Real world outcomes of biopsy‐proven oncocytic neoplasm of the kidney managed by surveillance

Abstract Objectives To evaluate outcomes of patients diagnosed with oncocytic renal neoplasms on routine renal mass biopsy and to describe the natural history of these tumours when managed with surveillance as opposed to immediate intervention. To report disease‐specific survival. Patients and methods Patients were identified from a retrospective review of pathology databases from three tertiary referral centres that utilise renal mass biopsy in routine clinical practice. All patients with biopsy‐proven oncocytic tumours were included and a retrospective review of online patient records was undertaken. Results There were 184 biopsy‐proven oncocytic renal neoplasms identified in 172 patients. There were two biopsy complications (both pneumothorax, Clavien–Dindo Grade I). Of these lesions, 135 were reported as oncocytomas or oncocytic renal neoplasms that were not further classified and 37 were reported as chromophobe carcinoma (ChRCC). The median age at diagnosis was 70 (33–88). The average tumour diameter at diagnosis was 33 mm. One hundred seven tumours were initially managed with surveillance (including 13 ChRCC) with a minimum follow‐up of 6 months and a median of 39 months (6–144) whereas 49 patients underwent immediate treatment. The mean growth rate across all oncocytic renal neoplasms managed by surveillance was 3 mm/year. There was no statistically significant difference in growth rates between oncocytic renal neoplasms and ChRCC. Thirteen patients with oncocytic renal neoplasms initially managed by surveillance moved on to an active management strategy during follow‐up. The clinical indication given for a change from surveillance was tumour growth in 12 cases and patient choice in 1 case. Where definitive pathology was available, there was 85% concordance with the biopsy. There were no cases of development of metastatic disease or disease‐related morbidity or mortality during the study. Conclusions This multicentre retrospective cohort study supports the hypothesis that selected biopsy‐proven oncocytic renal neoplasms can be safely managed with surveillance in the medium term. Routine renal mass biopsy may reduce surgery for benign or indolent renal tumours and the potential associated morbidity for these patients.

benign or indolent renal tumours and the potential associated morbidity for these patients.

K E Y W O R D S
biopsy, chromophobe carcinoma, oncocytic, oncocytoma, surveillance

| INTRODUCTION
The term oncocytic renal neoplasms describes a spectrum of renal tumours with oncocytic features ranging from benign Oncocytomas to malignant tumours such as chromophobe carcinoma (ChRCC). The 2016 WHO Classification 1 recognises oncocytoma and ChRCC as distinct entities; however, with advances in immunohistochemical and molecular testing, diagnosis is becoming more nuanced with several other tumours with oncocytic features now described. More recently, it has been appreciated that many of the low-grade-appearing oncocytic tumours show indolent behaviour and the term 'oncocytic renal neoplasm of low malignant potential, not further classified' is now commonly used when it is difficult to categorise such tumours. 2 An oncocytic renal neoplasm diagnosed on renal biopsy can pose a significant challenge to the histopathologist and the clinician with a real risk of overtreatment of indolent disease.
The diagnosis of renal tumours has increased in the last decades with much of this increase being put down to the expanding use of cross-sectional imaging. 3 It is recognised that a significant number of renal masses are benign with almost 50% of tumours less than 1 cm falling into this category. However, the likelihood of malignancy increases with larger masses, and only 6.3% of tumours that are greater than 7 cm or higher have been shown to be benign. 4 Despite this, overtreatment of benign tumours appears common be with 30% of tumours removed by partial nephrectomy in the United States having non-malignant histology. 5 In the United Kingdom, the reported figure is lower with 18% of partial nephrectomies performed for benign disease. 6 Routine renal mass biopsy may reduce surgery for benign tumours and the potential for short-term and long-term morbidity associated with these procedures. 7 However, the routine use of preoperative biopsy is not recommended by the American Urological Association or the European Association of Urology (EAU). The underutilisation of this technique is due to several concerns including difficulties in distinguishi ng between different types of benign and malignant oncocytic neoplasms, the safety of core biopsy and the accuracy of grading on such samples. Significant nondiagnostic rates have also been reported, 8 and concerns have been raised about a low negative predictive value suggesting that a non-malignant result may not be truly representative.
Oncocytoma is the second most common benign renal tumour accounting for 3%-7% of all renal masses whilst ChRCC is the third commonest subtype of renal malignancy making up about 5% of all renal cancers. 1 If the routine use of renal mass biopsy is to reduce the morbidity associated with overtreatment of benign renal tumours with surgery or ablation, there has to be an expectation that oncocytomas, and other oncocytic renal neoplasms can be properly classified and safely managed by surveillance or indeed discharged with a definitive diagnosis.
Previous studies have reported on the growth kinetics of oncocytic renal neoplasms; however, they are often limited by small numbers and short follow-up. In this study, we will report data on a large series of oncocytic renal neoplasms from three centres where routine renal mass biopsy has been adopted as standard of care. We aim to show how renal mass biopsy is safe to use in a contemporary clinical setting. We report the outcomes of patients diagnosed with oncocytic renal neoplasms when managed with surveillance or immediate intervention and describe the natural history of tumours managed with surveillance.

| PATIENTS AND METHODS
In this multicentre retrospective cohort review, patients with a diagnosis of an oncocytic renal neoplasm on a renal mass biopsy were identified from pathology records of three tertiary referral centres Statistical analysis was performed in SPSS (v27, IBM Chicago) using one-way ANOVA for continuous variables and χ 2 testing for categorical variables with significance taken at p < 0.05.

| RESULTS
The total cohort of oncocytic renal neoplasms included 184 lesions in 172 patients. The baseline demographic, clinical and tumour data are depicted in Table 1. The majority of patients were male with a median age at diagnosis of 69 years and a range of 33-88 years. The median tumour size at diagnosis was 33 mm. The majority of tumours were less than 4 cm; however, there were 40 that measured between 4 and 7 cm and 6 greater than 7 cm. Of patients, 81% were asymptomatic at presentation. Ten patients had a known genetic predisposition at diagnosis. In eight cases, this was Birt-Hogg-Dube Syndrome, and in the remaining two cases, there was a known mutation in the SDHB gene.
In 102 tumours (55%) specialist histopathologists reported Oncocytoma or an oncocytic neoplasm favouring Oncocytoma. There were 34 cases (18%) where the histopathologist reported ChRCC or an oncocytic lesion favouring ChRCC. Three cases were reported as hybrid oncocytic/chromophobe tumours, and in the remaining 45 lesions (24%), the histopathologist did not further subclassify the oncocytic neoplasm (this group was considered as indolent, oncocytic renal neoplasms of low malignant potential for the purposes of this study and grouped with the Oncocytomas). In six cases, a second renal mass biopsy was performed. This was because the initial biopsy was nondiagnostic in one case and in five cases, a repeat biopsies was undertaken due to growth of the tumour. In four of these cases, an initial diagnosis of oncocytoma was confirmed and in the remaining case an oncocytic tumour that was not further classified remained uncategorised and subsequently underwent a radical nephrectomy. There were two reported biopsy complications (both pneumothoraces, Clavien-Dindo Grade I).
Forty-nine patients (28%) elected to undergo immediate treatment of at least 1 tumour whilst 117 (68%) patients were initially managed with surveillance. Of these patients, 107 (62%) had at least 6-months follow-up and were included in the analysis. Six (3%) were discharged after diagnosis. Details are given in the consort diagram ( Figure 1). Of the patients undergoing immediate treatment, 24 had cryoablation and 25 had surgery (20 [80%] of these had a partial nephrectomy and 5 [20%] radical nephrectomy). Where the histopathologist had subcategorised the oncocytic renal neoplasm on the core biopsy, there was concordance with the definitive histopathology report following surgery in 85% of cases. In four (15%) cases initially classified as oncocytoma, there was discordance with final pathology results where the definitive histopathology was reported as follows: ChRCC (n = 2), oncocytic variant of papillary RCC (n = 1) and oncocytic RCC unclassified (n = 1). Importantly, there was no diseaserelated morbidity or mortality in patients undergoing immediate treatment throughout the follow-up period.
One hundred fourteen tumours in 107 patients (62%) were initially managed with surveillance and had at least 6-months follow-up.
The surveillance protocol was at the discretion of the treating physician. The maximum diameter of the tumour was measured on the initial and final imaging. The median diameter of tumours initially managed by surveillance was 33 mm (11-89), but this included 29 (25%) of tumours >4 cm. There was a median follow-up of 39 months (6-144) including 52 (46%) of tumours followed up for greater than 3 years and 15 (13%) for greater than 5 years. The mean growth rate across all oncocytic renal neoplasms was 3.0 mm/year, but there was a wide range within the surveillance cohort with 13 lesions actually regressing in size and a minimum growth rate of

| DISCUSSION
With the increasing use of abdominal ultrasound and cross-sectional imaging, there has been a surge in the detection of renal tumours. 7 Although surgical treatment remains the standard of care in many centres for larger renal tumours, it is recognised that a significant proportion, particularly of smaller tumours, may be benign and there is a concern that overtreatment of these tumours may result in Indeed, routine renal tumour biopsy has been shown to reduce surgery for benign tumours and the potential for short-term and longterm morbidity associated with these procedures by two thirds. 8 Perhaps the biggest concern for clinicians not using routine renal mass biopsy in their practice is the ability to distinguish between types of oncocytic renal neoplasms, especially oncocytoma and ChRCC, and accurately grade a tumour. There is a fear that some  16 Probably the most striking finding of the current study is that no patients with oncocytic renal neoplasms developed disease-related morbidity or mortality in this study despite a median follow-up of over 3 years. This is in contrast to comparable series of small renal mass surveillance without a biopsy where a small but significant 2% of patients have been shown to progress to metastatic disease, presumably due to the high incidence of malignant tumours included. 17 The safety of renal mass biopsy has been questioned; however, in our series, there were no significant biopsy complications. A previous meta-analyses has shown percutaneous renal tumour biopsy to be safe with major complications in <0.1% of cases and transfusion rates of 0.1%. Seeding has also historically been a concern; however, this is thought to be rare. 18 Questions have also been raised about the diagnostic accuracy of renal mass biopsy; however, the same metaanalysis reported sensitivity and specificity of diagnostic renal mass core biopsies of 99.1% and 99.7%, respectively.
Some authors have expressed concern that tumour growth, even of non-malignant lesions, will lead to a decline in renal function and development of symptoms. In one recent study the authors concluded that surveillance was associated with a greater decline in renal function than partial nephrectomy in patients with Oncocytoma and so justifying surgery for some of these tumours. 19 However, a large recent series has concluded that renal function does not seem to be negatively impacted by growing oncocytomas. 20  an inconsistency in our current approach to decision making around the management of small renal masses. In this cohort, patients were more likely to be managed with ablation or surgery if they were diagnosed with an oncocytic renal neoplasm at a younger age; however, we know the incidence of benign tumours is higher in younger age groups. 21 Enhanced immunohistochemical and molecular testing is now increasing our ability to differentiate between oncocytic renal neo- If adopting a surveillance strategy for oncocytic renal tumours is to become standard further work is needed to develop a protocol. In most instances clinicians rely on changes in diameter of the lesion on cross-sectional imaging or ultrasound to influence management decisions. Trigger points for definitive intervention following an initial period of surveillance have not been clearly identified although a fast growth rate was the most commonly cited reason here. Previous reports have suggested that oncocytomas measuring more than 5 cm or growing more than 5 mm/year should be definitively treated. 12 These arbitrary cut offs are not supported by our data as we have shown that oncocytic renal neoplasms grow at widely varying rates with no difference between tumours identified as benign, indolent or malignant. Indeed, some ChRCC in this series actually regressed over time.
In conclusion, we hope that this paper challenges a perceived wisdom that an enhancing mass in the kidney represents a surgical lesion that automatically requires excision without the need for a pretreatment biopsy. We acknowledge that the accurate diagnosis of oncocytic renal neoplasms relies on coordinated multidisciplinary expertise in urology, interventional radiology and histopathology.