reported higher diagnostic values (sensitivity and negative predictive value) for needles 18 G or larger, albeit this did not reach statistical significance [5]. In addition, in a cohort of laparoscopic cryoablations, needle size (18 vs 16 G) was not found to be associated with RMB diagnostic success [6]. The use of a coaxial biopsy cannula has been suggested to improve biopsy yield and increase standardisation of tissue samples [7] and may be viewed as an aid in preventing tumour seeding. However, larger studies are needed to determine whether the use of a sheath can result in improved performance of RMB. The panel agreed that 18 G or larger needles should be used for core biopsy of renal masses to allow for optimal diagnostic yield. Number of cores To date, the optimal number of RMB cores to be taken has not been defined. It has been suggested that increasing the number of cores improves the diagnostic yield [8] in an ex vivo investigation. A study of 88 RMBs reported 96.6% sufficient material for diagnosis when taking two or more cores [9]; however, in 5.7% the biopsy results were inconclusive, resulting in a total of 90.9% diagnostic yield. Similarly, Wang et al. [10] reported on 110 RMBs with at least two cores sampled achieving 91% diagnostic yield in percutaneous biopsy. Rybicki et al. [5] achieved 90.4% diagnostic yield using three to five cores with G needles. However, the number of cores taken was not associated with biopsy success during laparoscopic cryoablation in a study by Barwari et al. [6]. Finally, a recent study by Menogue et al. [11] evaluated the results of 268 RMBs for a SRM. The authors found that increasing the number of cores taken improved the diagnostic success of RMB on univariable analysis. However, on multivariable analysis, when adjusted for the amount of tissue available for diagnosis, the number of cores was no longer a significant predictor of success [11]. Increasing the number of cores taken extends the amount of tissue available for diagnosis. The quality of the tissue obtain is paramount for the success of RMB. The panel unanimously agreed that currently a minimum of two cores should be sampled during RMB striving for optimal quality of tissue obtained to maximise RMB diagnostic yield. Sampling patterns There is currently no definition of the optimal sampling pattern during RMB. Hobbs et al. [8] have evaluated the value of central vs peripheral sampling in an ex vivo series of RMB and concluded that while additional cores improve the diagnostic yield regardless of sampling locations, two peripheral cores consistently resulted in improved diagnostic yield. The topic of sampling patterns may be of increased 856 BJU International 2013 BJU International

4 Small renal mass biopsy importance in larger masses with higher incidence of central necrosis that may result in non-diagnostic tissue [12]. The panel agreed that RMB sampling should aim to avoid areas of evident necrosis. The panel also highlighted that in SRMs, attempting a peripheral sampling may increase the chances of yielding little to no diagnostic tissue due to the small size of the lesion, and thus obtaining a high quality biopsy core should be the goal rather than adherence to a specific sampling pattern. RMB for complex cystic lesions RMB has been proposed for the evaluation of complex cystic lesions, specifically Bosniak IIF and III [13,14]. Harisinghani et al. [13] reported on a series of 28 biopsies of complex cystic lesions; the authors were able to achieve sufficient material for diagnosis in all patients and, in surgically treated cases, RMB was consistently concordant with final pathology. Lang et al. [14] presented the results of 199 RMB of complex cystic lesions, with a 10% rate of insufficient tissue and 2.5% of misdiagnoses. Leveridge et al. [15] evaluated 345 RMBs and assessed parameters associated with a successful tissue diagnosis. They found that solid-appearing lesions were far more likely (odds ratio 13.9, CI ) to yield a successful RMB than their cystic counterparts on multivariable analyses. Biopsy of complex cystic lesions entails several difficulties. First, radiographic classification of these lesions must be accurate to obtain a precise a priori estimate of the biological nature of the lesion. Second, there is an objective difficulty with targeting the biopsy passes; when dealing with SRMs with a cystic component, the solid portions (septa, nodules) are even smaller in size and thus more difficult to sample precisely. Third, core biopsy of a cyst wall may result in its rupture and spillage of the material into the surrounding tissue. Having considered these issues, the panel agrees that there may be a role for core biopsy of select complex cystic lesions. However, the indication should consider likely lower diagnostic yield and increased technical difficulty and thus the decision should be made on an individual basis. Tumour size Several reports have suggested that diagnostic yield of RMB is dependent upon the size of the tumour. Lechevallier et al. [16] have reported a 37% biopsy failure rate in lesions of 3cm compared with 9% failures for those >3 cm. Leveridge et al. [15] have found a positive association between tumour size and biopsy success on multivariable analysis, estimating a three-fold increase in the likelihood of RMB success with every 1 cm increase in lesion size. However, a study of 110 RMBs in renal masses of 4 cm by Wang et al. [10] reported no difference in diagnostic yield or accuracy between lesions of <2.5 cm and larger. Similarly, Barwari et al. [6] could not find an association between tumour size and biopsy yield in a series of 100 RMBs during laparoscopic renal cryoablation for lesions of <4.5 cm. The panel agrees that while no tumour size limit should be set in the indications utilising RMB for SRMs, it should be considered during clinical decision-making that biopsy success in smaller masses could potentially be lower due to targeting difficulties. Anatomically challenging scenarios Currently, no anatomical characteristics of renal masses or kidney anatomical variants have been considered as contraindications for biopsy. Anatomical variants (e.g. a horseshoe or pelvic kidneys, etc.) may render the biopsy procedure technically more difficult and could potentially increase the risk of complications. The panel recommends considering these technically challenging cases on an individual basis in evaluating the risk of complications vs the potential benefit of RMB. Morbidity of RMB In a review of the literature, Volpe et al. [17] summarised the complications of RMB; they found rates of 0 2% significant complications requiring active treatment or hospital admission, with bleeding requiring treatment being the most common event [15,17]. While morbidity of RMB appears low inmodernseries,itislikelythattheincidenceof complications is underestimated due to lack of routine, prospective follow-up protocols. To date, only a study by Leveridge et al. [15] has assessed the entire range of potential complications, reporting a 10.4% incidence. In their study, almost all of the recorded complications were minor (Clavien grade 1), with haematoma formation accounting for the vast majority of complications. It remains unclear whether there are clinical, radiographic or intraoperative parameters that may be associated with increased risk of complications. Upon review of the literature, only isolated reports of track seeding have been found in the early experience with percutaneous biopsy [18] whereas in modern series tumour seeding has not been reported yet [17]. RMB morbidity is low and severe complications appear to be uncommon. Specifically, the risk of tumour seeding along the biopsy track is minimal with use of modern coaxial biopsy techniques, albeit the risk may be underestimated due to lack of long-term follow-up and underreporting. The panel highlights the need for more detailed reports on complications of RMB and further research into potential risk factors. The morbidity profile of RMB is favourable and would not preclude the procedure when indicated. Image guidance Typically either ultrasonography (US) or CT guidance is used for RMB; however, MRI could also be used for this purpose BJU International 2013 BJU International 857

5 Review [19]. There is no data to suggest superiority of one image guidance method over another [15]. While many lesions can be identified by US, lesions of the upper pole may be obscured by aerated lung, and obesity can limit US penetrance of anterior lesions. Furthermore, a reasonable window for biopsy needle passage is not always present due to rib configuration, particularly for upper pole lesions. However, US has the advantage of visualisation of vascular structures, low cost, accessibility and avoidance of ionizing radiation [20]. CT guidance provides excellent visualisation of extrarenal structures adjacent to the renal mass, e.g. bowel and ureter [21]. During CT guidance, the absence of i.v. contrast often prevents visualisation of endophytic lesions. The addition of i.v. contrast during targeting allows a limited window of up to several minutes, which may not be sufficient for adequate needle positioning. Furthermore, respiratory motion can render CT guidance difficult and inaccurate in patients with poor respiratory compliance, especially in SRMs. Overall, US guidance may be preferable to CT and MRI in view of avoiding ionizing radiation and lower cost, respectively. The panel identifies the need for further research to evaluate the different imaging guidance methods for RMB. Furthermore, the panel suggests choosing the image-guidance method based on availability, expertise and individual patient and tumour characteristics with preference for US guidance to limit radiation exposure and cost. Biopsy approach RMB approach (subcostal, supracostal) is largely guided by the anatomical characteristics and location of the mass. There is no data to suggest an effect of the approach on diagnostic yield of RMB. However, the supracostal approach could be associated with increased risk of pneumothorax, splenic and liver puncture, particularly with upper pole lesions in a cephalad oriented kidney, albeit clinically significant complications after RMB remain a rare occurrence. A lateral approach may also result in a higher risk of colonic, splenic or liver puncture depending on individual patient organ configuration. The panel agrees that the choice of RMB approach should be determined by the best available strategy to obtain high quality material for tissue diagnosis given the anatomical characteristics of the mass. There is no indication of superiority of a supra- or subcostal approach. Pre-procedural imaging should be carefully reviewed to identify the location of adjacent structures that should be avoided during biopsy. Accuracy and Reliability of RMB Non-diagnostic samples One of the main concerns about RMB is the rate of non-diagnostic samples. These could be samples with insufficient tissue for diagnosis, samples representing normal kidney parenchyma or other situations whereby the cause of the renal mass cannot be described by pathological diagnosis of the biopsy. Rates of non-diagnostic samples range between 0 and 47% in the different series [17]. Non-diagnostic samples appear to be more frequent in smaller lesions and those with cystic appearance on imaging [15,16]. There is a need for standardisation of the nomenclature on this topic. The panel agrees that the category of non-diagnostic biopsies should include those with insufficient tissue for analysis, as well as biopsies that upon pathological analysis do not yield a diagnosis that explains the aetiology of the renal mass (i.e. normal kidney parenchyma, insufficient cellularity, necrosis etc.). In addition, there is a consensus that tissue quality is paramount for accurate diagnosis and strategies to ensure adequacy of the sample need to be put in place. This could be done by visual confirmation, i.e. examining the tissue sample at the time of biopsy. It was felt that visual inspection of the samples harvested is a sufficient and cost-effective strategy to improve diagnostic yield whereas frozen section analyses or pathological confirmation of sample adequacy are not required. Repeat RMB for non-diagnostic samples Even with visual verification of tissue sample adequacy during RMB, non-diagnostic samples will still represent a clinical problem. There is evidence that repeat biopsy after an initial non-diagnostic result may achieve similar diagnostic rates as the initial procedure [15]. Moreover, delaying active treatment for SRMs has been shown to be safe and has not compromised future treatment options or oncological control [22]. We recommend repeating RMB in cases with an initial non-diagnostic outcome. However, the optimal timing for repeat RMB remains to be defined. It may be reasonable to consider an alternative imaging method for repeat biopsy guidance. It is important to highlight again the importance of obtaining adequate material for diagnosis in one procedure and reducing the need for subsequent re-biopsies. Diagnostic accuracy for malignancy The diagnostic accuracy of RMB in differentiating malignant from benign lesions is high and ranges between 86 and 100%, with specificity approaching 100% in most series [17]. Of note, repeat biopsy after an initial non-diagnostic one reportedly achieves similar success rates [15]. There is strong evidence that RMB can achieve very high accuracy in identifying malignancy. It is important to highlight that the interpretation of a biopsy sample can only be as good as the tissue sample provided and therefore the importance of an adequate and representative tissue sample cannot be overstated. 858 BJU International 2013 BJU International

6 Small renal mass biopsy Diagnostic accuracy for histological subtyping Histological subtyping of RCC provides additional prognostic value. The rates of accurate histological subtyping in a recent literature review were 86 98% [17] and inter-observer agreement is reportedly high [23]. While in most cases correct histological subtyping can be performed on a core biopsy sample, some instances remain problematic. For example, hybrid tumours combining areas of different histological architecture represent a problem for accurate definition of the malignant subtype depending on the area(s) of the tumour captured in the biopsy sample. Similarly, at times it may be difficult to distinguish low-grade chromophobe RCC from oncocytoma even with the aid of immunohistochemical markers. While the overall accuracy of histological subtyping is very good, the sampling nature of RMB may not adequately capture the entire morphology of a tumour, which may lead, in a small minority of cases, to inaccurate histological subtyping of RCC. The panel recommends that difficult diagnoses should be made in conjunction with an expert uropathologist. Diagnostic accuracy for grading Grading of RCC is in itself a debated issue with questions raised about the techniques of grading, the applicability of grading to histologies other than clear cell and prognostic significance of grade [24 27]. Having considered those issues affecting RCC grading, the reported accuracy of grading on RMB ranges between 46% and 76% whereby a simplified two-tier Fuhrman classification achieves better results (64 76%) [17]. The results in the literature indicate suboptimal performance of RMB for grading. The panel discussion raised several important issues to consider. First, due to the sampling nature of biopsy and non-homogeneity of grade in the tumour, identifying an area of low-grade cancer does not necessarily exclude the presence of higher grade morphology in the remainder of the lesion that may not have been sampled. This results in a high positive predictive value for high grade and lower value for low grade. These phenomena may have accounted for the findings of Harris et al. [28] suggesting under-grading of RCC on biopsy compared with final pathology. Second, there is evidence of considerable inter-observer variability in grading RCC even on final pathology specimens [24] and this is certainly reflected in a lower accuracy of RMB grading. The Fuhrman grading system was the one predominantly used in the studies evaluating RMB accuracy and no data exist on reproducibility of other proposed systems on biopsy material, albeit in most, inter-observer agreement has been suboptimal thus far [24]. In summary, the panel agrees that grading of RCC on biopsy material can be performed, considering the quality of the submitted specimens and the sampling nature of the biopsy. Identification of high-grade components on biopsy carries a very high positive predictive value. Moreover, the grading accuracy may be improved by using a two-tier system that reduces inter-observer variability inherent to RCC grading. The panel does not find that at present there is indication to suggest grading systems other than those currently in use for final pathology specimens. In non-clear cell pathology, in view of current debates over the validity and prognostic significance of nuclear and nucleolar grading systems [25,29 31], we recommend reaching a local agreement between the pathologist and the urologist on whether to and how to apply grading systems to those histologies. Diagnosis of oncocytic lesions While in most cases an accurate histological subtyping can be accomplished on biopsy material, in select and infrequent cases, the diagnosis can be difficult. The special case of such difficulty is the oncocytic neoplasm that includes in the differential diagnoses: oncocytoma, a hybrid oncocytoma-chromophobe RCC lesion, low-grade chromophobe RCC, and small or tangential biopsies of papillary type 2 (eosinophilic) RCC. The diagnostic problem with oncocytic lesions is rather limited for several reasons. First, inconclusive cases by light microscopy are frequently resolved with application of additional staining techniques, such as colloidal iron and widely available immunohistochemical markers. Second, an adequate tissue sample would markedly increase the likelihood of identifying a papillary type 2 RCC. Third, hybrid tumours are typically associated with known syndrome conditions, e.g. Birt Hogg Dube, and their sporadic appearance is not common. Finally, the natural history of hybrid oncocytoma/chromophobe tumours, low-grade chromophobe tumours and oncocytomas is characterised by low metastatic potential [32], especially in SRMs [29]. We submit that oncocytic appearing neoplasms may be, in a minority of cases, difficult to characterise on light microscopy. Use of additional staining and immunohistochemistry reduces the diagnostic dilemma to rare occasions. Adequate tissue sampling by core biopsy can provide the expert uropathologist sufficient material for these select cases to reach an agreement in classification. Moreover, from the clinical standpoint, the differences in classification of these tumours may have but a limited impact on clinical decision-making. Indications for RMB Biopsy for ablative techniques Obtaining information about the histology and grade of the lesion being treated is of paramount importance, both for BJU International 2013 BJU International 859

7 Review devising an adequate surveillance strategy after treatment and for evaluating the outcomes of cancer control for the given management approach. In the special case of ablative techniques, if biopsy of the treated mass was not obtained before the procedure, tissue samples can be obtained immediately before or after ablation. The theoretical advantages of biopsy after ablation include reduced potential for bleeding and seeding once the tumour has been destroyed. However, with ablative techniques there is concern that alterations in the tissue induced by ablation would render pathological interpretation challenging. In radiofrequency ablation for instance, disruption of tissue architecture and induction of coagulative necrosis and inflammatory response make histological interpretation of post-ablation biopsy difficult. Despite this, Margulis et al. [33] have reported that these predictable histological changes after radiofrequency ablation did not impact their ability to establish a histological diagnosis. However, the authors did not analyse the effect of post-ablation biopsy on their ability to grade the cancerous lesions. Cryoablation on the other hand, preserves tissue architecture by inducing rapid tissue freezing. The cryoablation literature suggests that biopsy before ablation may have a higher diagnostic yield and better accuracy of pathological diagnosis than after ablation [34]. In another study, obtaining biopsy tissue after one cycle of cryoablation did not significantly alter tissue architecture allowing for accurate assessment of histotype and grade [35]. Similar conclusions were reached in a preclinical model while obtaining tissue cores after double-freeze cycles [36]. To date, the purported advantages of post-ablation biopsy remain controversial and are not likely to outweigh the benefits of adequate tissue sampling. We strongly recommend performing a biopsy and obtaining a diagnosis for every patient treated with ablative approaches. In view of the importance of obtaining sufficient and adequate tissue for diagnosis, and considering the paucity of evident advantages of post-ablation biopsy, we favour performing a biopsy before tumour ablation. However, if additional tissue is required to render a diagnosis, it is reasonable to submit immediate post-ablation biopsies. Indications for RMB in SRMs The steadily climbing incidence of RCC is mainly due to increased detection of localised RCC, characterised by excellent oncological outcomes after treatment [37]. While the incidence of RCC is increasing, mortality rates fail to decline accordingly, so the question of over diagnosis and the associated overtreatment is inevitable [38]. In addition to the increasing detection of localised RCC, it has been shown that, in a contemporary patient population, SRMs may reveal benign pathology in 36% of cases [39]. The incidence of adverse pathological features, indicating aggressive biological potential of SRMs, is overall low and is related to the size of the lesion. Indeed, in renal masses of <2cmthatare pathologically confirmed RCC, 90% or more are low (Fuhrman 1 2) grade [39]. These data, along with a dramatic increase in the incidence of renal masses and the recognition of limited malignant potential of a large portion of those SRMs, combined with an ever aging population accumulating medical comorbidities, emphasise that knowledge of renal mass pathology can be beneficial in devising management strategies. AS of renal masses may be an appropriate approach for benign renal masses, and potentially for select RCCs with characteristics indicating low malignant potential. Conversely, an expedient extirpative or ablative approach would probably be favoured for those renal masses presenting pathological characteristics of potentially aggressive nature, especially in healthy individuals. The treatment decision should balance tumour characteristics with patient factors, i.e. comorbidities, that would impart an overall benefit of the proposed therapy [40]. A survey among urologists has shown that the use of RMB in characterisation of the renal mass remains limited at present, with only a minority of clinicians using biopsy in their practice [41]. Cost-effectiveness models have been developed to further evaluate the potential impact of RMB. A recent study [42] constructed a model considering immediate surgery vs initial biopsy; even assuming that 90% of biopsied patients would undergo surgery due to biopsy results, initial sampling of the renal mass proved to be cost-effective to guide treatment decisions. Similarly, Heilbrun et al. [43] evaluated RMB cost-effectiveness in a three-way scenario of AS vs immediate surgery vs biopsy-guided decision-making in masses of <2 cm and concluded that the role of RMB should be expanded. There is consensus by the panel that the role of RMB in renal mass characterisation should be expanded. The panel agrees that RMB should be recommended to patients with SRMs in consideration of treatment options, as pathological characterisation of the renal mass would allow for a more precise definition of the biological potential of the neoplasm and thus would provide important data elements to the clinician and the patient about the optimal management strategy. We think that RMB should be used in solid masses whenever imaging or clinical characteristics cannot suggest a specific categorisation of pathology (e.g. angiomyolipoma by imaging or in the setting of tuberous sclerosis complex, RCC in von Hippel Lindau syndrome [VHL], etc.) and the management options include both conservative and invasive strategies. The panel feels that RMB should be recommended to patients considering AS as a management strategy. Conversely, when the management options are limited (e.g. conservative management is not considered or possible active 860 BJU International 2013 BJU International

8 Small renal mass biopsy treatment is not contemplated), biopsy should be avoided, as the results would not alter the management strategy. We also submit that predictive models estimating the probabilities of the mass to harbour malignant and potentially aggressive pathology could aid in focusing the use of RMB in these patients. Routine vs selective use of RMB The main goal of obtaining more information about the biological risk of the renal mass is to estimate the benefits and the potential harms associated with the different management options. This decision-making process has to include patient factors, e.g. comorbidities, competing risks, systems of belief and personal preferences, to be weighed against the tumour characteristics and its potential to adversely affect not only life expectancy but also quality of life for the individual. The panel agrees that while the role of RMB should be expanded, its routine use in every patient with a renal mass should not be encouraged. We agree that in patients with syndromes associated with specific histology of renal tumours and those with clear imaging evidence of specific pathology, renal mass biopsy can be avoided, as its contribution to the management plan is likely to be minimal. RMB in patients with a history of malignancy Secondary renal metastases from other primary sites are uncommon. Indeed, in patients with a known non-renal malignancy of low stage, incidentally discovered renal masses are most often represented by de novo renal tumours with pathological characteristics not dissimilar from sporadic RCC [44]. In addition, the absence of other suspected metastatic deposits of the primary malignancy suggests a non-metastatic nature of the renal mass [44]. In patients without evidence of progression of a non-renal malignancy, the metastatic nature of the renal mass is inordinately uncommon [45]. For a history of primary renal tumours, both synchronous and metachronous renal lesions have shown the potential for diverse histology in the sporadic setting [46,47]. Another report on patients previously treated for oncocytoma has shown that the risk of metachronous renal lesions representing RCC is similar to the general population [48]. In view of the published evidence, the panel advocates RMB in the setting of a known, non-renal malignancy without evidence of progression. Similarly, with the exception of syndrome conditions suggesting monomorphic renal tumours (e.g. VHL, tuberous sclerosis, etc.) and clear evidence of local recurrence after RCC treatment, RMB should be indicated in patients with a prior history of RCC. In synchronous unilateral or bilateral multiple renal tumours, we do not advocate relying on the histology of one renal mass but rather recommend RMB of all visible tumours, that could be accomplished in a single or stages procedure. RMB for candidates considering AS ASforSRMshasgainedacceptanceasaviablemanagement strategy with encouraging results [49]. The panel highlights that AS with the possibility of delayed treatment should not be confused with watchful waiting whereby no intention of active treatment exists. We think that biopsy in the setting of AS has multiple roles. First, RMB results could indicate suitability for AS in an individual patient. Second, biopsy results could guide towards risk-stratified surveillance schemes. For example, patients with benign lesions could embark on a less intense imaging schedule, if any, as opposed to those with malignant pathology. Finally, obtaining pathological data will enable accurate comparisons between AS series as well as detailed delineation of the natural history of the various histological entities. The panel agrees that RMB has a pivotal role in AS protocols, both in selection of candidates and in risk-stratification for surveillance strategies. Conversely, in patients on watchful waiting whereby patient characteristics preclude active treatment, biopsy should be avoided. Conclusions This international consensus meeting outlined the recommendations for current practice, defined potential pitfalls and delineated the indications for biopsy of the SRM (Tables 2 4). Moreover, the panel discussion provided recommendations for RMB in specific settings and highlighted the future directions for research in the field of SRMs. Conflict of Interest M. del Pilar Laguna Pes has received institutional support from GSK. M. Aron has a teaching agreement with Intuitive Surgical. J.A. Meler is a Consultant for BTG and a Speaker for Bayer Pharmaceuticals. T.J. Polascik is a Consultant for Endocare and has also received institutional training support from Endocare. References 1 Barwari K, Kummerlin IP, Ten Kate FJ et al. What is the added value of combined core biopsy and fine needle aspiration in the diagnostic process of renal tumours? 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Synchronous renal masses in patients with a nonrenal malignancy: incidence of metastasis to the kidney versus primary renal neoplasia and 862 BJU International 2013 BJU International

10 Small renal mass biopsy differentiating features on CT. AJR Am J Roentgenol 2011; 197: W Sanchez-Ortiz RF, Madsen LT, Bermejo CE et al. A renal mass in the setting of a nonrenal malignancy: when is a renal tumor biopsy appropriate? Cancer 2004; 101: Capaccio E, Varca V, Simonato A, Toncini C, Carmignani G, Derchi LE. Synchronous parenchymal renal tumors of different histology in the same kidney. Acta Radiol 2009; 50: Patel AR, Lee BH, Campbell SC, Zhou M, Fergany AF. Bilateral synchronous sporadic renal tumors: pathologic concordance and clinical implications. Urology 2011; 78: Childs MA, Breau RH, Umbreit EC et al. Metachronous renal tumours after surgical management of oncocytoma. BJU Int 2011; 108: Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma-a meta-analysis and review. J Urol 2008; 179: Correspondence: Thomas J. Polascik, Division of Urology, Department of Surgery, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. polas001@mc.duke.edu Abbreviations: AS, active surveillance; FNA, Fine-needle aspiration; RMB, renal mass biopsy; SRM, small renal mass; US, ultrasonography/ultrasound; VHL, von Hippel Lindau syndrome. BJU International 2013 BJU International 863