Rationale for Percutaneous Biopsy and Histologic Characterisation of Renal Tumours

EUROPEAN UROLOGY 62 (2012) 491–504

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Platinum Priority – Collaborative Review – Kidney Cancer Editorial by Tobias Klatte on pp. 505–506 of this issue

Rationale for Percutaneous Biopsy and Histologic Characterisation of Renal Tumours Alessandro Volpe a,*, Antonio Finelli b, Inderbir S. Gill c, Michael A.S. Jewett b, Guido Martignoni d, Thomas J. Polascik e, Mesut Remzi f, Robert G. Uzzo g a

Department of Urology, University of Eastern Piedmont, Maggiore della Carita` Hospital, Novara, Italy; b Division of Urology, Department of Surgery and

Surgical Oncology, Princess Margaret Hospital and the University Health Network, University of Toronto, Toronto, ON, Canada; c USC Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; d Department of Pathology and Diagnostics, Anatomia Patologica, University of Verona, Verona, Italy; e Division of Urology, Duke Cancer Institute, Durham, NC, USA; f Department of Urology, Landesklinikum Weinviertel–Korneuburg, Korneuburg, Austria; g Department of Urologic Oncology, Fox Chase Cancer Centre, Philadelphia, PA, USA

Article info

Abstract

Article history: Accepted May 3, 2012 Published online ahead of print on May 11, 2012

Context: The use of percutaneous biopsy of renal tumours has been traditionally reserved for selected cases because of uncertainties regarding its safety, accuracy, and clinical utility. With the adoption of modern biopsy techniques and increasing expertise in interpreting biopsy specimens, renal tumour biopsy today has limited morbidity and allows histologic diagnosis in the majority of cases in centres with expertise. Objective: To review the current rationale, indications, and outcomes of percutaneous biopsies and histologic characterisation of renal tumours. Evidence acquisition: We conducted a systematic review of English-language articles on percutaneous biopsies of renal tumours published between January 1999 and December 2011 using the Medline, Embase, and Web of Science databases. One hundred twelve articles were selected with the consensus of all authors and analysed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria. Evidence synthesis: In recent years, the increasing incidence of incidental small renal masses (SRMs), the development of conservative and minimally invasive treatments for low-risk renal cell carcinoma (RCC), and the discovery of novel targeted treatments for metastatic disease have provided the rationale for expanding the indications for renal tumour biopsy. Percutaneous biopsy for diagnostic assessment of SRMs can avoid unnecessary surgeries and support treatment decisions, especially in patients at high surgical risk. Biopsies can confirm histologic success after thermal ablation of SRMs and support the selection of the appropriate systemic therapy for metastatic RCC. There is increasing evidence that further diagnostic and prognostic information can be obtained from renal tumour biopsies with the use of immunohistochemistry, cytogenetic and molecular analysis, and high-throughput gene expression profiling. Conclusions: Percutaneous biopsies have increasing indications and can significantly contribute to clinical management of renal tumours but are still underutilised in clinical practice. Further research is needed to define optimal and standardised patterns of biopsy and improve the accuracy of biopsies to determine tumour histology. Molecular and genetic analysis of biopsy specimens can provide additional information to support patient counselling and treatment decision making. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Keywords: Needle core biopsy Renal mass Renal cell carcinoma Diagnosis Prognosis Molecular markers Cytogenetic markers

* Corresponding author. Division of Urology, Maggiore della Carita` Hospital, University of Eastern Piedmont, Corso Mazzini 18, 28100 Novara, Italy. Tel. +39 0321 373 3201; Fax: +39 0321 373 3763. E-mail address: [email protected] (A. Volpe). 0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2012.05.009

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1.

EUROPEAN UROLOGY 62 (2012) 491–504

Introduction

The incidence of renal tumours has been steadily increasing over the past decades [1]. The widespread use of abdominal imaging for non-urologic complaints has led to a significant increase in the detection of incidental small renal masses (SRMs) [2], especially in older patients who are more likely to undergo radiologic examinations for other medical reasons. Nephron-sparing surgery (NSS) is the standard of care for small, localised renal tumours. However, alternative minimally invasive and conservative treatment options are possible in selected patients with shorter life expectancies [3–5]. Treatment decision making for SRMs is an increasingly frequent and challenging clinical problem, especially in elderly and unfit patients. The decision of the best treatment modality is based on clinical assessment of patient comorbidities and tumour characteristics. We know today that SRMs are represented by a heterogeneous group of benign and malignant histologic entities, with a range of biologic and clinical behaviours. However, the assessment of tumour malignancy generally relies on tumour size, shape, profile, and tissue enhancement at triphasic computed tomography (CT) and magnetic resonance imaging (MRI) alone. The use of renal tumour biopsies to obtain pathologic information to guide treatment decisions has been traditionally reserved for very selected cases of SRMs [6]. Before the advent of biologic targeted therapies, there was also limited interest in the histologic characterisation of advanced and metastatic renal tumours. Although the indications for biopsy are still generally dictated by local practice patterns and investigative interest, in the past few years, percutaneous biopsies have been increasingly used to clarify the histology of renal tumours to aid with treatment decisions for SRMs, confirm treatment success after thermal ablation of renal lesions, and select the most suitable targeted pharmacologic therapy in the setting of metastatic disease. Furthermore, there has been growing interest in the use of immunohistochemical, molecular, and genetic assessments that can potentially improve our ability to determine renal tumour biologic and clinical behaviour on percutaneous biopsies. We systematically reviewed the recent literature to provide a comprehensive outlook of the current rationale, indications, and outcomes of percutaneous biopsies and histologic characterisation of renal tumours. 2.

Evidence acquisition

A systematic literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria [7] (Fig. 1). The literature search was carried out on the Medline, Embase, and Web of Science databases using the terms renal mass, renal tumour, and renal carcinoma in conjunction with biopsy, molecular marker, and cytogenetic marker. We limited our search to English-language articles published between January 1999 and December 2011. In addition, cited references from the selected articles and from review articles retrieved in the

search were assessed to identify significant manuscripts that were not previously included. After exclusion of duplicates, case reports, and papers whose topic was not specific for this review, we identified a list of 245 papers. The full text of these articles was reviewed. Level of evidence provided, sample size, study design, and relevance of each study with regard to the topics of the review were assessed. Based on these criteria, 112 articles were selected with the consensus of all authors and critically analysed. This review is the result of an interactive peer-reviewing process by the expert panel. 3.

Evidence synthesis

3.1.

Rationale for percutaneous biopsy of renal tumours

In contrast with the management of other urologic neoplasms, such as prostate and bladder cancer, where histologic diagnosis is considered necessary before proceeding to radical treatment, the use of percutaneous biopsies to determine the histology of a renal mass has been historically limited. Biopsies have traditionally been indicated to rule out lymphoma, a renal abscess, or metastatic disease to the kidneys in the presence of a known extrarenal malignancy. Such histologic confirmation was deemed necessary because treatment is not surgical in the majority of these cases. Biopsies have also been performed to confirm the diagnosis of a renal primary tumour in the presence of disseminated metastases or unresectable retroperitoneal tumours [6]. Beyond these indications, renal tumour biopsy has not generally been advocated because of a series of concerns about its safety, diagnostic yield, and accuracy as well as the limited ability of biopsy to influence treatment decisions based on the perception that all solid SRMs have malignant potential and should be removed with surgery upfront. Until recently, this perception was made stronger by the absence of effective systemic salvage therapy for metastatic disease. Although limitations of renal tumour biopsies are still significant, some of these uncertainties have now been overcome because of (1) the adoption of modern biopsy techniques, including improved image guidance, (2) the increasing expertise of urologists and interventional radiologists in performing biopsies, (3) the increasing expertise of pathologists in interpreting biopsy specimens, and (4) the increasing confidence of urologists in using biopsy results to support treatment decisions based on a better knowledge of the various biologic and clinical behaviours of different renal tumour histologies. Meanwhile, the increasing detection of incidental SRMs, the development of treatment alternatives for these lesions in selected patients, and the discovery of several effective biologically targeted drugs for metastatic disease have raised the awareness that pretreatment information about tumour histology is needed to tailor the most appropriate treatment to each individual patient. These factors will be thoroughly analysed and overall constitute the rationale for an increasing use of renal tumour biopsies in current clinical practice.

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Identification

[(Fig._1)TD$IG]

Literature database searching:

Additional studies identified from

Medline, Embase, Web of Science

reference lists of articles

(n = 624)

(n = 135)

Articles after duplicates removed

Screening

(n = 716)

Articles excluded based on title and abstract: case reports, same institution’s series, articles not relevant to the topics of the review

Eligibility

Full-text manuscripts reviewed

(n = 471)

(n = 245)

Full-text articles excluded: low LE provided, small sample size, insufficient relevance to the topics of

Included

the review Studies included in the analysis for

(n = 133)

this review (n = 112)

Fig. 1 – Flow diagram: search and study selection process for this review. LE = level of evidence.

3.1.1.

Percutaneous biopsy of renal tumours is safe

Renal tumour biopsies can be performed today as an outpatient or short-stay procedure under ultrasound or CT guidance and with local anaesthesia in the majority of cases. One of the major concerns about biopsy was the perceived high risk of complications, especially tumour seeding and bleeding. Renal tumours are frequently vascular, so biopsy-induced intratumour and perinephric bleeding have been considered a significant issue. However, although mild perirenal and subcapsular haematomas can frequently be observed when routine postbiopsy CT scans are obtained, recent series have shown that clinically significant bleeding is unusual and generally selflimiting, with blood transfusions rarely required [8–16] (Table 1). The risk of bleeding is believed to be greater with larger (18-gauge) needles, but no study has directly compared

the complication rate of biopsies performed with needles of different sizes. Similarly, no study has clearly assessed the correlation among the number of cores obtained, tumour location, operator expertise, and the rates of postbiopsy bleeding and complications. The risk of tumour dissemination along the needle track can be considered anecdotal because only six cases of seeding from renal parenchymal tumours had been reported until 2001 [17], and no cases were described in recent series with the use of coaxial techniques that allow multiple biopsies to be performed through a coaxial guide or cannula, which avoids needle contact with the surrounding abdominal tissues [8–16]. Other complications are extremely rare. The risk of clinically significant pneumothorax is reported to be <1% and is virtually absent when a subcostal needle approach is chosen. Overall, the risk of complications in renal tumour

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Table 1 – Complications of needle core biopsies of renal masses in recent series No. of tumours biopsied

Image guidance

Needle size, gauge

No. of biopsies taken

88 235 78 119 152 100 110 150 345

CT CT/US CT CT/US CT/US CT/US CT/US US CT/US

18 18 18 18 18 18 18 18 18

2 1–4 2–3 1–4 2–4 2 2 1–2 2

Neuzillet et al. [8] Shannon et al. [9] Schmidbauer et al. [10] Lebret et al. [11] Maturen et al. [12] Volpe et al. [13] Wang et al. [14] Veltri et al. [15] Leveridge et al. [16]

No. of significant complications* (%) 0 2 1 0 2 1 2 0 1

(0.9) (1.3) (1.3) (1) (1.8) (0.3)

No. of seeding (%) 0 0 0 0 0 0 0 0 0

No. of significant bleeding** (%) 0 2 0 0 2 0 1 0 1

(0.9)

(1.3) (0.9) (0.3)

CT = computed tomography; US = ultrasound. Complications requiring active treatment or hospital admission. ** Bleeding requiring active treatment, including transfusions or hospital admission. *

biopsies is low, rarely clinically significant, and counterbalanced by the risk of treating patients with suboptimal clinical information, resulting in potential undertreatment or overtreatment and concomitant relative morbidity. 3.1.2.

Percutaneous biopsy of renal tumours has a good diagnostic

yield in centres with expertise 3.1.2.1. Diagnostic yield and accuracy of renal tumour biopsy. Major criticism about the clinical utility of renal tumour biopsy historically derived from the insufficient diagnostic yield and low negative predictive value (NPV) in initial clinical series [18,19]. Unfortunately, the rates of success and accuracy of percutaneous biopsies have not been reported in a consistent manner, and a standardised definition of failed, inadequate, and indeterminate biopsy is lacking. In fact, in historical series, a significant number of reported false-negative biopsies actually showed normal parenchyma, blood, or necrotic tissue, thereby likely representing technical failures resulting from difficult visualisation or erroneous targeting. However, with improved techniques and increased experience, the outcomes of biopsy have significantly improved. The diagnostic yield of renal tumour biopsies in the largest recent series ranges from 78% to 100%, and an erroneous diagnosis on adequate biopsy specimens is now rare [8–16] (Table 2). The reported sensitivity and specificity of biopsies for the diagnosis of malignancy are 86–100% and 100%, respectively [8–16] (Table 2). A relatively recent literature review analysing the results of 2474 renal tumour biopsies calculated an overall positive predictive value and NPV for the diagnosis of malignancy of 97.5% and 82%, respectively, with an overall sensitivity of 92.1% and specificity of 89.7% [20]. Diagnostic accuracy for tumour subtyping on core biopsies compared to final nephrectomy is also high in recent series, ranging from 86% to 98% [8–11,13–16]. Fuhrman nuclear grading from biopsies can be determined in 76–94% of cases [8,10,21], with accuracy rates of 63–76% [8,10,11,13,16] (Table 2). Percutaneous fine-needle aspiration (FNA) has also been used for cytologic diagnosis of renal masses. There is evidence that the accuracy of FNA for the diagnosis of malignancy is inferior to that of core biopsies and that

diagnosis of tumour histotype and grade is possible in fewer cases on cytologic specimens [13,15,16,22,23]. However, some authors suggest that the two techniques can provide complementary results and eventually increase diagnostic rates and accuracy [24–27]. When FNA is performed before biopsy, an intraoperative check of the quality of the specimen by a dedicated cytologist may confirm the correct position of the guiding cannula within the tumour, thereby possibly increasing the likelihood of a diagnostic biopsy. 3.1.2.2. Predictors of a diagnostic renal tumour biopsy. To date, few studies have looked at predictors of diagnostic success for percutaneous renal tumour biopsy. Although further research is needed in this regard, the available information is useful for the definition of biopsy indications and techniques and for patient counselling. 3.1.2.2.1. Tumour size. A few authors assessed the influence of tumour dimension on the diagnostic success of percutaneous biopsy and showed that a larger tumour size significantly correlates with diagnostic yield [13,16]. Leveridge et al. analysed a series of 345 percutaneous biopsies and observed that the odds ratio (OR) for a diagnostic result was 2.30 (95% confidence interval [CI], 1.54–6.28) for each 1-cm increase in tumour size ( p = 0.002) [16]. Urologists should be aware of the higher risk of biopsy failure with decreasing tumour size and inform patients accordingly. 3.1.2.2.2. Solid versus cystic tumour pattern. Percutaneous biopsies are mainly performed for clinical assessment of solid renal tumours, but some investigators have proposed their use for complex cystic renal masses as well [27,28]. There is now evidence that core biopsies are significantly less informative for the diagnosis of cystic lesions [13,16]. Leveridge et al. observed that the OR for a diagnostic result was 13.9 (95% CI, 3.78–50.7) for a solid versus cystic tumour pattern ( p < 0.0001) [16]. At present, the higher risk of biopsy failure, false-negative results, and potential spreading of tumour cells resulting from cystic rupture [13,16,29,30] leads many urologists to limit the indications of core biopsies to Bosniak IV cysts, where clear enhancing solid areas are visible within the lesion. In contrast, some

43 NR 68.9 NR 66.7/75** NR NR 63.5 RCC = renal cell carcinoma; CT = computed tomography; US = ultrasound; NR = not reported. Retrospective evaluation. ** Four-tiered Fuhrman classification/two-tiered simplified Fuhrman classification (Fuhrman I–II = low grade; Fuhrman III–IV = high grade). *

84 90.9 100 80.6 18 18 18 18 100 110 103 345 Volpe et al. [13] Wang et al. [14] Veltri et al. [15] Leveridge et al. [16]

2.4 2.7 3.4 2.5

20 36 40 74

CT/US CT/US US CT/US

2 2 1–2 2

79 96 1–4 2–4 18 18 CT/US CT/US 64 106 3.3 4.1 119 152 Lebret et al. [11] Maturen et al. [12]

495

authors favour a combination of FNA and core biopsy for the diagnostic work-up of complex renal cysts [10,24, 27,28]. In a series of 28 Bosniak III lesions, 39% of patients avoided unnecessary surgery following a benign diagnosis based on a combined core biopsy and FNA, with negative radiologic follow-up [28]. In a larger series of core biopsies and FNAs on 199 Bosniak IIF/III renal cystic masses, Lang et al. obtained a definitive diagnosis in 87.9% of cases, obviating surgery or invasive procedures in 70% of patients, with an average negative follow-up of 5.6 yr [27].

100 96.6 93.2 88

30.4 60.5 46/74** NR 86 NR

47.8 NR 24.3* 69.8 NR 76 92 98 91

92 100 Sensitivity 93.5 Specificity 100 86 Sensitivity 97.7 Specificity 100 100 100 NR 99.7 91 78 97 18 18 18 88 235 78 Neuzillet et al. [8] Shannon et al. [9] Schmidbauer et al. [10]

2.8 2.9 4.0

62 108 78

CT CT/US CT

2 1–4 2–3

Accuracy for malignancy, % Image guidance No. of pathologically confirmed tumours Mean tumour size, cm No. of tumours biopsied

Table 2 – Outcomes of needle core biopsies of renal masses in recent series

Needle size, No. of gauge biopsies taken

Diagnostic biopsies, %

Accuracy for Accuracy for RCC subtyping, % grading, %

Impact on management, %

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3.1.2.2.3. Tumour location and endophytic/exophytic pattern. Little information is available on the correlation between other tumour characteristics (anterior/posterior, longitudinal and rim location, endophytic/exophytic pattern, proximity to renal sinus and collecting system) and the diagnostic rate of percutaneous biopsies. In general, biopsies of anteriorly located, upper-pole, medial, perihilar, and endophytic tumours are considered more challenging. Longitudinal location (upper vs mid vs lower pole) was found to be a significant predictor of diagnostic biopsy in univariable but not multivariable analysis [16]. 3.1.2.2.4. Patient characteristics. Patient body habitus can potentially influence the diagnostic rate of biopsies. However, a relationship between a higher body mass index and a lower biopsy diagnostic rate has not been reported. 3.1.2.2.5. Image guidance. There seems to be no significant difference in diagnostic yield between biopsies performed with different image guidance [13,16]. Biopsies can generally be performed with the use of ultrasound, but CT is needed in difficult cases. In clinical practice, the most appropriate guidance should be selected in each case according to patient body habitus, tumour location, and visibility of the renal mass with the different imaging techniques. 3.1.2.2.6. Needle size. There are indications that a larger needle

size correlates with better diagnostic outcomes [20,31]. There is currently agreement that 18-gauge needles are ideal for renal tumour biopsies, allowing a safe procedure and sufficient tissue for an accurate diagnosis in the majority of cases [17,32]. 3.1.2.2.7. Biopsy pattern and quality of the specimen. The ideal number and location of biopsies for obtaining a diagnosis have not been defined. Obtaining multiple cores increases the amount of tissue available for histologic assessment and may improve diagnostic yield, but to date this hypothesis has not been clearly demonstrated. Regardless of the number of cores, the quality of the tissue retrieved is paramount to enhance biopsy success. In fact, a proper biopsy technique that avoids evident areas of necrosis and a careful check of the quality of the specimens are necessary for obtaining good diagnostic rates. Each biopsy core should be rolled evenly on a sponge to retain its straight, cylindrical shape and prevent fragmentation. Cores that are torn or <10 mm in length should be considered unsatisfactory, and further biopsies should be taken until good-quality cores are obtained [8]. Studies are needed to define the optimal

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tumour location from which biopsies should be taken. In a study of ex vivo renal tumour biopsies, Wunderlich et al. observed better diagnostic outcomes of peripheral compared to central biopsies for renal tumours >4 cm [21]. 3.1.2.2.8. Interdisciplinary approach and experience. Optimal diagnostic outcomes are more likely to be obtained in centres where expert multidisciplinary collaboration is possible. In fact, a close interaction among urologists, interventional radiologists, and dedicated genitourinary pathologists with expertise in taking and interpreting percutaneous biopsies is crucial to obtain high-quality specimens and maximise the diagnostic yield of renal tumour biopsies. 3.1.3.

Percutaneous biopsy of renal masses can decrease surgical

indications for benign disease

SRMs are benign in a significant proportion of cases, and the odds of benign pathology significantly increase with decreasing tumour size [33–35]. Frank et al. observed that 30% of renal lesions <4 cm that were removed by radical or partial open nephrectomy at the Mayo Clinic between 1970 and 2000 were benign at final pathology [36]. Similarly, 27.9% of SRMs were found to be benign in a multicentre series of 771 laparoscopic partial nephrectomies [37]. A definitive diagnosis of oncocytoma cannot be made without histologic assessment. A homogeneous hypervascular appearance and a central stellate scar on CT scan have been considered typical characteristics of oncocytomas but were found only in a small proportion of these tumours by Choudhary et al. in a recent series [38]. Likewise, Rosenkrantz et al. have recently shown that none of 16 qualitative MRI features allows an accurate differentiation between oncocytoma and chromophobe renal cell carcinoma (RCC) [39]. Angiomyolipoma (AML) is another common benign renal tumour. Although typical AMLs are easy to recognise on CT scans based on their fat component, fat-poor AMLs (leiomyoma-like and epithelioid variants) can frequently be misdiagnosed on imaging [40]. Overall, clinicians cannot rely on imaging alone to differentiate benign from malignant renal masses [41]. Remzi et al. showed that only 17% of all benign tumours were correctly defined on preoperative CT scan in their experience [42]. Pretreatment percutaneous biopsy can therefore potentially decrease the number of unnecessary surgeries for benign disease. In several large series of percutaneous biopsies, surgery was avoided in 16–17% of patients after histologic diagnosis of a benign renal lesion was made [8,13,16]. However, we have to be aware that the differential diagnosis of oncocytoma is challenging, and even expert genitourinary pathologists prefer the definition of oncocytic neoplasm most consistent with oncocytoma in pathology reports [43]. The risk of potential undertreatment after a diagnosis of oncocytoma resulting from incomplete sampling of hybrid oncocytic tumours, including areas of chromophobe RCC, should be also considered [10]. Furthermore, conservative treatment of biopsy-proven oncocytomas and selected asymptomatic AMLs is reasonable, but studies have shown that the majority of these tumours will grow over

time, and retroperitoneal bleeding can occur during followup of AMLs [43–47]. Further research is therefore needed to better characterise the natural history of these tumours and confirm safety and indications of conservative management of histologically proven benign renal neoplasms. Finally, in the presence of multiple and/or bilateral renal masses, we have to consider that the histology of a renal tumour does not predict the histologies of the other lesions. Therefore, if biopsy is considered in the case of synchronous renal tumours, all lesions should be biopsied [48]. 3.1.4.

Percutaneous biopsy can support treatment decision making

for renal tumours

Most renal tumours today are diagnosed as SRMs in asymptomatic patients who undergo non-invasive radiologic imaging [49]. A significant proportion of these masses are benign tumours or low-grade RCCs, with relatively indolent biologic and clinical behaviour [36,45,49,50]. In a Surveillance Epidemiology and End Results analysis including 19 932 patients with localised RCC, 84% of renal masses <4 cm in size presented low nuclear grade [50]. Furthermore, the largest increase in incidentally detected SRMs has occurred among patients 70–89 yr of age, in whom comorbidities are more frequent and the risk of competing-cause mortality is higher [51]. Recent studies have shown that non-RCC– related mortality after surgical treatment for SRMs is significant and correlates with age and comorbidity [52,53]. A population-based analysis of 26 618 patients who were surgically treated for locoregional kidney cancer between 1983 and 2002 showed that competing-cause mortality increases with increasing patient age, irrespective of tumour size (reaching 28.2% for patients >70 yr of age) [52]. In a retrospective review of 192 patients with clear cell RCC (ccRCC), Arrontes et al. observed that a higher Charlson Comorbidity Index (CCI) score (>2) is significantly associated with a worse overall survival (OS) after surgical treatment ( p < 0.001) [53]. Patient age and CCI score were found to be the only significant predictors of OS in a series of 537 patients >75 yr of age managed either with surgery or observation for clinically T1 renal tumours. In this series, surgical treatment was not associated with a significant survival advantage compared to observation [54]. The perception that active treatment for small renal lesions may not significantly influence OS in patients with a short life expectancy has led to the development of conservative and minimally invasive treatment options for select elderly and surgically high-risk patients with a SRM [55]. The concept of active surveillance is based on the assessment of the tumour growth rate by serial abdominal imaging over time, with delayed intervention reserved for those masses that show rapid growth or signs of clinical progression during follow-up [56]. However, although tumour kinetics can provide important information for the management of SRMs during surveillance, recent studies have shown that the assessment of growth rate alone is not sufficient to accurately determine malignancy of a small renal tumour. Kunkle at al analysed a series of SRMs that showed no growth during follow-up and observed that 83% of those that were biopsied were histologically malignant

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[57]. Furthermore, a multicentre prospective Canadian trial recently showed that the growth rate of histologically confirmed benign and malignant renal tumours during active surveillance is not significantly different [45]. The selection of the best-suited candidates for conservative and minimally invasive management and the definition of optimal follow-up schedules for each patient may be enhanced by the availability of information about pathology of SRMs obtained by a biopsy performed before treatment decisions are made. In fact, the Fuhrman grading system is known as an independent prognostic factor for ccRCC [58]. Although an independent prognostic role for RCC histotype has not been clearly established, singleinstitution and multicentre series showed significantly different oncologic outcomes among RCC histologic subtypes, with clear cell tumours showing worse outcomes than papillary and chromophobe histologies [59–61]. Renal tumour biopsy can provide useful information for patients with a SRM who are not ideal surgical candidates because of their age and/or comorbidities. In fact, conservative management may not be recommended in those with histologically proven high-grade RCC at biopsy for their higher risk of progression during follow-up. In this respect, percutaneous biopsy is particularly useful for renal masses >3 cm. In fact, Remzi et al. reviewed the specimens of 98 renal masses 3–4 cm in diameter and observed that 25.5% of these tumours were high grade as opposed to only 4.7% of masses <3 cm [62]. Furthermore, biopsy is useful in cases when a surveillance strategy is an option in order to stratify follow-up [3]. For example, histologically confirmed benign tumours might be followed with a less rigorous imaging schedule, thereby saving potential radiation exposure to the patient and cost to the health care system. Renal tumour biopsies can be useful in the management of all solid, contrast-enhancing SRMs when histologic diagnosis has the potential for supporting treatment decisions. However, at present, biopsy is not recommended in young and healthy patients because long-term oncologic outcomes of non-surgical therapies are not available, and there may be a risk of histologic transformation (eg, upgrading, development of sarcomatoid differentiation) when a renal tumour is observed for a long time. Finally, renal tumour biopsies may also play a role in the management of larger, clinically T1b–2, non-metastatic renal tumours. The current international guidelines recommend NSS as the standard of care for localised renal tumours <7 cm whenever it is technically feasible [3,4]. However, the risk of complications of partial nephrectomy increases with increasing anatomic complexity of renal tumours (larger size, non-polar location, proximity to the renal sinus and the urinary collecting system) [63,64]. Although the decision to perform a radical procedure or NSS is mostly based on preoperative imaging and consideration of tumour location, pretreatment histologic information on larger, surgically challenging tumours (eg, renal masses with a central or hilar location) may help surgical decisions, favouring radical treatment for tumours with aggressive pathology and conservative—albeit difficult—surgery in the presence of benign or less aggressive disease.

3.1.5.

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Percutaneous biopsy can support the assessment of treatment

outcomes after thermal ablation of small renal tumours

Thermal ablative therapies such as radiofrequency ablation (RFA) and cryoablation should be currently considered for treatment of incidental cortical SRMs in patients with comorbidities who are at high surgical risk, with the aim of minimising treatment morbidity [3,4]. In this category of patients, pretreatment biopsy should be carried out as a standard procedure to obtain histologic diagnosis and potentially identify the best-suited candidates for thermal ablation [3,4]. Preablation biopsy was shown to have a high diagnostic yield of 94.2% in a multicentre series of RFA [65]. Non-uniform and unproven criteria have been used to define treatment success and recurrence after thermal ablation of SRMs. Although the intermediate-term results of these techniques are encouraging [66,67], persistence of viable tumour after the procedure is possible, especially after RFA [68]. Routine postablation biopsy is rarely performed, and most authors use tumour shrinkage and radiographic loss of contrast enhancement on CT or MRI to assess treatment effect [69,70]. However, differentiation between the enhancement of post-treatment granulation tissue and residual viable tumour can be challenging [71]. Weight et al. observed that 46.2% of renal tumours with a postablation positive biopsy after RFA demonstrated no enhancement on post-treatment CT or MRI. Conversely, histologically proven treatment success remained high for cryoablation (93.8%) [72]. Based on these data, the American Urological Association (AUA) guidelines for management of SRMs state that percutaneous biopsy should be considered after thermal ablation, particularly if there is any suspicion of recurrence [4]. Routine follow-up biopsies have the potential to improve our ability to confirm the histologic success of minimally invasive ablative treatments and monitor for recurrence [20]. 3.1.6.

Percutaneous biopsy can support the selection of targeted

medical treatment for metastatic renal tumours

About 20–30% of RCCs present with metastatic disease, and a similar proportion of patients will develop metastases after surgical removal of their tumour [73]. Renal tumour biopsies have always been used when a renal mass is detected in the presence of a known extrarenal malignancy to differentiate a primary renal tumour from metastatic disease involving the kidney. It is interesting to note that in these cases, the biopsy is more likely to show a primary RCC than metastases or benign aetiologies [29,74]. However, much has changed in the treatment of metastatic disease in the past decade [75]. With expanding treatment options, there is an increasing need for predictive information to guide therapy. Percutaneous biopsies can potentially assess the presence of adverse prognostic factors that may affect treatment decisions. For example, the presence of sarcomatoid differentiation portends a poor prognosis with limited response to systemic treatment and may represent a contraindication to cytoreductive nephrectomy to avoid unnecessary morbidity [76–78].

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Abel et al. recently reviewed the records of 166 patients who underwent cytoreductive nephrectomy for metastatic RCC at the MD Anderson Cancer Centre and compared the results of biopsy with the histology of the final specimen. Fuhrman grade was assigned in 104 cases (62.6%). Full concordance of grade in biopsy and specimen was only 31.7%, which increased to 67.9% when considering only concordance of high (Fuhrman III–IV) or low (Fuhrman I–II) grade. Sarcomatoid features were present in 34 nephrectomy specimens (20.5%), of which only 4 (11.8%) were identified preoperatively [77]. Although the series includes cases that date back to 1991, when different biopsy techniques were used, this study suggests that caution should be used when utilising information about Fuhrman grade and sarcomatoid features to guide therapy in metastatic disease. However, the definition of RCC histologic subtype has been always useful for systemic treatment of metastatic renal tumours. In the cytokine era, two randomised trials have shown that patients with clear cell histology were more likely to benefit from adjuvant immunotherapy following cytoreductive nephrectomy [79,80]. With the advent of biologic targeted therapies, it was clear that pretreatment pathologic information plays an important role because the targeted therapies demonstrate different response rates to different histologic subtypes. In a retrospective multicentre review of patients with nonccRCC treated with sunitinib and sorafenib, Choueiri et al. showed that clinical responses to these drugs remain low overall in papillary RCC [81]. In contrast, data from an exploratory subgroup analysis from the phase 3 global Advanced Renal Cell Carcinoma trial show that the efficacy of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus (compared with interferon) appears more pronounced among patients with non-clear primary cell type and among patients with a papillary subtype than among those with clear cell histology or those without the papillary subtype [82]. Furthermore, phase 2 studies are evaluating the efficacy and safety of fully human monoclonal antibodies to hepatocyte growth factor/scatter factor, which is frequently mutated in papillary RCC [83]. At present, biopsy of the primary renal tumour is needed before starting systemic therapy for metastatic RCC to select the best-suited targeted therapy [3]. In particular, biopsy is

recommended in all cases when a cytoreductive nephrectomy is not indicated or when neoadjuvant systemic therapy is planned. In some health care systems, biopsy may be formally required to start therapy because drug approval may be limited to patients with specific RCC subtypes. 3.2.

Current indications, use, and limitations of percutaneous

renal tumour biopsies 3.2.1.

Current indications of renal tumour biopsies and impact on

treatment decisions

Based on previous considerations, current indications for renal tumour biopsies have expanded in recent years and are summarised in Table 3. In centres with experience in this field, percutaneous biopsies have a significant impact on clinical decisions. In recent series, biopsy results were shown to change clinical management (between surgery and other treatment options, including surveillance, percutaneous or laparoscopy-assisted tumour ablation, externalbeam radiation therapy, or systemic chemotherapy) in a significant proportion of patients (24–69%; Table 2) [8,10– 13,15]. With increasing expertise and confidence in biopsy interpretation, pretreatment biopsy may become necessary in many patients with renal masses to tailor the best treatment for each individual patient. However, at present, even a small number of false-negative results and especially the problem of managing a non-diagnostic biopsy remain the major concern for clinicians. In the presence of a negative or non-diagnostic biopsy and suspicious radiologic findings for malignancy, a further biopsy or surgical exploration should be always considered [84]. Several authors reported high diagnostic rates for repeat core biopsies after a first non-diagnostic one [9,11,16,24,84,85], but the role of repeat sampling of renal tumours must be confirmed in larger studies. Otherwise, a negative biopsy can lead to initial observation or decreased follow-up if surveillance was already planned before biopsy. 3.2.2.

Current use of renal tumour biopsies

Despite increasing indications and encouraging outcomes, the use of renal tumour biopsies in routine clinical practice is still limited outside academic centres and institutions with a special focus on urologic oncology. Khan et al.

Table 3 – Current indications and contraindications of percutaneous renal tumour biopsies Indications

Contraindications

 SRMs that are indeterminate on abdominal imaging (including selected indeterminate cystic lesions)  Renal masses that are suspicious for metastatic disease in the presence of a known extrarenal malignancy  Incidentally diagnosed SRMs in patients who are potentially candidates for active surveillance or minimally invasive ablative therapy to support treatment decisions  Renal tumours during follow-up of thermal ablation to confirm histologic success and monitor for recurrence  Primary renal tumours in the setting of metastatic disease to select the optimal biologic systemic therapy, particularly when a cytoreductive nephrectomy is not indicated or neoadjuvant systemic therapy is planned  Unresectable retroperitoneal renal tumours involving the kidney Absolute: Uncorrected coagulopathy Relative: Patients with limited life expectancy or locally advanced or disseminated metastatic disease who are not candidates for any surgical, ablative, or medical treatment except palliation of symptoms

SRM = small renal mass.

EUROPEAN UROLOGY 62 (2012) 491–504

performed a national questionnaire survey of 325 consultant urologists in the United Kingdom and observed that 43% of urologists never use biopsy and 23% use biopsy only for a select patient group. Mass in a solitary kidney, bilateral renal masses, and a past history of non-renal cancer were the main indications for the use of renal tumour biopsies. The risk of false-negative results and the perception that biopsy would not change the eventual management of their patients were the most common reasons not to perform biopsy [86]. In a survey of treatment for SRMs carried out by the AUA, few urologists declared that they routinely used biopsies in their practice (45.8% perform biopsies in >20% of patients with SRMs). The decision to biopsy was dictated mainly by suspicion of non-RCC malignancy and patient comorbidity [87]. Further surveys by the major urologic organisations are needed to better define the prevalence of biopsy use and understand the reasons for its current underutilisation. 3.2.3.

Current limitations of renal tumour biopsies and future

research prospects

Although the current diagnostic yield and outcomes of renal tumour biopsies in centres with experience are encouraging (Table 2), a definite assessment of biopsy accuracy remains difficult. Large, prospective, and well-designed studies of percutaneous biopsies are required to confirm the current results. These studies are needed to overcome the limitations of most current series, which are relatively small and single institutional, use different definitions for biopsy success and different follow-up protocols, and lack surgical confirmation of histology in a large proportion of cases. Particular efforts should be made by the urologic community and organisations to standardise the definitions of failed, indeterminate, and inaccurate biopsy to properly compare the results of different series. Most authors currently define a biopsy as failed when it does not provide sufficient or adequate tissue for diagnosis, indeterminate when the pathologist cannot make a definitive diagnosis using available tissues, and inaccurate (false negative or false positive) when there is a discrepancy between diagnosis on the biopsy and on the final pathologic specimen [20]. Beyond technical errors and the limitations of current clinical studies, the accuracy of renal tumour biopsies is hampered by factors intrinsic to the procedure (inconsistent tumour sampling), to the histology of renal tumours (difficult differential diagnosis of tumour histotypes, challenging evaluation of Fuhrman grade, presence of intratumoural heterogeneity), and to the interpretation of biopsy specimens (interobserver variability in pathologic assessment). With regard to tumour sampling, further clinical research is needed to define the optimal number of cores that should be taken and the optimal biopsy pattern that should be used. Although no clinical practice guidelines are available, there is agreement that at least two good-quality cores should be obtained in each case [8]. Increasing the number of cores may increase the diagnostic yield of the procedure. Biopsies of the peripheral part of the tumour should be preferred for larger lesions to avoid central necrosis, while both central and peripheral biopsies should be performed for SRMs [21]. However, a sampling of the entire lesion may be useful for

499

tumours of any size because the diagnosis of intratumoural necrosis has prognostic significance [88]. Histotype heterogeneity in renal tumours is rare, but 18% of oncocytomas were shown to harbour areas of chromophobe RCC [10]. Although oncologic outcomes of these hybrid tumours were shown to be similar to that of pure oncocytomas, this finding represents a possible reason for biopsy inaccuracy with some malignant tumours that may be considered benign at biopsy [89]. The differential diagnosis among oncocytoma, eosinophilic variants of chromophobe RCC, oncocytic papillary RCC, and conventional RCC with granular cytoplasm remains the major challenge for pathologists in the interpretation of biopsy specimens, especially in the presence of limited pathologic material. Kummerlin et al. recently showed substantial interobserver and intraobserver agreement in pathologic subtyping of renal tumours on needle core biopsy taken on the bench after surgery. However, the diagnosis was less reproducible for chromophobe RCCs with the use of haematoxylin and eosin staining only [90]. Assessment of Fuhrman grade on renal tumour biopsies is challenging, and accuracy is not optimal [8,10,11,13,16,91]. When biopsies are performed on the bench after nephrectomy, grade accuracy is higher, reaching 85% [21]. A higher agreement between preoperative and postoperative grading can be achieved when tumours are simply defined as low (Fuhrman I–II) or high (Fuhrman III–IV) grade [8,11,85,92]. Accuracy in the evaluation of tumour grade is paramount if this information is used for clinical decision making but is limited by tumour heterogeneity and interobserver variability. Intratumoural grade heterogeneity has been reported in 5–25% of renal tumours [6,10]. Its potential impact on biopsy accuracy can be reduced by performing multiple biopsies in different areas of the tumour. Interobserver concordance for grade assessment was found to be only moderate (k = 0.253) in a series of biopsies taken ex vivo after nephrectomy [93]. Finally, the prognostic utility of Fuhrman grade for non-clear cell histologies and especially for chromophobe RCC is controversial [94]. Despite these limitations, Jeldres et al. observed that models including other patient and tumour clinical characteristics cannot reliably predict Fuhrman grade and therefore cannot substitute percutaneous biopsy for grade assessment [95]. Improving our ability to obtain samples that allow a reliable and accurate evaluation of tumour grade is clearly one of the main future goals of clinical research on renal tumour biopsies. 3.3.

Rationale for molecular and genetic characterisation of

renal tumours on percutaneous biopsies

Translational research in the past decade has provided great insight into the biologic mechanisms leading to the development and progression of RCC, and there is increasing evidence that further diagnostic and prognostic information can be obtained with the use of immunohistochemistry (IHC), cytogenetic and molecular analysis, and high-throughput gene expression profiling. Errors in differential diagnosis between RCC histotypes, including translocation RCC, oncocytoma, and epithelioid

500

EUROPEAN UROLOGY 62 (2012) 491–504

at 100% [102]. Assessment of the S100A1 protein by IHC or real-time PCR was also found to be potentially useful for the differential diagnosis between chromophobe RCC and oncocytoma [103]. Fluorescence in situ hybridisation (FISH) analysis using centrometric probes to evaluate the gains of chromosomes 7 and 17 and the losses of chromosomes 1,2,3p,6,10,17 and Y have been also shown to improve the accuracy of renal tumour biopsies. Another study on 14-gauge biopsies taken ex vivo after nephrectomy confirmed the feasibility of FISH analysis on biopsies. In cases with adequate tissue, histology alone was 87% accurate for the diagnosis of tumour subtype, while the accuracy increased to 94% with the addition of cytogenetic information [101]. Chyhrai et al. performed multicolour interphase FISH on percutaneous biopsies taken before tumour excision in 25 patients with indeterminate renal masses. The combination of histopathologic examination and FISH led to higher (95.5% vs 90.5%) diagnostic fidelity compared to histology alone [104]. Brunelli et al. observed that interphase FISH analysis is useful in differentiating chromophobe RCC from oncocytoma, especially in renal tumour biopsies when limited tissue is available for analysis [105]. Beyond diagnosis, molecular and genetic tests on renal tumour biopsies have the potential to provide prognostic information that can be useful for treatment decisions, especially for SRMs in patients with limited life expectancy. Several molecular and genetic tissue markers have been investigated as potential prognosticators for RCC, including markers typically associated with renal cell carcinogenesis and progression (von Hippel-Lindau, hypoxia-induced factor 1 alpha [HIF-1a], VEGF, CAIX, pS6, phosphatase and tensin homolog) and markers that have been extensively described and investigated in other malignancies (p53, Ki67, CXCR3, CXCR4, matrix metalloproteinases 2 and 9, IGF II mRNA binding protein, epithelial cell adhesion molecule, vimentin, fascin, livin, survivin) [99].

AML, can be minimised with the use of IHC and chromosomal analysis on formalin-fixed, paraffin-embedded specimens [96,97]. An IHC panel, including CD10, parvalbumin, a-methylacyl-coenzyme A racemase (AMACR), cytokeratin 7 (CK7), S100A1, cathepsin K, and carbonic anhydrase IX (CAIX), seems to be the most promising (Table 4). Studies of IHC for CAIX have shown the significant prognostic potential of decreased levels of this marker, which are independently associated with poor survival in advanced RCC [98]. Reliable diagnostic and prognostic serum and urine markers for RCC would greatly ease screening and management of patients with renal tumours by providing important diagnostic and prognostic information with a completely non-invasive approach. However, at the present time, only a few promising reports about potential markers in peripheral blood (CAIX messenger RNA [mRNA], vascular endothelial growth factor [VEGF], insulin-like growth factor [IGF]-1) are available, and the literature on urinary markers is scant, with little potential for clinical application in the near future [99]. Conversely, there are encouraging data on the diagnostic and prognostic accuracy of tissue tumour markers. To date, most of the evidence derives from studies performed on whole-tumour specimens. However, the assessment of molecular and genetic markers on adequate biopsy and FNA specimens is possible and can potentially provide important information before treatment decisions [100–102]. Molecular diagnosis of RCC histotypes on biopsies is feasible. Barocas et al. performed 14-gauge needle core biopsies of 72 renal tumours after nephrectomy and were able to extract RNA and perform quantitative real-time polymerase chain reaction (PCR) for a panel of genes codifying CAIX, AMACR, parvalbumin, and kidney-specific basolateral chloride channel. The addition of this molecular diagnostic algorithm to standard histology increased the overall accuracy for histotype diagnosis from 83.3% to 95%, with sensitivity and NPV for diagnosing the clear cell variant

Table 4 – Immunohistochemical and cytogenetical panel for differential diagnosis of renal tumours Different histotype of renal cell neoplasms ccRCC

IHC

FISH

CD10 PV AMACR CK7 S100A1 Cathepsin K CAIX 3p 1 2 6 7 10 17 tXp11

+

Papillary RCC

Chromophobe RCC

+

+/ + LOSS

Epithelioid AML

/+ +

/+

Oncocytoma

+ + +/

Xp11 translocation RCC /+

+ +/

+/

/+ + + N/A

/+ LOSS LOSS LOSS

/+ +/ /+

LOSS

GAINS GAINS

LOSS LOSS PRESENT

ccRCC = clear cell renal cell carcinoma; RCC = renal cell carcinoma; AML = angiomyolipoma; IHC = immunohistochemistry; CK7 = cytokeratin 7; AMACR = a-methylacyl-coenzyme A racemase; CAIX = carbonic anhydrase IX; N/A = not available; FISH = fluorescence in situ hybridisation.

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The largest study to investigate prognostic molecular markers for ccRCC assessed the expression of 29 different markers mainly related to the HIF and mTOR pathways in 170 patients who underwent nephrectomy for localised RCC. The expression of Ki-67, p53, endothelial VEGF receptor 1 (VEGFR-1), epithelial VEGFR-1, and epithelial VEGF-D were shown to be independent predictors of disease-free survival after adjustment for standard clinical and pathologic variables. The molecular signature based on these markers was more accurate than T stage and University of California, Los Angeles Integrated Staging System in predicting patient outcomes. A nomogram combining these molecular markers with clinical and pathologic variables yielded a prognostic accuracy of 90% [106]. Other studies have looked at the prognostic role of cytogenetic alterations in renal tumours. Brunelli et al. carried out FISH in 73 patients with ccRCC and observed loss of chromosome 9p in 13 tumours (18%). This 9p loss was found to correlate with a significantly worse 5-yr cancerspecific survival (CSS; p < 0.001) and was confirmed as an independent outcome predictor after adjustment for other important clinical and pathologic factors at multivariable analysis [107]. These findings were recently confirmed by Klatte et al. in a larger study of 282 patients with ccRCC. The same authors developed a nomogram with high prognostic accuracy to predict 3-yr CSS, combining loss of 9p with the TNM staging system and the Fuhrman nuclear grading system [108]. Core biopsies can produce specimens that are also suitable for extraction and—if needed—amplification of DNA or RNA for genomic analyses, such as complementary DNA expression microarrays or comparative genomic hybridisation. There is evidence that gene-expression profiles obtained with high-throughput microarray technology can identify histologic subtypes of RCC and predict clinical outcomes of the disease [109,110]. Lane et al. recently identified a 44-gene expression profile that was able to distinguish two groups of ccRCCs with significantly different clinical behaviour (5-yr recurrence-free survival 68% and 42%, respectively; p = 0.032) [111]. Overall, the results of available studies on molecular and genetic tissue markers for RCC are highly promising. However, most of them are based on retrospective series with small sample sizes and relatively short follow-up. Furthermore, most of the studies focus on the prognosis of ccRCCs, and little information in this regard is available for other tumour histotypes [112]. Based on these considerations, the AUA recommendations for the management of localised renal tumours clearly defines the study of molecular and genetic profiling on percutaneous renal tumour biopsies as a research priority. Well-designed, multicentre, prospective studies are needed to validate the currently available findings, and clinical research needs to investigate new biomarkers to increase our ability to estimate the aggressiveness of renal tumours, predict their outcomes and response to different treatment modalities, and promote more rational treatment selection. The combination of selected markers in prognostic panels and the integration of molecular and

501

genetic information with clinical and pathologic variables in predictive nomograms have the potential to improve the accuracy of traditional prognostic information for renal tumours. 4.

Conclusions

Renal tumour biopsies had historically selective indications. With the use of modern techniques, percutaneous biopsies can be performed with low morbidity, virtually no risk of seeding, and good diagnostic yield and accuracy for malignancy and histotype in centres with expertise. In recent years, the increasing incidence in the diagnosis of incidental SRMs, the development of conservative and minimally invasive treatments for low-risk RCC, and the discovery of novel targeted treatments for metastatic disease have provided the rationale for expanding indications of renal tumour biopsies. At present, percutaneous biopsy is recommended in the diagnostic work-up of renal tumours that are indeterminate on imaging and of incidentally detected, radiologically suspicious SRMs in patients at high surgical risk to support treatment decisions and avoid unnecessary surgery. When clinically indicated, biopsies should be also increasingly performed after thermal ablation of renal tumours to confirm histologic success and monitor for recurrence. Finally, percutaneous biopsies of the primary renal tumour are needed before starting systemic therapy for metastatic RCC to select the best-suited targeted therapy, particularly when a cytoreductive nephrectomy is not indicated or neoadjuvant systemic therapy is planned. Despite the increasing experience and indications, biopsies are still significantly underutilised. Further clinical research is needed to overcome the current limitations of renal tumour biopsies and increase their application in clinical practice. Well-designed studies are necessary to determine the definition of optimal and standardised biopsy techniques, reliable criteria to assess specimen quality, and guidelines for categorisation of pathology results. Furthermore, efforts should be made to improve the ability of biopsies to accurately determine tumour grade and differentiate among eosinophilic renal cell tumours with different clinical behaviour to increase the confidence of clinicians in using biopsy information to support treatment decisions. Experienced centres should increasingly investigate biopsy specimens at the genetic, RNA, and protein level to obtain additional diagnostic and prognostic information. Finally, histologic, molecular, and genetic data from renal tumour biopsy could be integrated with clinical information in algorithms and nomograms to be used for counselling and treatment decision making. Author contributions: Alessandro Volpe 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: Volpe, Finelli, Gill, Jewett, Martignoni, Polascik, Remzi, Uzzo. Acquisition of data: Volpe.

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Analysis and interpretation of data: Volpe, Finelli, Gill, Jewett, Martignoni, Polascik, Remzi, Uzzo. Drafting of the manuscript: Volpe. Critical revision of the manuscript for important intellectual content: Finelli, Gill, Jewett, Martignoni, Polascik, Remzi, Uzzo. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Finelli, Gill, Jewett, Martignoni, Polascik, Remzi, Uzzo. Other (specify): None.

[15] 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;21:393–401. [16] Leveridge MJ, Finelli A, Kachura JR, et al. Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol 2011;60:578–84. [17] Volpe A, Kachura JR, Geddie WR, et al. Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy. J Urol 2007;178:379–86. [18] Dechet CB, Zincke H, Sebo TJ, et al. Prospective analysis of computerized tomography and needle biopsy with permanent sec-

Financial disclosures: Alessandro Volpe 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: None. Funding/Support and role of the sponsor: None.

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