Active surveillance for renal angiomyolipoma: outcomes and factors predictive of delayed intervention

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1 Active surveillance for renal angiomyolipoma: outcomes and factors predictive of delayed intervention Idir Ouzaid*, Riccardo Autorino*, Richard Fatica*, Brian R. Herts*, Gordon McLennan, Erick M. Remer* and Georges-Pascal Haber* *Glickman Urological and Kidney Institute, and Imaging Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Objective To present the outcomes of active surveillance (AS) for renal angiomyolipomas (AMLs) and to assess the clinical features predicting delayed intervention of this treatment option. Patients and Methods We retrospectively reviewed the outcomes of patients diagnosed with AMLs on computed tomography (CT) who were managed with AS at our institution. The AS protocol consisted of 6- and 12-month, then annual follow-up visits, each one including a physical examination and CT imaging. Discontinuation of AS was defined as the need or decision for an active procedure during the follow-up period. Causes of delayed intervention, as well as the type of active treatment (AT), were recorded. Clinical features at presentation of patients failing AS were compared with those who remained under AS at the time of the last follow-up. Predictive factors of delayed intervention were analysed using univariate and multivariate Cox regression models. Results Overall, 130 patients were included in the analysis, of whom 102 (78.5%) were incidentally diagnosed, while 15 (11.5%) and 13 patients (10%) presented with flank pain and haematuria, respectively. After a mean (SD) follow-up of 49 (40) months, 17 patients (13%) discontinued AS and underwent AT. Patients who underwent delayed intervention were more likely to present with a higher body mass index, larger tumours and symptomatic disease. Angioembolization represented the first-line AT after AS (64.7%), whereas partial nephrectomy was adopted in 29.4% of patients. On the univariate analysis, risk factors for delayed intervention included tumour size 4 cm, symptoms at diagnosis, and history of concomitant or contralateral kidney disease. On the multivariate analysis, only tumour size and symptoms remained independently associated with discontinuation of AS. Conclusions Tumour size and symptoms at initial presentation were highly predictive of discontinuation of AS in the management of AMLs. Selective angioembolization was the first-line option used for AT after AS was discontinued. Keywords angiomyolipomas, active surveillance, computed tomography, nephron-sparing surgery, partial nephrectomy, angioembolization Introduction Renal angiomyolipomas (AMLs) are benign tumours of the kidney that account for 3% of all renal tumours [1,2]. Smooth muscle, aneurismal vessels and adipose tissue are three pathological components that define AMLs [3]. In most cases, the fatty component is easily identified on CT, resulting in high specificity for this imaging technique [4]. Eighty percent of AMLs are sporadic but may be associated with genetic patterns [5]. The natural history of the disease is characterized by bulking-effect complications such as flank pain or, more importantly, aneurysmal vessel rupture and retroperitoneal haemorrhage. This latter, also known as Wunderlich syndrome, can be life-threatening [6]. Recent trends in the management of small renal masses emphasize nephron-sparing strategies [7]. Active surveillance (AS) has been introduced as the safest option in patients with low-risk or benign small renal masses, including AMLs, because of the maximum preservation of renal function and lack of potential morbidities associated with any active treatment (AT) [8 10]. Current series of AS for renal tumours have focused on RCC, while specific AS series on AMLs are scarce, and those reported have small sample sizes [11,12]. Current guidelines on AMLs suggest prophylactic treatment in patients with large tumours, females of child-bearing age, and patients in whom follow-up or access to emergency care may be inadequate [7]. The former recommendation of a size BJU Int 2014; 114: wileyonlinelibrary.com BJU International 2013 BJU International doi: /bju Published by John Wiley & Sons Ltd.

2 Active surveillance for renal angiomyolipoma threshold of >4 cm [2] for intervention is disputed [1,11,13]. Currently, higher level evidence answering the question whether prophylactic intervention is superior to AS is lacking. The aims of the present study were to report the outcomes of AS for patients with renal AMLs and to identify the clinical features predictive of delayed intervention in these patients. Patients and Methods Study Design We queried our The Health Insurance Portability and Accountability Act (HIPPA)-compliant institutional database to retrieve patients who were diagnosed with AML on CT and primarily treated with AS. The database included patients referred to our centre with the final diagnosis of renal mass. Diagnosis of AML required a clearly identified fat component on CT [14]. Then, the natural history of the disease for every patient was followed to identify those who underwent a secondary AT during the surveillance period, which was defined as delayed intervention. Age, gender, presence of tuberous sclerosis complex, tumour size, year of diagnosis, concomitant or past contralateral kidney disease (cyst, RCC), chronic kidney disease stage, and clinical presentations were assessed as potential predictive factors for AS discontinuation. In addition, causes of delayed intervention, subsequent treatment options, and associated complications were also recorded. Active Surveillance Protocol The AS protocol consisted of a physical examination and CT imaging at 6 months, 12 months, and then annually. AT included partial or radical nephrectomy, angioembolization, cryoablation and medical therapy. The duration of follow-up was calculated as the time elapsed between the diagnosis and date of last follow-up. Tumour growth was estimated as the difference in tumour size between the first and the last available CT. Statistical Analysis Data are presented as mean (SD) values or proportions when appropriate. Categorical and continuous variables were assessed using chi-squared (or Fisher exact test) and Student-t tests, as appropriate. Tumour growth difference was assessed using a paired t-test. The correlation between tumour growth and size was assessed using linear regression. Univariable and forward stepwise multivariable Cox regression models were used to investigate the clinical risk factors of delayed intervention. All P values were two-sided and a P value <0.05 was considered to indicate statistical significance using SPSS version 20.0 (IBM Corp, Armonk, NY, USA) statistical package. Results Overall, 400 patients with AMLs were managed at our institution during the study period. Among these, 270 (67.5%) received AT whereas 130 (32.5%) underwent AS and were included in the present analysis. In all, 102 patients (78.5%) were asymptomatic at presentation, whereas 15 (11.5%) and 13 patients (10%) presented with flank pain and haematuria, respectively. After a mean (SD) follow-up of 49 (40) months, 17 patients (13%) discontinued AS and underwent AT. Patients who underwent delayed intervention were more likely to present with a higher body mass index, larger tumours and symptomatic disease at the time of diagnosis (Table 1). The primary causes of discontinuation included flank pain, mass growth on follow-up imaging, retroperitoneal haemorrhage, patient preference and gross haematuria in six (35.2%), four (23.5%), three (17.7%), three (17.7%) and one (5.9%) of the cases, respectively. Patients were treated with angioembolization, partial nephrectomy and sirolimus in 11 (64.7%), five (29.4%) and one (5.9%) of the cases, respectively. One patient was admitted to the intensive care unit because of haemodynamic instability subsequent to retroperitoneal bleeding and was successfully treated with angioembolization. One patient underwent a partial nephrectomy after failure of angioembolization to control tumour growth and flank pain. In addition, two patients needed transfusions at the time of AT. While the mean (SD) follow-up periods of patients who remained under AS and patients who underwent AT were similar (43 [41] vs 62 [48] months; P = 0.054), tumours were more likely to have accelerated growth (P < 0.001) in the failure group (5.66 ± 1.19 cm) vs the success group (2.54 ± 2.39 cm). In addition, tumour growth appeared to be correlated with size at diagnosis (coefficient = 0.72, P < 0.001). Among the 38 patients with tumours 4 cm, only 13 (34.2%) discontinued AS. In addition, 67% symptomatic patients were managed with AS without delayed intervention. Risk factors for delayed intervention included tumour size 4 cm, symptoms at diagnosis, and history of concomitant or contralateral kidney disease in the univariate analysis. Only tumour size and symptoms remained independently associated with AS discontinuation (Table 2). Time-to-event analysis for these factors showed they were significant (Fig. 1). Discussion Widespread use of cross-sectional imaging has resulted in a significant increase in incidentally diagnosed small renal masses over the last decades [15]. These masses rarely progress to metastases, and 20% of them present benign histology [8]. As a result, concerns about over-treatment paradigms have been raised and AS has been introduced as a management option for selected cases. BJU International 2013 BJU International 413

3 Ouzaid et al. Table 1 Patient characteristics. All: n = 130 AS success: n = 113 AS discontinued: n = 17 P Mean (SD) age, years, 53.3 (16.5) 54.3 (16.7) 46.6 (13.9) Body mass index, kg/m (4.2) 27.9 (4.3) 25.3 (4.2) Gender, n (%) Female 101 (22.3) 87 (78) 14 (76.5) Male 29 (77.7) 26 (22) 3 (23.5) Side, n (%) Right 60 (46.2) 54 (47.7) 6 (35.3) Left 48 (36.9) 43 (38.1) 5 (29.4) Bilateral 22 (16.9) 16 (14.2) 6 (35.3) Tuberous sclerosis syndrome, n (%) No 120 (92.3) 106 (93.8) 14 (82.3) Yes 10 (7.7) 7 (6.2) 3 (7.7) Tumour size, n (%) <0.001 <4 cm 92 (70.8) 88 (77.9) 4 (23.5) 4 cm 38 (29.2) 25 (22.1) 13 (76.5) Presentation, n (%) <0.001 Incidental 102 (78.5) 94 (83.2) 8 (47.1) Symptomatic 28 (21.5) 19 (16.8) 9 (52.9) Contralateral kidney disease, n (%) No 106 (81.5) 93 (82.3) 13 (76.5) Yes 24 (18.5) 20 (17.7) 4 (23.5) CKD stage, n (%) (40) 53 (46.9) 9 (52.9) 2 49 (37.7) 48 (42.5) 6 (35.3) 3 13 (10) 11 (9.7) 2 (11.8) 4 1 (0.8) 1 (0.9) 0 (0) AS, active surveillance; CKD, chronic kidney disease. Table 2 Univariate and multivariate Cox regression model predicting delayed intervention. Features Univariate Multivariate HR (95% CI) P HR (95% CI) P Age (continuous) ( ) 0.27 Gender 0.18 Female ( ) Male ( ) BMI (continuous) ( ) 0.91 Tuberous sclerosis syndrome 0.35 No ( ) Yes ( ) Tumour size <4 cm ( ) ( ) >4 cm ( ) ( ) Presentation Incidental ( ) ( ) Symptomatic ( ) ( ) Contralateral kidney disease No ( ) ( ) Yes ( ) ( ) CKD stage = ( ) > ( ) Year of diagnosis (continuous) ( ) HR, hazard ratio. Unlike malignant neoplasms, where metastatic progression represents the main concern, AS for benign tumours is intended to preserve renal function and avoid treatment-related complications in patients with competing morbidities. Many series have demonstrated the feasibility of AS for AMLs [11,12,16,17]. To our knowledge, the current series represents the largest one reported that looks specifically at AS for patients diagnosed with AMLs on CT imaging. 414 BJU International 2013 BJU International

4 Active surveillance for renal angiomyolipoma Fig. 1 Kaplan Meier curves plotting the probability of delayed intervention in patients treated with active surveillance (AS) with respect to A, tumour size and B, symptoms at the time of diagnosis. A Probability of AS Discontinuation B Probability of AS Discontinuation <4 CM 4 CM No Yes <4 cm 4 cm Size at diagnosis Log Rank p= Time, months Number of patients with risk of delayed intervention No Yes Symptoms at diagnosis Log Rank p= Time, months Number of patients with risk of delayed intervention The baseline characteristics of the present study population were similar to those in previous reports [1,2,11,12,16,17]. The proportion of patients who presented without symptoms confirms the increasing diagnosis rates of incidental masses. Among symptomatic patients, flank pain was the primary symptom (53% of cases) and was in accordance with rates reported by Nelson and Sanda [1]. Patients who discontinued AS primarily chose to undergo selective angioembolization as an active secondary treatment. Disease was controlled in all but one patient who ultimately underwent a partial nephrectomy after the failure of embolization. Angioembolization is reliable in preventing or treating active bleeding and to resolve flank pain associated with AMLs, although repeat procedures may be necessary in up to 29% of the patients [18]. The success rate for angioembolization is reportedly up to 96%, with 5-year freedom from surgery at 94% [13]. In the case of failure of primary or repeat selective angioembolization, nephron-sparing surgery should be considered [12,13]. Currently, active intervention for newly diagnosed AMLs is considered in young, female, and symptomatic patients assuming a high probability of complications [7]. Prophylactic intervention remains controversial. AS cohort studies with long-term follow-up are sparse in the current literature so our knowledge of the natural history of AML is limited. For example, patients who undergo early intervention without any monitoring do not have the chance to be assessed for the advent of complications or delayed intervention and thus might have been over-treated. To address some of these issues, we selected patients diagnosed with AMLs on CT and primarily managed with AS. The most common indication of surgical excision of uncomplicated AMLs is suspicion for malignancy based on preoperative imaging. To offset selection bias, we only included patients with clearly identified fat-containing masses, which was acceptable because of the high diagnostic accuracy of CT [19]. Our results indicate that size of mass at diagnosis and symptoms at initial presentation are significatively associated with AS failure. These findings mirrored those reported in a smaller study by De Luca et al. [12]. Mues et al. [11] also reported the results of 91 patients with AMLs, of whom 48 were placed on an AS protocol as a primary management strategy. During follow-up, four patients underwent AT. Using a logistic regression model, the authors reported that age, symptomatic presentation and tumour size (>3 cm) were not significantly associated with AT. Our conflicting results may be the result of a smaller number of events that occurred (four in the study by Mues et al. vs 17 in the present cohort) or an abbreviated follow-up as compared to our study. Most importantly, a time-to-event analysis, such as a Cox regression model, is more relevant for assessing AS failure. We were aware that the number of events has a major effect on the stability of the model; therefore, we used stepwise forward regression modelling to select variables included in the final regression analysis. Of all patients referred to our institution and diagnosed with AMLs, a considerable proportion were selected to undergo AT based on practice guidelines that suggest AT for patients with large tumours (>4 cm) to prevent haemorrhage [2]. The results could have been different if more patients were managed with AS. Furthermore, we do not know how many patients with AMLs were not referred for urological consultation, but this number would be expected to be small and the patients asymptomatic. BJU International 2013 BJU International 415

5 Ouzaid et al. We acknowledge that the present analysis included the whole cohort of patients that were managed with AS, including subgroups of patients that might be of little clinical significance, such as older patients with small asymptomatic tumours. Moreover, the analysis looked at the whole cohort and used some patient factors as both an indication for treatment and a future predictor of delayed intervention, which might be considered as self-evident and weakens the model. Tumour size ( 4 cm) and symptoms are the main drivers of AT for AMLs, as confirmed by the present findings; however, traditional thresholds to trigger AT could be disputed, based on that which we observed in the subgroup of 38 patients with tumours 4 cm. Among those, only 13 failed AS. Hence, AT for all tumours 4 cm would have resulted in a remarkably high 65% over-treatment rate. In addition, 67% of symptomatic patients were managed with AS without any complications. Future studies should define a new threshold for optimum outcomes as the necessity of prophylactic intervention remains controversial. In fact, the few patients in whom complications occurred were able to undergo selective angioembolization with a success rate of 90% in the present series. Nephron-sparing surgery is the second-line treatment in patients who fail angioembolization. In addition, mammalian target of rapamycin inhibitors, which have been recently approved for in the treatment of AMLs in patients with tuberous sclerosis complex, represent an additional treatment option for AMLs in patients who have not responded to AT [20]. Active treatment is associated with surgical complications and long-term impairment of renal function. The advantages offered by AS over AT in the treatment of AMLs should be weighed against the costs related to the follow-up investigations carried out with small renal masses [21,22]. The present results might be of great benefit in designing follow-up protocols. In fact, symptomatic patients with AMLs 4 cm should be monitored more closely than asymptomatic counterparts who have smaller lesions. Asymptomatic >4cm AMLs could also be managed with AS. Another limit of AS studies is the lack of confirmatory pathological data as all patients have not undergone percutaneous biopsy. Although only non-ambiguous cases were selected based on the CT reports, fat-containing RCC (as opposed to fat-poor AML) could not be excluded [23,24]. To conclude, in the present study, the tumour size and symptoms at presentation were highly predictive of delayed intervention in patients with AMLs and primarily managed with AS. Given its high success rate, selective angioembolization should be considered as the first-line treatment when a delayed intervention is indicated. Our findings also provide guidance for the appropriate selection of patients who are more likely to benefit from AS as opposed to those who should undergo close monitoring protocols. AS should be considered as the standard for all uncomplicated AMLs at presentation. Conflict of Interest G-PH reports personal fees from Surgical Intuitive, Merck and Baxter, outside the submitted work. References 1 Nelson CP, Sanda MG. Contemporary diagnosis and management of renal angiomyolipoma. J Urol 2002; 168: Oesterling JE, Fishman EK, Goldman SM, Marshall FF. The management of renal angiomyolipoma. J Urol 1986; 135: Tamboli P, Ro JY, Amin MB, Ligato S, Ayala AG. Benign tumors and tumor-like lesions of the adult kidney. Part II: benign mesenchymal and mixed neoplasms, and tumor-like lesions. Adv Anat Pathol 2000; 7: Simpfendorfer C, Herts BR, Motta-Ramirez GA et al. Angiomyolipoma with minimal fat on MDCT: can counts of negative-attenuation pixels aid diagnosis? 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6 Active surveillance for renal angiomyolipoma 20 Bissler JJ, Kingswood JC, Radzikowska E et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381: Heilbrun ME, Yu J, Smith KJ, Dechet CB, Zagoria RJ, Roberts MS. The cost-effectiveness of immediate treatment, percutaneous biopsy and active surveillance for the diagnosis of the small solid renal mass: evidence from a Markov model. J Urol 2012; 187: Chang SL, Cipriano LE, Harshman LC, Garber AM, Chung BI. Cost-effectiveness analysis of nephron sparing options for the management of small renal masses. J Urol 2011; 185: Kim JK, Park SY, Shon JH, Cho KS. Angiomyolipoma with minimal fat: differentiation from renal cell carcinoma at biphasic helical CT. Radiology 2004; 230: Richmond L, Atri M, Sherman C, Sharir S. Renal cell carcinoma containing macroscopic fat on CT mimics an angiomyolipoma due to bone metaplasia without macroscopic calcification. BrJRadiol2010; 83: e Correspondence: Georges-Pascal Haber, Center for Laparoscopic and Robotic Surgery, The Glickman Urological and Kidney Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. HABERG2@ccf.org Abbreviations: AS, active surveillance; AML, angiomyolipoma; AT, active treatment. BJU International 2013 BJU International 417