- Email: [email protected]
Renal mass biopsy for the small renal mass
Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
News and Topics
Renal mass biopsy for the small renal mass Sapan N. Ambani, M.D.a,*, James Stuart Wolf Jr., M.D.b a
b
Department of Urology, University of Michigan Health System, Ann Arbor, MI Department of Surgery, Dell Medical School, University of Texas at Austin, Austin, TX
Received 16 July 2017; received in revised form 18 September 2017; accepted 26 September 2017
Abstract Opponents of premanagement biopsy of small renal masses are not difficult to find. Many urologists contend that the benefits of biopsy do not outweigh the risks, arguing that the results do not influence management substantially and that the most useful information from renal mass biopsy can be attained with advanced imaging. In this article, we develop the counter arguments and demonstrate that renal mass biopsy should be implemented into the small renal mass management algorithm. r 2017 Elsevier Inc. All rights reserved.
Keywords: Small renal mass; Renal mass biopsy
Biopsy of the small renal mass (SRM) (clinical T1a) continues to incite controversy. Those opposed to the performance of renal mass biopsy (RMB) generally attack its safety, accuracy, and lack of use. Proponents of RMB cite accumulating evidence supporting its usage in the evaluation of the SRM that is suspicious for renal cell carcinoma. In this News and Topics article, we address popularly stated reasons to forego RMB, review contemporary RMB data, and argue that RMB deserves a role in the evaluation and management of SRMs. Is RMB necessary? Opponents of RMB contend that a SRM is extremely likely to harbor malignancy, and therefore management options can safely be discussed without a pathologic diagnosis. In actuality, of SRMs (clinical T1a lesions, so o4 cm in maximal diameter), 25% are benign [1]. Many surgical series report a 25% rate of benign tumors, but we feel that a 25% risk of unnecessary surgery is excessive. Inasmuch as RMB can reduce this rate to a more reasonable risk, they are useful. Moreover, although the ability to radiologically differentiate benign and malignant lesions continues to develop, with impressive improvements in radiologic characterization over the years, current technology still is insufficiently accurate to be considered a substitute for histologic diagnosis. Millet et al. [2] performed a retrospective review to determine whether Corresponding author. Tel.: þ1-734-936-5801; fax: þ1-734-936-9127. E-mail address: [email protected] (S.N. Ambani). *
http://dx.doi.org/10.1016/j.urolonc.2017.09.025 1078-1439/r 2017 Elsevier Inc. All rights reserved.
computed tomography characteristics could accurately identify SRM pathology, and concluded that computed tomography was unable to differentiate between benign and malignant lesions. Some success has been demonstrated at discriminating among renal cell carcinoma subtypes [3]. Sun et al. [4] demonstrated that dynamic contrast-enhanced magnetic resonance imaging could differentiate between papillary and clear cell renal cell carcinoma with up to 94% accuracy. Despite this, a serious limitation of radiologic imaging is its inability to differentiate high grade cancers from those that are relatively indolent [5]. This is particularly important given that approximately only 20% of SRMs demonstrate aggressive histology [6] and the ability to reliably differentiate these tumors from indolent ones would reduce both overtreatment and undertreatment. Is RMB dangerous? Although many have raised concerns about the safety of RMB, modern literature supports the idea that RMB has a low risk of complications [7]. The most common adverse event is hematoma (4.9%), which rarely requires transfusion (0.4%) [8]. Other associated complications with RMB including pain (1.2%), gross hematuria (1.0%), and pneumothorax (0.6%) are similarly minor or rare [8,9]. A potentially disastrous complication of RMB is tumor seeding. In the contemporary literature, only a few cases have been reported when appropriate coaxial technique was used [10,11]. A systematic review of the literature reported no tumor seeding events among 20 studies including 3,113 RMB on 2,979 patients [8].
2
S.N. Ambani, J.S. Wolf Jr. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
A meta-analysis by Marconi et al. [12] similarly noted no RMB tumor seeding for renal cell carcinoma. With the estimated rate of tumor seeding after RMB to be less than 0.01%, this overly emphasized complication can be considered anecdotal [13,14]. Is RMB accurate? With refinements in technique, RMB has grown into a highly accurate diagnostic test. RMB has the ability to differentiate between benign and malignant SRMs, with reported sensitivity of 97.5% to 99.7%, specificity of 96.2% to 99.1%, and positive predictive value of 99.8% in 2 large meta-analyses [8,12]. Patel et al. [8] reported a concerning negative predictive value of 68.5%, however, this is based on the limited number of benign and nondiagnostic biopsies with gold standard surgical pathology. Among 17 studies, only 79 (16.8%) of 468 benign biopsies had surgical pathology, of which 29 (36.7%) were falsely negative. Of these, 19 (65.5%) were concentrated in 2 studies, one of which represented an early experience in RMB using a fine needle aspiration technique, while the other included 6 patients with masses greater than 4 cm [15,16]. Most contemporary studies reveal a substantially lower false-negative rate among benign biopsies [8]. In addition, the false-negative rate of benign RMB is likely subject to selection and verification bias as surgical excision was likely performed in the most concerning of benign renal masses. Nondiagnostic biopsies, in which biopsy resulted in insufficient tissue, normal kidney parenchyma, fibrosis, or necrosis, occurs in 10% to 20% of RMB [8]. This rate can be significantly improved upon with repeat biopsy. Another attempt at RMB yields diagnostic results at a rate of approximately 80%, thus decreasing the frequency of nondiagnostic RMB to less than 10% [17]. In one series, 22.3% of nondiagnostic RMB went on to definitive surgery and 90.4% of these masses were malignant [8]. Although diagnostic accuracy of RMB continues to improve, these results suggest that management of nondiagnostic RMB should proceed with caution. As data suggest RMB to be accurate with a low rate of adverse events, we argue that it deserves an integral role in the management of SRMs. Our group has previously published a SRM algorithm implementing RMB-influenced risk stratification [18]. Reviewing 133 patients with both RMB and surgical pathology from an excised SRM, we evaluated whether RMB pathology allowed accurate risk assignment and treatment as compared to the “ideal management” as determined by surgical pathology. RMB incorrectly assigned 4 of 133 (3.0%) patients, all of which were incorrectly assigned to surveillance. Accuracy of RMB-guided management was quite high, as it demonstrated a sensitivity for treatment of 96%, specificity for surveillance of 100%, a positive predictive value of treatment of 100%, and a negative predictive value of surveillance of 86%. Although this analysis excluded patients with benign and nondiagnostic RMB, it provided accurate treatment assignment of malignant RMB results when compared
to final surgical pathology. A multi-institutional retrospective study by Rahbar et al. [19] of 1,175 robotic partial nephrectomy specimens reported that up to 52% of surgeries in their cohort could have been avoided had they known the pathology prior to surgery. Although based on the theoretical assumption of 100% concordance between RMB and surgical pathology, it suggests that surgical treatment (and associated risks) of many SRMs could be avoided with the implementation of RMB-based risk stratification. RMB-guided management has also been shown to be superior to other risk-stratification nomograms. RENAL nephrometry score (RNS) nomograms have been used to predict malignancy and risk-stratify patients [20]. In 281 patients, Osawa et al. [21] evaluated whether an RMBbased algorithm was superior to RNS nomograms in accurately predicting and risk-stratifying SRMs. RMB demonstrated superior accuracy in predicting malignancy (99% vs. 29% concordance) as well as high-risk malignancy (67% vs. 61% concordance). The addition of RNS, as well as age and gender, to RMB and tumor size did not improve the accuracy of a risk-stratification algorithm previously published by Halverson et al. [18,22]. One area of concern is with RMB false-negatives. This is primarily based on lower rates of nuclear grade concordance, with most studies demonstrating RMB under-grading. Tumor heterogeneity and hybrid histology have been put forth as contributing reasons for inaccuracy [13,23]. A risk of RMB-based risk stratification is incorrectly assigning a patient with a high-risk tumor to surveillance when they should be treated. This danger can be mitigated if patients with adverse pathology who are (incorrectly) assigned to surveillance can be identified and diverted to delayed intervention without compromising outcomes. Hawken et al. [24] described 495 SRMs treated with surgical excision. A period of surveillance followed by delayed intervention was performed for 94 patients (median ¼ 386 days, IQR: 272–702), whereas the remaining 401 underwent early intervention (median ¼ 84 days, IQR: 59–121). Delayed intervention was not associated with adverse pathology (P ¼ 0.8). Interestingly, greater annual SRM growth demonstrated a modest but significant association with adverse pathology for patients on surveillance (odds ratio ¼ 1.2, 95% CID: 1.03–1.3 mm/y, P ¼ 0.02). This supports the often-applied practice (heretofore based on clinical principle rather than evidence) of using growth as a determining factor for delayed intervention for patients on active surveillance. Outcomes of these patients were no worse than for those whom underwent early intervention, thus assuaging some of the concerns about false-negative RMB. With increasing amounts of data supporting the diagnostic ability of RMB, current debate is centered around its clinical use [25]. Some proponents of RMB implore its use in the majority of SRMs [17,26], whereas others argue for a more limited role [25]. The appropriate usage of RMB is
S.N. Ambani, J.S. Wolf Jr. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
likely selective. RMB, like any other diagnostic test, should only be used if it will change management. Identifying the tumor histology would be beneficial in allowing a patient to avoid intervention in the case of benign or nonaggressive tumors, however, the young, healthy patient is unlikely to be interested in surveillance, particularly given the low reported complication rate with contemporary partial nephrectomy. Similarly, the older patient with major comorbidities would likely not be a candidate for treatment regardless of the RMB results, and therefore the use of RMB may be limited in this group as well. Information gleaned from RMB may also adjust the surgical plan in those patients in whom surgery is a foregone conclusion. An aggressive malignancy may lead to increased usage of radical over partial nephrectomy due to concerns for multifocality or positive margins. On review of the SRM database at the University of Michigan, Montgomery et al. [27] evaluated 854 SRMs from 2007 to 2015 who underwent active surveillance, ablative therapy, or partial/radical nephrectomy, with 366 (42.9%) having interpretable RMB data to assist with the management decision. Any malignancy on biopsy was associated with an increased rate of initial treatment over surveillance (P o 0.01). Worse pathology on RMB was associated with an increased rate of radical nephrectomy in patients between 55 and 75 years old (P o 0.01), suggesting the greatest clinical use of RMB may be in patients between these ages who harbor a 2 to 4 cm SRM. RMB is helpful at selecting patients for active surveillance, however do RMB surveillance patients benefit from more information about their SRM? Do patients with benign and low-risk malignancy feel more assurance about maintaining surveillance, particularly since illness uncertainty is associated with a negative effect on quality of life [28]? Do urologists have confidence in RMB results, particularly in the face of a growing mass or concerned patient? Our institution performed a retrospective study of 118 SRM on active surveillance to determine risk factors for delayed intervention [29]. Multivariate analysis revealed that delayed intervention was significantly related to initial tumor size 42 cm (hazard ratio ¼ 3.65, P ¼ 0.015) and growth rate (hazard ratio ¼ 1.26, P o 0.01, mm/y), but not RMB (P ¼ 0.29). Although this may be used as fuel for the anti-RMB fire, this result is more an indictment of practice pattern than the clinical use of RMB. Even at an institution that emphasizes the use of RMB, we have yet to use RMB to its full potential. Conclusion For many years, the SRM has avoided what most other tumors have been subjected to: a biopsy. RMB has been considered unnecessary in the management of the SRM. However, with accumulating data, the clinical paradigm is shifting toward increased usage of RMB. RMB is safe,
3
accurate, and deserves a prominent role in the evaluation of SRMs. Contemporary guidelines embrace RMB in the appropriately selected patient [9]. The future of RMB only looks bright, as advances in molecular markers and DNA sequencing will allow us to better characterize and identify worrisome renal masses. Current evidence supports using RMB as a risk-stratifying tool, and urologists are advised to incorporate this into their management scheme for SRMs. Further implementation of an RMB-based algorithm would be enhanced with a well-designed prospective clinical trial.
References [1] Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol 2003;170:2217–20, http://dx.doi.org/10.1097/01. ju.0000095475.12515.5e. [2] Millet I, Doyon FC, Hoa D, Thuret R, Merigeaud S, Serre I, et al. Characterization of small solid renal lesions: can benign and malignant tumors be differentiated with CT? AJR Am J Roentgenol 2011;197:887–96, http://dx.doi.org/10.2214/AJR.10.6276. [3] Gorin MA, Rowe SP, Baras AS, Solnes LB, Ball MW, Pierorazio PM, et al. Prospective evaluation of 99mTc-sestamibi SPECT/CT for the diagnosis of renal oncocytomas and hybrid oncocytic/chromophobe tumors. Eur Urol 2016;69:413–6, http://dx.doi.org/10.1016/j. eururo.2015.08.056. [4] Sun MRM, Ngo L, Genega EM, Atkins MB, Finn ME, Rofsky NM, et al. Renal cell carcinoma: dynamic contrast-enhanced MR imaging for differentiation of tumor subtypes—correlation with pathologic findings. Radiology 2009;250:793–802, http://dx.doi.org/10.1148/radiol.2503080995. [5] Egbert ND, Caoili EM, Cohan RH, Davenport MS, Francis IR, Kunju LP, et al. Differentiation of papillary renal cell carcinoma subtypes on CT and MRI. AJR Am J Roentgenol 2013;201:347–55, http://dx.doi. org/10.2214/AJR.12.9451. [6] Thompson RH, Kurta JM, Kaag M, Tickoo SK, Kundu S, Katz D, et al. Tumor size is associated with malignant potential in renal cell carcinoma cases. J Urol 2009;181:2033–6, http://dx.doi.org/10.1016/ j.juro.2009.01.027. [7] Lane BR, Samplaski MK, Herts BR, Zhou M, Novick AC, Campbell SC. Renal mass biopsy—A renaissance? J Urol 2008;179:20–7, http: //dx.doi.org/10.1016/j.juro.2007.08.124. [8] Patel HD, Johnson MH, Pierorazio PM, Sozio SM, Sharma R, Iyoha E, et al. Diagnostic accuracy and risks of biopsy in the diagnosis of a renal mass suspicious for localized renal cell carcinoma: systematic review of the literature. J Urol 2016;195:1340–7, http://dx.doi.org/ 10.1016/j.juro.2015.11.029. [9] Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, et al. Renal mass and localized renal cancer: AUA guideline. J Urol 2017, http://dx.doi.org/10.1016/j.juro.2017.04.100. [10] Soares D, Ahmadi N, Crainic O, Boulas J. Papillary renal cell carcinoma seeding along a percutaneous biopsy tract. Case Rep Urol 2015;2015:925254, http://dx.doi.org/10.1155/2015/925254. [11] Viswanathan A, Ingimarsson JP, Seigne JD, Schned AR. A singlecentre experience with tumour tract seeding associated with needle manipulation of renal cell carcinomas. Can Urol Assoc J 2015;9: E890–3, http://dx.doi.org/10.5489/cuaj.3278. [12] Marconi L, Dabestani S, Lam TB, Hofmann F, Stewart F, Norrie J, et al. Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. Eur Urol 2016;69:660–73, http: //dx.doi.org/10.1016/j.eururo.2015.07.072. [13] Tomaszewski JJ, Uzzo RG, Smaldone MC. Heterogeneity and renal mass biopsy: a review of its role and reliability. Cancer Biol Med 2014;11: 162–72, http://dx.doi.org/10.7497/j.issn.2095-3941.2014.03.002.
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[14] Volpe A, Finelli A, Gill IS, Jewett MAS, Martignoni G, Polascik TJ, et al. Rationale for percutaneous biopsy and histologic characterisation of renal tumours. Eur Urol 2012;62:491–504, http://dx.doi. org/10.1016/j.eururo.2012.05.009. [15] Campbell SC, Novick AC, Herts B, Fischler DF, Meyer J, Levin HS, et al. Prospective evaluation of fine needle aspiration of small, solid renal masses: accuracy and morbidity. Urology 1997;50:25–9 http://dx.doi.org/10.1016/S0090-4295(97)00111-8. [16] Londoño DC, Wuerstle MC, Thomas AA, Salazar LE, Hsu J-WY, Danial T, et al. Accuracy and implications of percutaneous renal biopsy in the management of renal masses. Perm J 2013;17:4–7 http://dx.doi.org/10.7812/TPP/12-110. [17] Richard PO, Jewett MAS, Bhatt JR, Kachura JR, Evans AJ, Zlotta AR, et al. Renal Tumor Biopsy for Small Renal Masses: A Singlecenter 13-year Experience. Eur Urol 2015;68:1007–13, http://dx.doi. org/10.1016/j.eururo.2015.04.004. [18] Halverson SJ, Kunju LP, Bhalla R, Gadzinski AJ, Alderman M, Miller DC, et al. Accuracy of determining small renal mass management with risk stratified biopsies: confirmation by final pathology. J Urol 2013;189:441–6, http://dx.doi.org/10.1016/j.juro.2012.09.032. [19] Rahbar H, Bhayani S, Stifelman M, Kaouk J, Allaf M, Marshall S, et al. Evaluation of renal mass biopsy risk stratification algorithm for robotic partial nephrectomy—could a biopsy have guided management? J Urol 2014;192:1337–42, http://dx.doi.org/10.1016/j.juro. 2014.06.028. [20] Kutikov A, Smaldone MC, Egleston BL, Manley BJ, Canter DJ, Simhan J, et al. Anatomic features of enhancing renal masses predict malignant and high-grade pathology: a preoperative nomogram using the RENAL nephrometry score. Eur Urol 2011;60:241–8, http://dx. doi.org/10.1016/j.eururo.2011.03.029. [21] Osawa T, Hafez KS, Miller DC, Montgomery JS, Morgan TM, Palapattu GS, et al. Comparison of percutaneous renal mass biopsy and R.E.N.A.L. nephrometry score nomograms for determining benign vs. malignant disease and low-risk vs high-risk renal tumors.
[22]
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[24]
[25]
[26] [27]
[28]
[29]
Urology 2016;96:87–92, http://dx.doi.org/10.1016/j.urology.2016. 05.044. Osawa T, Hafez KS, Miller DC, Montgomery JS, Morgan TM, Palapattu GS, et al. Age, gender and R.E.N.A.L. nephrometry score do not improve the accuracy of a risk stratification algorithm based on biopsy and mass size for assigning surveillance versus treatment of renal tumors. J Urol 2016;195:574–80, http://dx.doi.org/10.1016/j. juro.2015.10.137. Ball MW, Bezerra SM, Gorin MA, Cowan M, Pavlovich CP, Pierorazio PM, et al. Grade heterogeneity in small renal masses: potential implications for renal mass biopsy. J Urol 2015;193:36–40, http://dx.doi.org/10.1016/j.juro.2014.06.067. Hawken SR, Krishnan NK, Ambani SN, Montgomery JS, Caoili EM, Ellis JH, et al. Effect of delayed resection after initial surveillance and tumor growth rate on final surgical pathology in patients with small renal masses (SRMs) 486.e9–e15. Urol Oncol Semin Orig Investig 2016, http://dx.doi.org/10.1016/j.urolonc.2016.05.032. Kutikov A, Smaldone MC, Uzzo RG, Haifler M, Bratslavsky G, Leibovich BC. Renal mass biopsy: always, sometimes, or never?. Eur Urol 2016;70:403–6, http://dx.doi.org/10.1016/j.eururo.2016.04.001. Ordon M, Landman J. Renal mass biopsy: just do it. J Urol 2013;190:1638–40, http://dx.doi.org/10.1016/j.juro.2013.08.013. Montgomery JS, Krishnan NK, Hawken SR, Ambani SN, Morgan TM, Hafez KS, et al. Renal mass biopsy influences the management of small renal masses. J Endourol 2015;29:A162:[MP21-2]. Parker PA, Alba F, Fellman B, Urbauer DL, Li Y, Karam JA, et al. Illness uncertainty and quality of life of patients with small renal tumors undergoing watchful waiting: a 2-year prospective study. Eur Urol 2013;63:1122–7, http://dx.doi.org/10.1016/j.eururo.2013.01.034. Ambani SN, Morgan TM, Montgomery JS, Gadzinski AJ, Jacobs BL, Hawken S, et al. Predictors of delayed intervention for patients on active surveillance for small renal masses: does renal mass biopsy influence our decision? Urology 2016;98:88–96, http://dx.doi.org/ 10.1016/j.urology.2016.04.067.
News and Topics
Renal mass biopsy for the small renal mass Sapan N. Ambani, M.D.a,*, James Stuart Wolf Jr., M.D.b a
b
Department of Urology, University of Michigan Health System, Ann Arbor, MI Department of Surgery, Dell Medical School, University of Texas at Austin, Austin, TX
Received 16 July 2017; received in revised form 18 September 2017; accepted 26 September 2017
Abstract Opponents of premanagement biopsy of small renal masses are not difficult to find. Many urologists contend that the benefits of biopsy do not outweigh the risks, arguing that the results do not influence management substantially and that the most useful information from renal mass biopsy can be attained with advanced imaging. In this article, we develop the counter arguments and demonstrate that renal mass biopsy should be implemented into the small renal mass management algorithm. r 2017 Elsevier Inc. All rights reserved.
Keywords: Small renal mass; Renal mass biopsy
Biopsy of the small renal mass (SRM) (clinical T1a) continues to incite controversy. Those opposed to the performance of renal mass biopsy (RMB) generally attack its safety, accuracy, and lack of use. Proponents of RMB cite accumulating evidence supporting its usage in the evaluation of the SRM that is suspicious for renal cell carcinoma. In this News and Topics article, we address popularly stated reasons to forego RMB, review contemporary RMB data, and argue that RMB deserves a role in the evaluation and management of SRMs. Is RMB necessary? Opponents of RMB contend that a SRM is extremely likely to harbor malignancy, and therefore management options can safely be discussed without a pathologic diagnosis. In actuality, of SRMs (clinical T1a lesions, so o4 cm in maximal diameter), 25% are benign [1]. Many surgical series report a 25% rate of benign tumors, but we feel that a 25% risk of unnecessary surgery is excessive. Inasmuch as RMB can reduce this rate to a more reasonable risk, they are useful. Moreover, although the ability to radiologically differentiate benign and malignant lesions continues to develop, with impressive improvements in radiologic characterization over the years, current technology still is insufficiently accurate to be considered a substitute for histologic diagnosis. Millet et al. [2] performed a retrospective review to determine whether Corresponding author. Tel.: þ1-734-936-5801; fax: þ1-734-936-9127. E-mail address: [email protected] (S.N. Ambani). *
http://dx.doi.org/10.1016/j.urolonc.2017.09.025 1078-1439/r 2017 Elsevier Inc. All rights reserved.
computed tomography characteristics could accurately identify SRM pathology, and concluded that computed tomography was unable to differentiate between benign and malignant lesions. Some success has been demonstrated at discriminating among renal cell carcinoma subtypes [3]. Sun et al. [4] demonstrated that dynamic contrast-enhanced magnetic resonance imaging could differentiate between papillary and clear cell renal cell carcinoma with up to 94% accuracy. Despite this, a serious limitation of radiologic imaging is its inability to differentiate high grade cancers from those that are relatively indolent [5]. This is particularly important given that approximately only 20% of SRMs demonstrate aggressive histology [6] and the ability to reliably differentiate these tumors from indolent ones would reduce both overtreatment and undertreatment. Is RMB dangerous? Although many have raised concerns about the safety of RMB, modern literature supports the idea that RMB has a low risk of complications [7]. The most common adverse event is hematoma (4.9%), which rarely requires transfusion (0.4%) [8]. Other associated complications with RMB including pain (1.2%), gross hematuria (1.0%), and pneumothorax (0.6%) are similarly minor or rare [8,9]. A potentially disastrous complication of RMB is tumor seeding. In the contemporary literature, only a few cases have been reported when appropriate coaxial technique was used [10,11]. A systematic review of the literature reported no tumor seeding events among 20 studies including 3,113 RMB on 2,979 patients [8].
2
S.N. Ambani, J.S. Wolf Jr. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
A meta-analysis by Marconi et al. [12] similarly noted no RMB tumor seeding for renal cell carcinoma. With the estimated rate of tumor seeding after RMB to be less than 0.01%, this overly emphasized complication can be considered anecdotal [13,14]. Is RMB accurate? With refinements in technique, RMB has grown into a highly accurate diagnostic test. RMB has the ability to differentiate between benign and malignant SRMs, with reported sensitivity of 97.5% to 99.7%, specificity of 96.2% to 99.1%, and positive predictive value of 99.8% in 2 large meta-analyses [8,12]. Patel et al. [8] reported a concerning negative predictive value of 68.5%, however, this is based on the limited number of benign and nondiagnostic biopsies with gold standard surgical pathology. Among 17 studies, only 79 (16.8%) of 468 benign biopsies had surgical pathology, of which 29 (36.7%) were falsely negative. Of these, 19 (65.5%) were concentrated in 2 studies, one of which represented an early experience in RMB using a fine needle aspiration technique, while the other included 6 patients with masses greater than 4 cm [15,16]. Most contemporary studies reveal a substantially lower false-negative rate among benign biopsies [8]. In addition, the false-negative rate of benign RMB is likely subject to selection and verification bias as surgical excision was likely performed in the most concerning of benign renal masses. Nondiagnostic biopsies, in which biopsy resulted in insufficient tissue, normal kidney parenchyma, fibrosis, or necrosis, occurs in 10% to 20% of RMB [8]. This rate can be significantly improved upon with repeat biopsy. Another attempt at RMB yields diagnostic results at a rate of approximately 80%, thus decreasing the frequency of nondiagnostic RMB to less than 10% [17]. In one series, 22.3% of nondiagnostic RMB went on to definitive surgery and 90.4% of these masses were malignant [8]. Although diagnostic accuracy of RMB continues to improve, these results suggest that management of nondiagnostic RMB should proceed with caution. As data suggest RMB to be accurate with a low rate of adverse events, we argue that it deserves an integral role in the management of SRMs. Our group has previously published a SRM algorithm implementing RMB-influenced risk stratification [18]. Reviewing 133 patients with both RMB and surgical pathology from an excised SRM, we evaluated whether RMB pathology allowed accurate risk assignment and treatment as compared to the “ideal management” as determined by surgical pathology. RMB incorrectly assigned 4 of 133 (3.0%) patients, all of which were incorrectly assigned to surveillance. Accuracy of RMB-guided management was quite high, as it demonstrated a sensitivity for treatment of 96%, specificity for surveillance of 100%, a positive predictive value of treatment of 100%, and a negative predictive value of surveillance of 86%. Although this analysis excluded patients with benign and nondiagnostic RMB, it provided accurate treatment assignment of malignant RMB results when compared
to final surgical pathology. A multi-institutional retrospective study by Rahbar et al. [19] of 1,175 robotic partial nephrectomy specimens reported that up to 52% of surgeries in their cohort could have been avoided had they known the pathology prior to surgery. Although based on the theoretical assumption of 100% concordance between RMB and surgical pathology, it suggests that surgical treatment (and associated risks) of many SRMs could be avoided with the implementation of RMB-based risk stratification. RMB-guided management has also been shown to be superior to other risk-stratification nomograms. RENAL nephrometry score (RNS) nomograms have been used to predict malignancy and risk-stratify patients [20]. In 281 patients, Osawa et al. [21] evaluated whether an RMBbased algorithm was superior to RNS nomograms in accurately predicting and risk-stratifying SRMs. RMB demonstrated superior accuracy in predicting malignancy (99% vs. 29% concordance) as well as high-risk malignancy (67% vs. 61% concordance). The addition of RNS, as well as age and gender, to RMB and tumor size did not improve the accuracy of a risk-stratification algorithm previously published by Halverson et al. [18,22]. One area of concern is with RMB false-negatives. This is primarily based on lower rates of nuclear grade concordance, with most studies demonstrating RMB under-grading. Tumor heterogeneity and hybrid histology have been put forth as contributing reasons for inaccuracy [13,23]. A risk of RMB-based risk stratification is incorrectly assigning a patient with a high-risk tumor to surveillance when they should be treated. This danger can be mitigated if patients with adverse pathology who are (incorrectly) assigned to surveillance can be identified and diverted to delayed intervention without compromising outcomes. Hawken et al. [24] described 495 SRMs treated with surgical excision. A period of surveillance followed by delayed intervention was performed for 94 patients (median ¼ 386 days, IQR: 272–702), whereas the remaining 401 underwent early intervention (median ¼ 84 days, IQR: 59–121). Delayed intervention was not associated with adverse pathology (P ¼ 0.8). Interestingly, greater annual SRM growth demonstrated a modest but significant association with adverse pathology for patients on surveillance (odds ratio ¼ 1.2, 95% CID: 1.03–1.3 mm/y, P ¼ 0.02). This supports the often-applied practice (heretofore based on clinical principle rather than evidence) of using growth as a determining factor for delayed intervention for patients on active surveillance. Outcomes of these patients were no worse than for those whom underwent early intervention, thus assuaging some of the concerns about false-negative RMB. With increasing amounts of data supporting the diagnostic ability of RMB, current debate is centered around its clinical use [25]. Some proponents of RMB implore its use in the majority of SRMs [17,26], whereas others argue for a more limited role [25]. The appropriate usage of RMB is
S.N. Ambani, J.S. Wolf Jr. / Urologic Oncology: Seminars and Original Investigations ] (2017) ∎∎∎–∎∎∎
likely selective. RMB, like any other diagnostic test, should only be used if it will change management. Identifying the tumor histology would be beneficial in allowing a patient to avoid intervention in the case of benign or nonaggressive tumors, however, the young, healthy patient is unlikely to be interested in surveillance, particularly given the low reported complication rate with contemporary partial nephrectomy. Similarly, the older patient with major comorbidities would likely not be a candidate for treatment regardless of the RMB results, and therefore the use of RMB may be limited in this group as well. Information gleaned from RMB may also adjust the surgical plan in those patients in whom surgery is a foregone conclusion. An aggressive malignancy may lead to increased usage of radical over partial nephrectomy due to concerns for multifocality or positive margins. On review of the SRM database at the University of Michigan, Montgomery et al. [27] evaluated 854 SRMs from 2007 to 2015 who underwent active surveillance, ablative therapy, or partial/radical nephrectomy, with 366 (42.9%) having interpretable RMB data to assist with the management decision. Any malignancy on biopsy was associated with an increased rate of initial treatment over surveillance (P o 0.01). Worse pathology on RMB was associated with an increased rate of radical nephrectomy in patients between 55 and 75 years old (P o 0.01), suggesting the greatest clinical use of RMB may be in patients between these ages who harbor a 2 to 4 cm SRM. RMB is helpful at selecting patients for active surveillance, however do RMB surveillance patients benefit from more information about their SRM? Do patients with benign and low-risk malignancy feel more assurance about maintaining surveillance, particularly since illness uncertainty is associated with a negative effect on quality of life [28]? Do urologists have confidence in RMB results, particularly in the face of a growing mass or concerned patient? Our institution performed a retrospective study of 118 SRM on active surveillance to determine risk factors for delayed intervention [29]. Multivariate analysis revealed that delayed intervention was significantly related to initial tumor size 42 cm (hazard ratio ¼ 3.65, P ¼ 0.015) and growth rate (hazard ratio ¼ 1.26, P o 0.01, mm/y), but not RMB (P ¼ 0.29). Although this may be used as fuel for the anti-RMB fire, this result is more an indictment of practice pattern than the clinical use of RMB. Even at an institution that emphasizes the use of RMB, we have yet to use RMB to its full potential. Conclusion For many years, the SRM has avoided what most other tumors have been subjected to: a biopsy. RMB has been considered unnecessary in the management of the SRM. However, with accumulating data, the clinical paradigm is shifting toward increased usage of RMB. RMB is safe,
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accurate, and deserves a prominent role in the evaluation of SRMs. Contemporary guidelines embrace RMB in the appropriately selected patient [9]. The future of RMB only looks bright, as advances in molecular markers and DNA sequencing will allow us to better characterize and identify worrisome renal masses. Current evidence supports using RMB as a risk-stratifying tool, and urologists are advised to incorporate this into their management scheme for SRMs. Further implementation of an RMB-based algorithm would be enhanced with a well-designed prospective clinical trial.
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