Author's Accepted Manuscript

Bosniak classification for complex renal cysts re-evaluated - a systematic review

Ivo G. Schoots , Keren Zaccai , Myriam G. Hunink , Paul C.M.S. Verhagen

PII: S0022-5347(17)39242-X
DOI: 10.1016/j.juro.2016.09.160
Reference: JURO 14608

To appear in: The Journal of Urology

Accepted Date: 15 September 2016

Please cite this article as: Schoots IG, Zaccai K, Hunink MG, Verhagen PCMS, Bosniak classification for
complex renal cysts re-evaluated - a systematic review, The Journal of Urology® (2017), doi: 10.1016/
j.juro.2016.09.160.

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 ACCEPTED MANUSCRIPT
1 Bosniak classification for complex renal cysts re-evaluated - a systematic review
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3 1. Ivo G. Schoots a, i.schoots@erasmusmc.nl
4 2. Keren Zaccai b, kerenzaccai@gmail.com
5 3. Myriam G. Hunink a, c, m.hunink@erasmusmc.nl
6 4. Paul C.M.S. Verhagen b p.verhagen@erasmusmc.nl

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8 a Erasmus MC - University Medical Center Rotterdam, Department of Radiology and

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9 Nuclear Medicine, Rotterdam, the Netherlands
10 b Erasmus MC - University Medical Center Rotterdam, Department of Urology,

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11 Rotterdam, the Netherlands
12 c Erasmus MC - University Medical Center Rotterdam, Department of Epidemiology,
13 Rotterdam, the Netherlands, and Harvard School of Public Health, Harvard University,
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Department of Health Policy and Management, Boston, USA.
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17 Contact address:
18 Ivo G. Schoots, Department of Radiology and Nuclear Medicine, Erasmus MC University
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19 Medical Centre, P.O. Box 2040, ’s Gravendijkwal 230, 3000 CA, Rotterdam, The
20 Netherlands.
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21 email: i.schoots@erasmusmc.nl
22
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23 Keywords (9):
24 Renal cyst; kidney cyst; complex cyst; Bosniak; classification; diagnostic test accuracy;
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25 systematic review; outcome; number needed to treat.

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26
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28 Running title: Good outcome may support surveillance of Bosniak III cysts
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30 Word count of text: 3978
31 Word count of the abstract: 250
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1 Abstract
2
3 Objective: To systematically evaluate the Bosniak classification, with malignancy rates
4 of each Bosniak category, and to assess the effectiveness related to surgical treatment
5 and oncological outcome, based on recurrence and/or metastasis.
6 Methods: A systematic review (according to the PRISMA statement and the QUADAS-2

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7 criteria) selected 39 publications for inclusion in this analysis and categorised into: 1)
8 “surgical“ cohorts- all cysts underwent surgery, and 2) “radiological” cohorts- cysts

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9 underwent either surgical treatment or radiological follow-up.
10 Results: A total of 3036 complex renal cysts were categorized into Bosniak II, IIF, III and

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11 IV. In surgical and radiological cohorts, pooled estimates showed malignancy prevalence
12 of 0.51 [0.44, 0.58] in Bosniak III, and 0.89 [0.83, 0.92] in Bosniak IV cysts, respectively.
13 Stable Bosniak IIF cysts showed a malignancy rate of less than 1% during radiological
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follow-up (surveillance). Bosniak IIF cysts, which showed reclassification to the Bosniak
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15 III/IV category during radiological follow-up (12%), showed malignancy in 86%,
16 comparable to Bosniak IV cysts. Estimated surgical NNT to avoid metastatic disease of
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17 Bosniak III and IV cysts was 140 and 40, respectively.

18 Conclusions: The effectiveness of the Bosniak classification system for complex renal
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19 cysts was high in category II, IIF, and IV, but low in category III; 49% of Bosniak III cysts
20 was overtreated because of benign outcome. This surgical overtreatment in combination
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21 with the excellent outcome in Bosniak III cysts may suggest that surveillance is a
22 rational alternative to surgery. It will require further study to see if surveillance of
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23 Bosniak III cysts will prove safe.

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1 Patient summary: We reviewed the Bosniak classification (categorizing complex renal
2 cysts) to assess its predictive value for cystic renal cancer. Surveillance of Bosniak IIF
3 cysts is safe and effective. Resection of Bosniak IV cysts is efficacious, because of high
4 risk of malignancy. Bosniak III lesions are usually resected, however, in 49% surgery is
5 unnecessarily performed. Given the excellent outcome of these patients in general,
6 surveillance is proposed as an alternative to surgery, although further study is required

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7 to prove surveillance of Bosniak III cysts will be safe.
8

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9 Twitter:
10 Surveillance of Bosniak III cysts: alternative to surgery

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1 1. Introduction
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3 In 1986, Bosniak proposed a classification of renal cysts, distinguishing four categories
4 from I to IV. The diagnosis and management of complex renal cysts was contentious, and
5 a combination of computed tomography (CT), ultrasound (US) and urography was being
6 used to distinguish between benign and malignant cystic renal lesions. The Bosniak

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7 classification was the first to connect radiological findings to a treatment advice:
8 complex renal cysts categorized as Bosniak III and IV were expected to be malignant

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9 lesions, and advised to be resected. This classification was fully embraced by
10 international urology and radiological societies and implemented into guidelines.

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11 Competing systems have not been published so far.
12 Within the past decades, the Bosniak classification has been modified and has
13 influenced clinical practice. The most important modifications include the introduction
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of Bosniak category IIF in 1993, to bridge category II and III with the option of
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15 radiological follow-up, and the decreased importance of nodular calcifications in 2003,1
16 which qualify a lesion to category II or IIF, instead of class III. Furthermore, the original
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17 classification in 1986 was based on CT. The CT technique has evolved over the years,
18 which implies that current CTs show details that were not visible in 1986. New imaging
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19 modalities such as Magnetic Resonance Imaging (MRI) and contrast-enhanced

20 ultrasound (CEUS) have become available and may contribute to the current Bosniak
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21 classification system (Figure 1).

22 The Bosniak classification system has been discussed in many reviews; however,
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23 no systematic review has been conducted. We systematically reviewed the published

24 literature on the Bosniak classification for renal cysts. We undertook this review (1) to
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25 assess malignancy risk in the different Bosniak categories, and (2) to assess long-term
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26 oncological outcome of patients managed in concordance with this system, based on

27 radiological recurrence and metastatic disease. Parallel, (3) we collected evidence on
28 inter-observer variability between radiologists using the Bosniak classification system.
29 The combination of these data should allow us to evaluate the effectiveness (clinical
30 value) of this classification system in the different Bosniak categories.
31 The Bosniak system may be safe from an oncological point of view, however, up
32 till now considerable surgical overtreatment in Bosniak category IIF and III has been
33 regarded as inevitable and therefore acceptable. In this review we aim to estimate the
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1 amount of overtreatment and risks related to complex renal cysts and question
2 ourselves if active surveillance of Bosniak III complex renal cysts could be a reasonable
3 alternative to surgery.
4

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1 2. Methods
2
3 2.1. Objective
4 We aimed to systematically evaluate the Bosniak renal cyst classification introduced by
5 Morton A. Bosniak with the intention to establish the effectiveness (clinical value), based
6 on malignancy rates of the Bosniak categories, in combination with the oncological

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7 outcome.
8

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9 2.2. Search strategy
10 The search strategy is provided as online supplementary material; in summary, for each

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11 database the search terms used were ‘kidney cyst’, ‘kidney*’ ‘renal’ or ‘nephro*’, in
12 relation to ‘cyst’, ‘cystic’ or ‘cysts’, and in combination with ‘complex’, ‘complicated’ or
13 ‘multiloc*’. Furthermore, the search terms ‘bosniak’, ‘bosniac’, ‘bosniack’, and
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‘classification’ or 'diagnostic accuracy' were used. The search was limited to humans
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15 and adults. A critical review of the Embase, Medline (OvidSP), Web-of-science, PubMed
16 publisher, Google Scholar and Cochrane library was performed. The search was updated
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17 to August 12, 2016.

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19 2.3. Inclusion and exclusion criteria

20 The included studies all focus on adults with complex renal cysts, categorized by the
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21 Bosniak classification system (Figure 1). We selected only studies with imaging
22 evaluation by CT or MR according to the Bosniak classification, in combination with
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23 surgical resection and histopathology analysis.

24 Reports with patient selection based on malignancy in pathology databases were
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25 excluded; in these reports all cystic masses were malignant, thereby overestimating the
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26 malignancy rate in the Bosniak categories. Furthermore, duplicates and reports with a
27 reference standard of histopathology analysis from percutaneous biopsies only were
28 also excluded. Reports with imaging evaluation by CEUS only or no sufficient data
29 available were excluded. Unpublished data or abstracts were excluded because
30 information, that is needed to correctly assess the study quality (Quadas-2) and
31 interpret the results, was not available in abstracts.
32 The index test was defined as CT or MR imaging for categorizing complex renal
33 cysts by the Bosniak classification system. The reference test was defined as
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1 histopathological analysis of surgically resected complex renal cysts. A positive
2 reference test was defined by malignancy.
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4 2.4. Data collection and data extraction
5 The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
6 process for reporting included and excluded studies was followed, with the

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7 recommended flowchart showing the numbers of papers identified and included or
8 excluded at each stage (Figure 2). Titles and abstracts were reviewed for relevance to

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9 the defined review question. The references cited in all full-text articles were also
10 assessed for additional relevant articles. The search was carried out by three reviewers

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11 (I.S, K.Z. and P.V.), independently. Discrepancies between the reviewers were resolved
12 via discussion.
13 Data regarding study methodology, patient population, conduct of imaging, and
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outcomes were extracted. We identified two categories of published reports: 1)
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15 “surgical“ cohorts on complex renal cysts, in which the cysts all underwent surgery, and
16 2) “radiological” cohorts on complex renal cysts, in which some of the cysts underwent
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17 radiological follow-up instead of surgery. In the category of surgical reports, papers both
18 before and after the introduction of the Bosniak IIF in 1993 were identified. In the
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19 category of radiological reports, only papers after the introduction of the Bosniak IIF
20 were encountered.
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21
22 2.5. Assessment of publication bias and study quality
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23 Identified reports were reviewed according to the Quality Assessment of Diagnostic

24 Accuracy Studies (QUADAS)-2 instrument (supplementary table 2#).
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25
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26 2.6 Data syntheses and analysis

27 To synthesize the results, we performed a random-effects meta-analysis using
28 generalized linear mixed models for single arm studies on the malignancy prevalence of
29 Bosniak II, IIF, III and IV categories, and also the category of reclassified Bosniak IIF
30 cysts to III/IV. Heterogeneity was assessed using the X2 statistic and the I2 statistic. 95%
31 confidence intervals were constructed with the Wilson score interval. A continuity
32 correction was applied where necessary. Analyses were performed using R Statistical
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1 Software (version 3.2.1.; R Foundation for Statistical Computing, Vienna, Austria). The
2 meta-analysis was performed using the metafor package.
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1 3. Results and Discussion
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3 Thirty-nine studies were eligible for inclusion in this review.1-39 Table 1 shows
4 individual data on outcome results. A summary analysis is presented in Table 2.
5 Additional data on methodology, patient population, conduct of imaging are presented
6 in supplementary Table 1#.

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8 3.1. Publication bias and study quality
9 None of the individual studies explicitly followed the STARD guidelines for diagnostic

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10 studies. A summary of the results of the QUADAS-2 assessment for all included studies is
11 presented (Figure 3). According to these QUADAS-2 criteria, we conclude that the

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12 overall quality of the studies was poor, with high risk of bias and concerns about
13 applicability, which limits the strengths of the conclusions that can be made. A detailed

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14 description of signalling questions, assessment of study quality, and additional
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15 explanations are available as an online supplement.
16 Selection bias was present in all studies. Surgical cohorts only reported the
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17 complex renal cysts that have been surgically resected. Radiological cohorts only
18 reported complex renal cysts detected by CT or MR, as these imaging modalities can
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19 accurately categorize cysts. Prospective and consecutive series were absent. Test review
20 bias may occur when interpretation of the results of the index test may be influenced by
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21 the knowledge of the results of the reference standard (histopathology analysis after
22 surgical resection). This was not reported.
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23 The index test was defined by renal cyst imaging by CT or MR. The definition of
24 pre-specification of the threshold of the index test was set by the Bosniak classification
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25 system of renal complex cysts. Results may differ between the two imaging modalities.
26 Also different CT and MR protocols have been used. In some studies, additional
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27 information was conducted by the use of ultrasound (US) or contrast-enhanced

28 ultrasound (CEUS) (online supplement).
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30 3.2 Inter-observer variability
31 We evaluated the inter-observer variability between radiologists, by using the
32 (weighted) Cohen’s kappa and agreement percentages. The inter-observer variability of
33 the Bosniak classification system was reported in 8 studies (Table 3).5, 15, 28, 33, 40-43
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1 Cohen’s Kappa values as a measure for variability ranged from 0.57-0.98 (moderate -
2 very good). Moderate, good and very good agreements were scored in respectively 2, 3
3 and 1 out of 6 reports, respectively. The value of kappa in inter-observer variability
4 reports is divided in four categories: fair (0.21-0.40), moderate (0.41-0.60), good (0.61-
5 0.80) and very good (0.81-1.00). Despite reasonable kappa values within the evaluated
6 studies, a large range of disagreement is reported between observers, ranging from 6 to

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7 75%, especially within the categories II, IIF and III (Table 3). The extreme Bosniak
8 categories (I and IV) are easier to categorise by radiologists, which leads to reasonable

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9 kappa values, while considerable disagreement remains among the categories in
10 between. Some studies report on separate variables, such as the presence or absence of

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11 enhancing septum or cyst wall, rather than reporting on the Bosniak classification,
12 which showed better agreement.40, 42 Finally, we may conclude that the inter-observer
13 variability for Bosniak categories II, IIF and III is large for a clinical imaging test, as
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demonstrated by a disagreement up to 75%. This underscores the clinical need to
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15 develop a more robust system to identify patients in which surgical treatment is
16 necessary and in which overtreatment is limited.
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18 3.3. Prevalence of malignancy in complex renal cysts
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19 This review comprised a total of 3036 complex renal cysts, categorized into Bosniak II,
20 IIF, III and IV (Table 1). In surgical cohorts, before the introduction of the Bosniak
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21 category IIF, pooled data of 329 complex renal cysts showed malignancy prevalence of
22 0.08 [0.04, 0.15], 0.46 [0.23, 0.71] and 0.93 [0.66, 0.99] in respectively the Bosniak II, III and
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23 IV categories. In surgical cohorts, after the introduction of the Bosniak category IIF,
24 pooled data of 972 complex renal cysts showed malignancy prevalence of 0.09 [0.05, 0.14],
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25 0.18 [0.12, 0.26], 0.51 [0.42, 0.61] and 0.86 [0.81, 0.89] in respectively Bosniak II, IIF, III and
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26 IV category (Table 1,2). In radiological cohorts, all after the introduction of the Bosniak
27 category IIF, accumulated data of 1735 complex renal cysts showed malignancy rates
28 prevalence of 0.54 [0.45, 0.63] and 0.95 [0.79, 0.99] in respectively Bosniak III and IV
29 category. Bosniak category III and IV did not show significantly different malignancy
30 prevalence between surgical and radiological cohorts (Table 1, 2).
31 Pooled Bosniak II malignancy data is not present in radiological cohorts, because
32 complex renal cysts in this category did not undergo surgical resection or follow-up. The
33 malignancy prevalence of the Bosniak IIF is also more difficult to extrapolate in
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1 radiological cohorts. From the 954 Bosniak IIF cysts (without increase in Bosniak
2 category during follow-up), less than 1% (9/954) turned out to be malignant, following
3 resection in 54 cases. In these resected IIF cysts, the malignancy prevalence was
4 comparable to surgical cohorts, 0.14 [0.03, 0.50] vs 0.18 [0.12, 0.26], respectively. We do not
5 have additional information why these 54 cysts have been resected, but remarkably, in
6 these studies no increase from a Bosniak IIF to Bosniak III/IV cyst was reported during

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7 follow-up. This suggests a malignancy overestimation of the IIF category by focussing
8 only on the resected IIF cysts. The malignancy prevalence of the whole Bosniak IIF

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9 category would be more likely to be less than 1%.
10 During radiological follow-up 0.12 [0.08, 0.17] of the Bosniak IIF complex renal

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11 cysts were reclassified to Bosniak III/IV (Table 1). Among these radiological reclassified
12 cysts, 0.85 [0.74, 0.92] turned out to be malignant following resection. Therefore,
13 substantial change within a complex renal cyst, firstly categorized as Bosniak IIF,
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resulting in reclassification to Bosniak III/IV, has a high positive predictive value for
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15 malignancy.
16 The group categorized as Bosniak IV showed a positive predictive value of 0.89
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17 [0.83, 0.92] (Table1, 2), which is quite acceptable to select patients for surgery.

18 Bosniak III category demonstrated a positive predictive value of 0.51 [0.44, 0.58]
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19 (Table 2); in other words, 49% has been operated for a benign renal cyst. Considerable
20 surgical overtreatment in the Bosniak III category has been regarded as inevitable and
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21 therefore acceptable. However, we should question ourselves if active surveillance of

22 Bosniak III could be a reasonable alternative to surgery.
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23 Data on changes in Bosniak III complex renal cysts is not available. However, as
24 change within a Bosniak IIF complex cyst has proven to be very helpful to distinguish
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25 malignant from benign, would change within a Bosniak III cysts also be helpful to
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26 distinguish malignant from benign? In addition, we anticipate more consistency in the

27 selection of patients for surgery, because we assume it is easier to accurately assess
28 change in a complicated cyst on a repeat CT, than it is to assess Bosniak category
29 without previous imaging.
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31 3.4 Oncological outcome of complex renal cysts
32 The clinical use of active surveillance depends on the oncological outcome, based on the
33 chance to progress and metastasise. In addition to the main outcome (prevalence of
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1 malignancy in complex renal cysts), data from the included studies was collected to
2 evaluate the oncological outcome of complex renal cysts, based on local recurrence,
3 metastasis or disease related death (Table 4). Only 13 out of 39 included studies
4 showed some information on follow-up and clinical outcome. A total of 1535 complex
5 cysts were collected with a prevalence of 24% (373/1535) malignancy in these series;
6 88% of the 373 malignant cysts were categorised in Bosniak III and IV.

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7 In this review we identified 5/373 (1.3%) patients who developed a local
8 recurrence within a follow-up of 31 months (estimated average), all having a Bosniak III

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9 or IV renal cyst (Table 4). All local recurrences were retreated, and no patients died
10 from disease progression during follow-up. Additional information on initial positive

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11 resection margins or fluid spill during surgical resection was not available.
12 In the selected reports, 3/373 (0.8%) patients had metastatic disease during
13 initial presentation (Bosniak III/IV). Only 1/373 (0.2%) patients developed metastatic
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disease during follow-up (Bosniak III). This patient, with a history of a solid renal cell
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15 carcinoma, developed local tumour progression and metastatic disease after thermal
16 ablation of a Bosniak III renal cyst that grew over an 8-year period of observation,
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17 triggering a change in management and thermal ablation of the cyst. Three years after
18 subsequent thermal ablation and oligometastasectomy of the lung metastasis, the
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19 patient was alive and had no apparent disease.35

20 The exact characteristics of the complex renal cysts (i.e. Bosniak category,
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21 histological type and grading, lesion size) may affect prognosis, however, only limited
22 data could be extracted from the included reports. Several reports on cystic renal cell
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23 carcinoma (RCC) show the low risk of local progression or metastases, when managed
24 according to the Bosniak system.16, 44, 45 A risk ratio of 0.06 to die from clear-cell RCC
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25 with a cystic architecture was reported in comparison to solid RCC.46 In the selected
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26 reports within this review, almost two-third (63%) of the malignant complex malignant
27 renal cysts appears to be a cystic clear-cell RCC, the other third is a heterogeneous group
28 of malignancies (Table 4). Furthermore, multilocular cystic RCC, a subtype of clear-cell
29 RCC is reported to account for 10-30% of cystic renal cancers.27, 30, 45 This entity is now
30 regarded as a tumour of low malignant potential since metastases have been reported
31 very rarely.44 In this review approximately a quarter of the cystic clear-cell RCC counts
32 for multilocular cystic RCC (Table 4, footnote: 19/74 (26%)).27, 30, 35 During a follow-up
33 of 31 months, the oncological outcome of Bosniak III/IV in this review was good with
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1 only 1% (4/373) of metastatic disease, at presentation (0.8%) or during surveillance
2 (0.2%). Although imaging is currently not able to select only those Bosniak III cysts
3 which are safe to observe, the substantial number of clear-cell RCC and its subtype
4 multilocular cystic RCC within complex renal cysts, together with its good prognostic
5 outcome, may support surveillance in this category, or at least, may support restraint to
6 proceed to immediate surgical resection.

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8 3.5 Surveillance in complex renal cysts
9 While applying the Bosniak classification system is safe from an oncological point of

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10 view, the presented results raise the question whether a more conservative approach is
11 appropriate in certain cases. Surveillance in Bosniak IIF is effective, considering the fact

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12 that this systematic review revealed not a single patient in whom metastases or local
13 recurrences were identified following surveillance or delayed resection.

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14 The oncological outcome following resection of Bosniak III and IV lesions are also
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15 good, and immediate surgery might not be necessary in selected patients. The Bosniak
16 classification, introduced in the late eighties, focused on detection of malignancy in
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17 complex renal cysts. If the primary outcome would be malignancy, the number needed
18 to treat (NNT) (= surgery) in Bosniak III and IV category is 1.92 and 1.11, respectively
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19 (Table 5).
20 From this point of view, the diagnostic pathway with the Bosniak classification is
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21 good. However, if the primary outcome for the Bosniak III category would be the
22 avoidance of metastatic disease on top of malignancy (positive predictive value of 0.013;
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23 Table 5), the estimated NNT would be 140. In this calculation, metastatic disease at
24 initial presentation is also included, which might even underestimate the NNT.
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25 Nevertheless, this number should be considered as a large number of surgical

26 overtreatment in the Bosniak III category, and may support an active surveillance
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27 approach. For the Bosniak IV category, the estimated NNT to avoid metastatic disease is
28 40, based on higher positive predictive values of malignancy and metastatic disease.
29 Obviously, oncological surveillance data of Bosniak III cysts are lacking. Although
30 the presented oncological outcome on Bosniak III cysts shows a very low-risk to
31 metastasize, it will require further study to see if surveillance of Bosniak III cysts will
32 prove safe.
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1 3.6 Disadvantages of surgery or surveillance
2 These NNTs should also be considered in the light of the number of complications and
3 loss of kidney function associated with surgical resection. Only two recent studies report
4 details on the type of surgery for Bosniak III or IV renal cysts. Weibl and colleagues
5 reported partial and total nephrectomy for Bosniak III cysts in 37/54 (69%) and 17/54
6 (31%), respectively.36 Smith and co-workers reported partial and total nephrectomy in

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7 50/86 (58%) and 36/86 (42%), 35 with no distinction made between Bosniak III or
8 Bosniak IV category. These numbers of total nefrectomies underscores the

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9 overtreatment and the need for better surgical selection.
10 One of the included studies (Smith and co-authors) described complications

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11 associated with surgery.35 They report moderate to severe complications in 19% of
12 patients managed by surgery and 0% of patients managed by imaging surveillance,
13 respectively. Severe complications (Clavien grade 4a) related to the management of
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Bosniak renal cysts occurred in 7% of surgical cases and included multi-organ failure,
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15 acute myocardial infarction, conversion to hemodialysis-dependent chronic kidney
16 disease, acute ischemic stroke, and severe postoperative hemorrhage. This may support
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17 an active surveillance approach of the Bosniak III category, in order to reduce the
18 number of moderate and severe complications related to surgical resection. However,
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19 we acknowledge the associated downsides of surveillance, such as costs, exposure to X

20 rays, risk of non-compliance and psychological stress, which should be investigated on
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21 the long-term. A more liberal use of surveillance must be restricted to patients informed
22 about the advantages and disadvantages of all options.
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24 3.7 Role of biopsy
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25 Only limited information is available on the role of biopsy in cystic renal lesions. Some
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26 reports showed correct identification of malignancy in the majority of complex renal

27 cysts (60-70%), with low inadequate sampling (10%) and misdiagnosis (2%).47
28 However, if a biopsy result is negative, can this negative result be trusted? Also in solid
29 renal lesions this is a concern. Biopsies of solid renal masses during surgical resection
30 showed non diagnostic rates of 11-17%, and sensitivity of 77-84% and specificity of 60-
31 73%.48 For cystic lesions biopsied in vivo, these figures are expected to be worse.
32 Another drawback of performing biopsy of a complex cyst is the change of aspect
33 of the cystic lesion afterwards, which will interfere with the interpretation of repeat
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1 imaging. This current review shows that the surveillance strategy in cases with low
2 malignancy risk (Bosniak IIF) is very successful and cannot easily be improved by an
3 invasive procedure. We believe therefore that the use of biopsies will remain limited in
4 the diagnosis of complex renal cysts, although it may be helpful in selected cases.
5
6 3.8 Size of complex renal cysts

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7 Lesion size is related to risk of progression in solid and cystic RCC. In solid RCC the 10-
8 year cancer specific survival for T1a renal lesions (smaller than 4 cm) is approximately

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9 96%, thus, 4% will have died from cancer within 10 years.49 The relative risk to die from
10 a clear-cell RCC with cystic architecture is 0.06, as mentioned before.46 This could be

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11 extrapolated to a 0.2% (4% * 0.06) risk to die from a Bosniak III and IV cyst smaller than
12 4 cm. From a large retrospective database of patients who underwent surgical
13 resections for cystic RCC, irrespective of size, the cancer specific mortality was 1.8%.50
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This estimate is in agreement with the low numbers of metastatic disease in Bosniak
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15 III/IV (4/330, 1.2%) we found in this systematic review, irrespective of lesion size
16 (averaged ranging from 2.8 to 5.6 cm; Table 4). The criteria for size selection cannot be
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17 defined on the basis of this review. However, size should be considered in surveillance
18 management of renal cysts, as small renal lesions are more indolent than large renal
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19 lesions, just as cystic lesions are more indolent than solid lesions.
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21 3.9. Surveillance schemes

22 Several surveillance schemes for Bosniak IIF renal cysts Bosniak has been
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23 recommended, with an initial 4 to 6 months interval and a total duration of 5 years,

24 which has been proven to be very effective. Several patient related factors (anatomical
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25 location of the cyst, body weight, kidney function, allergies, exposure to irradiation and
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26 claustrophobia) may influence the choice of the optimal imaging technique during
27 surveillance. At present, recommendations on surveillance schemes can only be made
28 based on assumptions, and the disadvantages of surveillance should be included, and
29 weighed on a patient basis.
30
31 3.10. Limitations and strengths
32 Adjustments of the Bosniak system since its first publication in 1986, the use of
33 alternative imaging modalities to CT (MRI and CEUS), and the lack of prospective trials,
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1 have made the systematic analysis of complex renal cysts challenging, as discussed in
2 section 3.1. Nevertheless, we believe that valuable information on this topic has been
3 published and that this review allows us to draw conclusions important for urologists,
4 radiologists and others who are involved in the care for patients with a complex renal
5 cyst.
6

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7 4. Conclusion
8 In surgical and radiological cohorts of complex renal cysts, pooled data showed

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9 malignancy prevalence of 51% in Bosniak III, and 89% in Bosniak IV complex renal
10 cysts. Stable Bosniak IIF complex renal cysts (without reclassification to Bosniak III/IV)

SC
11 showed a malignancy rate of less than 1% during radiological follow-up (active
12 surveillance). Bosniak IIF complex renal cysts showed progression to the Bosniak III/IV
13 category during radiological follow-up in 12%, of which 86% showed malignancy,
14
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comparable to the malignancy rates of Bosniak IV complex cysts.
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15 We conclude that the effectiveness of the Bosniak system is high for Bosniak I, II,
16 IIF and IV categories, and that the effectiveness is low in the Bosniak III category, as a
M

17 result of surgical overtreatment of 49% benign cysts. The effectiveness, in our opinion,
18 could be improved if surveillance is also offered in Bosniak III complex renal cysts, as an
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19 alternative to surgical treatment.

20 Oncological outcome of surgically resected complex renal cysts is very good,
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21 based on the limited local recurrence or metastatic disease during follow-up.

22 Surveillance has shown to be very efficacious in Bosniak IIF lesions. Surveillance data
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23 for Bosniak III lesions are lacking. Although the presented oncological outcome on
24 resected Bosniak III cysts shows a very low-risk to metastasize, it will require further
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25 study to see if surveillance of Bosniak III cysts will prove safe. For surveillance
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26 management the disadvantages of surgical overtreatment must be carefully weighed

27 against the downsides of surveillance.
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1 Take home message
2
3 Surgical overtreatment of 49% of Bosniak III complex renal cysts, in combination with
4 good outcome of these patients in general, may support a surveillance approach as an
5 alternative to surgery, carefully weighing the disadvantages of surgery and surveillance.
6

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7 Acknowledgement
8 The authors thank Mr. W.M. Bramer, information specialist medical library, Erasmus MC

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9 University Medical Center, Rotterdam, with conducting this systematic literature search,
10 and Mr. D. Nieboer, statistician, Erasmus MC University Medical Center, Rotterdam, with

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11 conducting the statistical analysis.

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AN
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C EP
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Identifier Results

Total  complex   Bosniak  II Bosniak  IIF Reclassified Bosniak  III Bosniak  IV
cysts (n=351) (n=1074) Bosniak  IIF  to  III/IV (n=1001) (n=527)
(n=3036) (n=77)
Reference Year Cysts Malignant ratio 95%  CI Cysts Malignant ratio 95%  CI Reclassified   ratio 95%  CI Malignant ratio 95%  CI Cysts Malignant ratio 95%  CI Cysts Malignant ratio 95%  CI

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cysts  / [LL,  UL] cysts  / [LL,  UL] cysts [LL,  UL] cysts  / [LL,  UL] cysts  / [LL,  UL] cysts  / [LL,  UL]
Resections Resections /  all  IIF Resections Resections Resections
Surgical  cohorts:  cysts  which  underwent  surgery
Reports  without  Bosniak  IIF  category

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Aronson  et  al  (..) 1991 16 4 0/4 0.00 [0.01,  0.49] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 7 4/7 0.57 [0.25,  0.84] 5 5/5 1.00 [0.57,  1.00]
Bellman  et  al  (..) 1995 10 5 0/5 0.00 [0.00,  0.43] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 5 0/5 0.00 [0.00,  0.43] -­‐ -­‐ -­‐
Cloix  et  al  (..) 1996 30 7 1/7 0.14 [0.01,  0.51] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 13 4/13 0.31 [0.13,  0.58] 10 7/10 0.70 [0.40,  0.89]
Siegel  et  al  (..) 1997 48 8 1/8 0.13 [0.01,  0.47] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 11 5/11 0.45 [0.21,  0.72] 29 26/29 0.90 [0.74,  0.96]

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Balci  et  al  (..) 1999 46 18 0/18 0.00 [0.00,  0.18] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 3 0/3 0.00 [0.00,  0.56] 25 14/25 0.56 [0.37,  0.73]
Bielsa  Gali  et  al  (..) 1999 20 8 1/8 0.13 [0.01,  0.47] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 9 7/9 0.78 [0.45,  0.94] 3 3/3 1.00 [0.44,  1.00]
Curry  et  al  (..) 2000 78 11 0/11 0.00 [0.00,  0.26] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 49 29/49 0.59 [0.45,  0.72] 18 18/18 1.00 [0.82,  1.00]
Koga  et  al  (..) 2000 24 2 1/2 0.50 [0.03,  0.97] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 10 10/10 1.00 [0.72,  1.00] 12 12/12 1.00 [0.76,  1.00]
Limb  et  al  (..) 2002 57 28 3/28 0.11 [0.04,  0.27] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 29 8/29 0.28 [0.15,  0.46] -­‐ -­‐ -­‐

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329 91 7/91 0.08 [0.04,  0.15] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 136 67/136 0.46 [0.23,  0.71] 102 85/102 0.93 [0.66,  0.99]
Reports  with  Bosniak  IIF  category
Spalivieroet  al  (..) 2005 46 9 2/9 0.22 [0.06,  0.55] 4 1/4 0.25 [0.01,  0.70] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 12 6/12 0.50 [0.25,  0.75] 21 19/21 0.91 [0.71,  0.97]

AN
Loock  et  al  (..) 2006 37 6 0/6 0.00 [0.00,  0.39] 10 2/10 0.20 [0.06,  0.51] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 14 3/14 0.21 [0.08,  0.48] 7 6/7 0.86 [0.49,  0.99]
Kostiukov  et  al  (..) 2008 25 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 21 8/21 0.38 [0.21,  0.59] 4 3/4 0.75 [0.30,  0.99]
Song  et  al  (..) 2009 104 26 3/26 0.12 [0.04,  0.29] 3 0/3 0.00 [0.00,  0.56] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 38 21/38 0.55 [0.40,  0.70] 37 32/37 0.87 [0.72,  0.94]
Kim  et  al  (..) 2010 91 22 3/22 0.14 [0.05,  0.33] 10 3/10 0.30 [0.11,  0.60] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 26 19/26   0.73 [0.54,  0.86] 33 28/33 0.85 [0.69,  0.93]
Pinheiro  et  al  (..) 2011 37 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 15 5/15 0.33 [0.15,  0.58] 22 19/22 0.86 [0.67,  0.95]

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Han  et  al  (..) 2012 98 9 0/9 0.00 [0.00,  0.30] 18 3/18   0.17 [0.06,  0.39] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 39 21/39 0.54 [0.39,  0.68] 32 29/32 0.91 [0.76,  0.97]
Mei  et  al  (..) 2013 52 24 1/24 0.04 [0.00,  0.20] 28 4/28 0.14 [0.06,  0.31] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐
Goenka  et  al  (..) 2013 107 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 107 59/107 0.55 [0.46,  0.64] -­‐ -­‐ -­‐
Bata  et  al  (..) 2014 19 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 19 16/19 0.84 [0.62,  0.94] -­‐ -­‐ -­‐

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Reese  et  al  (..) 2014 113 16 2/16 0.14 [0.03,  0.36] 6 2/6   0.33 [0.10,  0.70] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 32 21/32 0.66 [0.48,  0.80] 59 50/59 0.85 [0.73,  0.92]
Boulma  et  al  (..) 2015 22 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 10 3/10 0.30 [0.11,  0.60] 12 11/12 0.92 [0.65,  1.00]
Ho,  Seo  (..) 2016 221 53 2/53 0.04 [0.01,  0.13] 41 7/41 0.17 [0.09,  0.31] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 71 27/71 0.38 [0.28,  0.50] 56 46/56 0.82 [0.70,  0.90]

TE
972 165 15/165 0.09 [0.05,  0.14] 120 22/120 0.18 [0.12,  0.26] -­‐ -­‐ -­‐ -­‐ 404 209/404 0.51 [0.42,  0.61] 283 243/283 0.86 [0.81,  0.89]
Radiological  cohorts:  cysts  which  underwent  follow-­‐up  or  surgery
Reports  all  with  Bosniak  IIF  category
Israel,  Bosniak  *  (..) 2003 81 21 0/0 -­‐ -­‐ 19 0/3   0.00 [0.00,  0.56] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 25 9/21 0.43 [0.24,  0.63] 16 16/16 1.00 [0.81,  1.00]
Israel,  Bosniak  *  (..) 2003 42 -­‐ -­‐ -­‐ -­‐ 39 0/0   -­‐ -­‐ -­‐ -­‐ -­‐ 2/3   0.67 [0.21,  0.98] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐
EP
Ascenti  et  al  (..) 2007 44 24 0/0 -­‐ -­‐ 10 0/0   -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 7 3/6 0.50 [0.19,  0.81] 3 3/3 1.00 [0.44,  1.00]
Clevert  et  al  (..) 2008 38 15 0/0 -­‐ -­‐ 8 0/1   0.00 [0.00,  0.95] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 8 3/6 0.50 [0.19,  0.81] 7 7/7 1.00 [0.65,  1.00]
Quaia  et  al  (..) 2008 40 3 0/0 -­‐ -­‐ 6 0/0   -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 13 3/12 0.25 [0.09,  0.53] 18 18/18 1.00 [0.82,  1.00]
Gabr  et  al  (..) 2009 50 -­‐ -­‐ -­‐ -­‐ 43 0/0   -­‐ -­‐ 7/50 0.14 [0.07,  0.26] 5/7 0.71 [0.36,  0.92] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐
O’Malley  et  al  (..) 2009 112 -­‐ -­‐ -­‐ -­‐ 69 0/0   -­‐ -­‐ 12/81 0.15 [0.09,  0.24] 5/5 1.00 [0.57,  1.00] 31 22/28 0.79 [0.60,  0.90] -­‐ -­‐ -­‐
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Weibl  et  al  **  (..) 2011 113 26 0/2 0.00 -­‐ 15 2/3   0.67 [0.21,  0.98] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 28 15/27 0.56 [0.37,  0.72] 44 30/39 0.77 [0.62,  0.87]
Hwang  et  al  ***  (..) 2012 215 -­‐ -­‐ -­‐ -­‐ 201 0/23 0.00 [0.00,  0.14] 14/215 0.07 [0.04,  0.11] 10/12 0.83 [0.55,  0.95] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐
Smith  et  al  (..) 2012 213 -­‐ -­‐ -­‐ -­‐ 69 4/16 0.25 [0.10,  0.49] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 144 58/107 0.54 [0.45,  0.63] -­‐ -­‐ -­‐
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Elmussarehet  al  (..) 2013 42 -­‐ -­‐ -­‐ -­‐ 41 0/0   -­‐ -­‐ 1/42 0.02 [0.00,  0.12] 0/0 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐
Graumann  et  al  (..) 2013 44 -­‐ -­‐ -­‐ -­‐ 39 0/0   -­‐ -­‐ 5/44 0.11 [0.05,  0.24] 2/3   0.67 [0.21,  0.98] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐
El  Mokadem  et  al  (..) 2014 134 -­‐ -­‐ -­‐ -­‐ 68 0/0   -­‐ -­‐ 10/78 0.13 [0.07,  0.22] 7/8 0.88 [0.53,  0.99] 31 10/16 0.63 [0.39,  0.82] 25 12/14 0.86 [0.60,  0.96]
Hindman  et  al  (..) 2014 156 -­‐ -­‐ -­‐ -­‐ 137 0/0   -­‐ -­‐ 19/156 0.11 [0.08,  0.18] 17/19 0.89 [0.69,  0.97] -­‐ -­‐ -­‐ . -­‐ -­‐
Smith  et  al  (..) 2015 293 -­‐ -­‐ -­‐ -­‐ 159 3/8 0.38 [0.14,  0.69] -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 112 29/72 0.40 [0.30,  0.52] 22 18/20 0.90 [0.70,  0.97]
Weibl  et  al  (..) 2015 85 -­‐ -­‐ -­‐ -­‐ 18 0/0   -­‐ -­‐ 9/27 0.33 [0.19,  0.52] 8/9 0.89 [0.57,  0.99] 58 37/54 0.69 [0.55,  0.79] -­‐ -­‐ -­‐
Ferreira  et  al  (..) 2016 33 9 0/0 -­‐ -­‐ 13 0/0 -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 4 2/4 0.50 [0.15,  0.85] 7 7/7 1.00 [0.65,  1.00]
1735 95 n.a. n.a. -­‐ 954 9/54 0.14 [0.03,  0.50] 77/693 0.12 [0.08,  0.17] 54/63 0.85 [0.74,  0.92] 461 191/353 0.54 [0.45,  0.63] 142 111/124 0.95 [0.79,  0.99]
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Malignancy  prevalence Bosniak  II Bosniak  IIF Reclassified  Bosniak  IIF  to  III/IV Bosniak  III Bosniak  IV
(n=232) (n=174) (n=66) (n=893) (n=509)
pooled   95%  CI I2 X2 pooled   95%  CI I2 X2 pooled   95%  CI I2 X2 pooled   95%  CI I2 X2 pooled   95%  CI I2 X2
Group

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estimate [low,  high] (%) (p-­‐value) estimate [low,  high] (%) (p-­‐value) estimate [low,  high] (%) (p-­‐value) estimate [low,  high] (%) (p-­‐value) estimate [low,  high] (%) (p-­‐value)

Surgical  cohorts:  

RI
Reports  without  Bosniak  IIF  category 0.08* [0.04,  0.15] 0% 9.7  (0.285) -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ -­‐ 0.46 [0.23,  0.71] 83% 37.8  (0.000) 0.93 [0.66,  0.99] 80% 26.1  (0.000)

Reports  with  Bosniak  IIF  category 0.09* [0.05,  0.14] 0% 7.3  (0.291) 0.18* [0.12,  0.26] 0% 3.3  (0.855) -­‐ -­‐ -­‐ -­‐ 0.51 [0.42,  0.61] 68% 33.5  (0.000) 0.86 [0.81,  0.89] 0% 2.5  (0.981)
Radiological  cohorts:

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Reports  all  with  Bosniak  IIF  category -­‐ -­‐ -­‐ -­‐ 0.14* [0.03,  0.50] 70% 16.3  (0.006) 0.85 [0.74,  0.92] 0% 4.2  (0.754) 0.54 [0.45,  0.63] 55% 23.3  (0.010) 0.95 [0.79,  0.99] 58% 16.6  (0.020)

Combined  cohorts 0.09* [0.05,  0.12] 0% 17.1  (0.313) 0.18* [0.13,  0.25] 7% 19.6  (0.104) 0.85 [0.74,  0.92] 0% 4.2  (0.754) 0.51 [0.44,  0.58] 70% 95.6  (0.000) 0.89 [0.83,  0.92] 45% 47.1  (0.003)

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Table 3. Data table of studies on inter-observer variability (kappa) between radiologists using Bosniak classification system.

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Reference Year Obs. Total Bosniak Benign Malignant Agree Kappa
cysts I II IIF III IV (%)

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Siegel et al. [38] 1997 3 70 22 8 - 11 29 38 32 59 1 0·57
Siegel et al. [70] 1999 3 69 20 - - - - - - 93 2 -

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Benjaminov et al. [71] 2006 2 32 - 0-5 2-7 8-13 12-17 11 21 50 0·52 3
Bertolotto et al. [8] 2010 2 70 - 18-23 26-27 12-17 8-9 84 15 4 - 0·64 3

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Kim et al. [9] 2010 2 125 30-34 22-32 10-13 24-26 26-33 72 53 61 0·70
Weibl et al. [10] 2011 2 71 - 7-25 3-12 5-8 3-26 25 46 25-88 -

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El-Mokadem et al. [11] 2014 2 96 - 8-13 50-53 21-28 7-12 94 29 4 70 0·69 3
Graumann et al. [12] 2015 3 100 18-19 16-27 6-13 9-19 17-22 - - 66-94 5 0·85-0·98 3

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1 41% disagreement; 11% disagreement on category I or II versus category III or IV, thus with consequences for therapy

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2 agreement reported only on presence or absence of enhancement (cut-off in protocol 15 HU)

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3 weighted kappa
4 histology available in part of cysts only
5 agreement with consensus classification (performed by the same observers)
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Table 4. Data on oncological outcome of complex renal cysts, categorized by Bosniak classification system.

Reference Year Total Malig Bosniak Histological Follow- Size Local Metas Comments

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nant malignant diagnosis up(mo) (cm) recur tatic
rence diseas
e

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clear-
non
cell
II IIF III# IV

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Cloix et al. [37] 1996 30 12 1 - 4 7 1 1 32 4·3 1 0 1 local recurrence (BIV, 3 yr FU); re-resection
Limb et al. [43] 2002 57 11 3 - 8 - 0 - 40 5·6 0 0
Israel , Bosniak 2003 42 2 - - 2 - 0 - 70 3·9 0 0

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[55]
Spaliviero et al. 2005 46 28 2 1 6 19 1 8 14 3·4 1 0 1 local recurrence (BIII, 1 yr FU); re-resection

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[45]
Gabr et al. [59] 2009 50 5 - - 5 - 0 2 14 3·0 0 0
O’Malley et al. 2009 112 27 - - 27 - 0 8 6 3·4 0 0

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[60]
Hwang et al.[61] 2012 201 10 - 10 - - 0 4 23 3·2 0 0
Smith et al. [62] 2012 213 62 - 4 58 - 0 25 25-37 - 0 0

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El-Mokadem et 2014 134 29 - 7 10 12 0 11 28 4·5 0 0
al. [11]

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Hindman et al. 2014 156 17 - - 17 - 0 8 50 2·8 0 0
[65]
Reese et al. [54] 2014 113 75 2 2 21 50 1 29 43 14<4 1 0 1 local recurrence (BIII/IV, 21 mo FU)
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23>4 (2)* *2 metastatic disease at presentation
(BIII/IV)
Smith et al. [66] 2015 296 50 - 3 29 18 1 23 29 - 1 1 1 local recurrence (BIII, 8yr FU); re-ablation
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(2)* and oligometastectomy (history of solid RCC)

*1 metastatic disease at presentation (BIV)
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and related death

Weibl et al. [67] 2015 85 45 - 8 37 - 1 14 36 3·7 1 0 1 local recurrence (BIII, ?FU); re-resection

Cumulative 1535 373 8 35 224 106 5 133 31^ 5 1

totals (24) (2) (9) (60) (28) (1) (37) (1) (0)
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# upgraded from IIF included

$ estimated values from Figure in the original study.
^ estimated value, calculated from the total number of patients multiplied by the number of averaged months for each study.

* not included in progression during follow-up; already metastatic disease at presentation.

O’Malley et al. [60]: 8/10 clear-cell RCC were sub-classified as multiloculated cystic RCC

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Smith et al. [62]: 6/37 clear-cell RCC were sub-classified as multiloculated cystic RCC
Smith et al. [66]: 5/27 clear-cell RCC were sub-classified as multiloculated cystic RCC

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Table 5. Number needed to treat of Bosniak III and IV renal cysts, considering the outcome of either malignant cysts or metastatic
disease if malignant.

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Outcome: Malignant Metastatic disease

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Bosniak III IV III/IV III IV

SC
Combined cohorts 467/893 439/509 4/330 3/224^ 3/106*
Positive predictive value 0.51 [0.44, 0.58] 0.89 [0.83, 0.92] 0.012 0.013 0.028

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Number needed to treat (NNT) 1.96 1.12 - 140 40

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^ Some complex renal cysts were not discriminated in either Bosniak III or IV (Table 2), and were added to this group, suspected to be a
Bosniak III cyst, in order to rather underestimate than overestimate the number needed to treat (NNT). For local recurrence and
metastatic disease this was one and two cysts, respectively.

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* Some complex renal cysts were not discriminated in either Bosniak III or IV (Table 2), and were added to this group, suspected to be a

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Bosniak IV cyst, in order to rather underestimate than overestimate the number needed to treat (NNT). For local recurrence and
metastatic disease this was one and two cysts, respectively.
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Imaging  features

Bosniak   Terminology Likelihood  of   Management Wall Septa High  attenuation Calcifications Wall  /  septum   Enhancing  soft   Representing  image
category malignancy   enhancement tissue  

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(Likert  scale) components

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I Simple  cyst Highly  unlikely  to   No  follow-­‐up Hairline-­‐thin  and   No No No No No
be  malignant smooth

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II Mildly  complex     Unlikely  to  be   No  follow-­‐up Hairline-­‐thin  and   A  few  hair-­‐line  septa   With  or  without  high   Yes,  fine  or  short   Perceived  (but  not   No
(complicated)   malignant smooth may  be  appreciated,   attenuation.  If  high  attenuation,   segment  calcification   measurable)  

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benign  cyst however  no   than  uniform  and  homogenous   may  be  present  in  wall   enhancement  (10-­‐15  
enhancement lesions  of  <  3  cm  in  diameter,   or  septa   HU)
sharply  marginated,  and  no  
enhancement.

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IIF Moderately   Equivocal  to  be   Follow-­‐up  to   Minimal  thickening,   Multiple  hairline-­‐thin   Conform  category  II.  Totally   Yes,  calcification  may   Perceived  (but  not   No
complex  cyst benign  or   demonstrate   with  perceived  (but  not   or  minimal  thickening   intrarenal  nonenhancing  high-­‐ be  thick  and  nodular  in   measurable)  

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malignant stability  and   measurable)   septa,  with  perceived   attenuating  renal  lesions  and/or   septa  and  wall enhancement  (10-­‐15  
therefore   enhancement (but  not  measurable)   >3  cm  in  diameter,  that  are   HU)

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benignity EP enhancement generally  well  marginated.  

III Indeterminate   Likely  to  be   Surgery  in  most   Thickened  irregular   Thickened  irregular   Conform  category  IIF Conform  category  IIF Yes,  measurable   No
complex  cyst malignant cases,  or  strict   (nodular)  or  smooth   (nodular)  or  smooth   enhancement  (>15  HU)
follow-­‐up  to   walls,  in  which  contrast   septa,  in  which  
demonstrate   enhancement  is   contrast  
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stability measurable enhancement  is  

measurable
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IV Complex  cystic   Highly  likely  to   Surgery Thickened  irregular   Thickened  irregular   Conform  category  III Conform  category  III Conform  category  III Yes
mass be  malignant (nodular),  in  which   (nodular),  in  which  
contrast  enhancement   contrast  
is  measurable enhancement  is  
measurable
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Key of Definitions for Abbreviations:

CT - Computed Tomography
MRI - Magnetic Resonance Imaging
RCC - Renal Cell Carcinoma
NNT - Number Needed to Treat

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Identifier Methodology Population Imaging Results

Total  complex  
cysts
(n=3036)
Reference Year Location Design Dates  of   Patients Age  (y) Sex Modality CT  Slice Consensus
recruitment (mean  /  range) (M/F) (mm) reading

PT
Surgical  cohorts:  complex  renal  cysts  which  underwent  surgery
Reports  without  Bosniak  IIF  category
Aronson  et  al  (..) 1991 Bethesda,  MA,  USA Retrospective 1986  -­‐  1990 15 53  (22-­‐67) 12/3 CT NR no 16
Bellman  et  al  (..) 1995 New  York,  NY,  USA Retrospective 1993  -­‐  1994 10 50  (35-­‐64) 5/5 CT+US NR no 10

RI
Cloix  et  al  (..) 1996 Lyon,  France Retrospective 1987  -­‐1999 30 48  (25-­‐80) 24/6 CT+US NR no 30
Siegel  et  al  (..) 1997 St.  Louis,  MO,  USA Retrospective 1989  -­‐  1995 46 NR NR CT 5-­‐10 yes 48
Balci  et  al  (..) 1999 Chapel  Hill,  NC,  USA Retrospective 1992  -­‐  1998 37 NR NR MR 7-­‐10 yes 46
Bielsa  Gali  et  al  (..) 1999 Barcelona,  Spain Retrospective -­‐ 19 -­‐ -­‐ CT+US -­‐ -­‐ 20

SC
Curry  et  al  (..) 2000 Charleston,  SC,  USA Retrospective 1990  -­‐  1998 77 60  (NR-­‐81) NR CT 3-­‐10 yes 78
Los  Angeles,  CA,  USA
Koga  et  al  (..) 2000 Nagasaki,  Japan Retrospective 1986  -­‐  1998 35 64  (36-­‐82) 27/8 CT NR yes 24
Limb  et  al  (..) 2002 Los  Angeles,  CA,  USA Retrospective 1993  -­‐  2000 57 54  (18-­‐87) 31/26 CT NR no 57
329
Reports  with  Bosniak  IIF  category

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Spalivieroet  al  (..) 2005 Cleveland,  OH,  USA Retrospective 1999  -­‐  2003 46 58  (±  13) 28/18 CT 5 no 46
Loock  et  al  (..) 2006 Besançon,  France Retrospective 1995  -­‐  2003 37 -­‐ -­‐ -­‐ -­‐ -­‐ 37
Kostiukov  et  al  (..) 2008 Moscow,  Russia Retrospective 1998  -­‐  2005 25 -­‐ -­‐ -­‐ -­‐ -­‐ 25

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Song  et  al  (..) 2009 Seoul,  Korea Retrospective 1997  -­‐  2007 104 51  (25-­‐75) NR CT NR yes 104
Seongnam,  Korea
Kim  et  al  (..) 2010 Seoul,  Korea Retrospective 2001  -­‐  2006 125 54  (22-­‐75) 85/40 CT 2.5-­‐5 no 91
Pinheiro  et  al  (..) 2011 Sao  Paulo,  Brazil Retrospective 2000  -­‐  2009 36 55  (33–80) 24/13 CT/MRI NR no 37
Han  et  al  (..) 2012 Seoul,  Korea Retrospective 2001  -­‐  2010 77 49  (1-­‐76) 52/25 CT NR yes 98
Mei  et  al  (..) 2013 Hangzhou,  China Retrospective 2004  -­‐  2011 52 48  (NR-­‐NR) 32/20 CT NR no 52

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Goenka  et  al  (..) 2013 Cleveland,  OH,  USA Retrospective 1994  -­‐  2009 101 NR NR CT NR no 107
Bata  et  al  (..) 2014 Budapest,  Hungary Retrospective 2007  -­‐  2013 19 57  (±16) 11/8 CT 2 no 19
Reese  et  al  (..) 2014 Philadelphia,  PA,  USA Retrospective 2004  -­‐  2011 133 57  (NR-­‐NR) 80/53 CT NR yes 113
Boulma  et  al  (..) 2015 -­‐,  Tunis Retrospective 2001  -­‐  2010 22 52  (23-­‐78) 14/8 CT NR no 22
Ho,  Seo  (..) 2016 Iksan,  Korea Retrospective 2001  -­‐  2014 221 60  (±11.9) 121/100 CT NR yes 221

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Radiological  cohorts:  number  of  lesions  which  underwent  surgery  
Reports  all  with  Bosniak  IIF  category

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Israel,  Bosniak  *  (..) 2003 New  York,  NY,  USA Retrospective 1996  -­‐  NR 79 64  (23-­‐86) 49/30 CT 3-­‐10 yes 81
Israel,  Bosniak  *  (..) 2003 New  York,  NY,  USA Retrospective NR 42 58  (30–86) 25/16 CT 3-­‐10 yes 42
Ascenti  et  al  (..) 2007 Messina,  Italy Prospective 2001  -­‐  2004 40 NR 23/17 CT+CEUS 3-­‐5 yes 44
Clevert  et  al  (..) 2008 Munich,  Germany Retrospective 2004  -­‐  2007 32 NR  (39-­‐72) 18/14 CT+CEUS 3 no 38
Quaia  et  al  (..) 2008 Trieste,  Italy Retrospective 2001  -­‐  2007 40 NR NR CT+CEUS 3-­‐5 yes 40
Gabr  et  al  (..) 2009 Ann  Arbor,  MA,  USA Retrospective 2004  -­‐  2007 43 63  (25–85) 24/19 CT/MRI NR no 50
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O’Malley  et  al  (..) 2009 New  York,  NY,  USA Retrospective 1999  -­‐  2007 112 64  (30-­‐95) NR CT/MRI NR no 112
Weibl  et  al  **  (..) 2011 Vienna,  Austria Retrospective 1996  -­‐  2009 104 61  (y23-­‐88)
59   ears,   64/40 CT 5 no 113
Bratislava,  Slovak  Republic
Hwang  et  al  ***  (..) 2012 Seoul,  Korea Retrospective 1996  -­‐  2011 201 60  (±14.6) 133/68 CT 2.5-­‐5 no 215
Smith  et  al  (..) 2012 Cleveland,  OH,  USA   Retrospective 1994  -­‐  2009 193 NR NR CT/MRI 3-­‐5 no 213
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Elmussarehet  al  (..) 2013 Leicester,  UK Retrospective 2003  -­‐  2008 40 68  (38–88) 29/11 CT+CEUS NR yes 42
Graumann  et  al  (..) 2013 Fredericia,  Denmark Retrospective 2003  -­‐  2009 44 67  (14–87) 26/18 CT 2.5 yes 44
Odense,  Denmark
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Skejby,  Denmark
El  Mokadem  et  al  (..) 2014 Dundee,  Scotland,  UK Retrospective 2000  -­‐  2010 124 67  (36–89) 83/41 CT 1.2 yes 134
Hindman  et  al  (..) 2014 New  York,  NY,  USA Retrospective 1996  -­‐  2011 144 64  (22-­‐85) 98/46 CT/MRI NR yes 156
Smith  et  al  (..) 2015 Jackson,  MS,  USA Retrospective 2000  -­‐  2011 286 60  (22–95) 161/125 CT/MRI/US NR NR 293
Birmingham,  AL,  USA
Winston-­‐Salem,  NC,  USA
Weibl  et  al  (..) 2015 Vienna,  Austria Retrospective 2003  -­‐  2012 85 60  (51–69) 49/36 CT/MRI NR no 85
Plzenˇ,  Czech  Republic
Bratislava,  Slovak  Republic
Ferreira  et  al  (..) 2016 Sao  Paulo,  Brazil Retrospective 2001  -­‐  2014 33 51  (11-­‐82) NR CT/MRI NR yes 33
1735
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Table 2# (online supplement): tabular presentation for QUADAS-2 results.
Study RISK OF BIAS APPLICABILITY CONCERNS
PATIENT INDEX REFERENCE FLOW PATIENT INDEX REFERENCE
SELECTION TEST STANDARD AND SELECTION TEST STANDARD
TIMING

Surgical reports without Bosniak IIF category

Aronson et al (..)
☺ ☺
☺
☺
Bellman et al (..)
☺ ☺
☺
☺
Cloix et al (..)
☺ ☺
☺
☺

PT
Siegel et al (..)
☺ ☺
☺
☺
Balci et al (..)
☺ ☺
☺
☺
Bielsa Gali et al (..)
☺ ☺
☺
☺

RI
Curry et al (..)
☺ ☺
☺
☺
Koga et al (..)
☺ ☺
☺
☺
Limb et al (..)
☺ ☺
☺
☺

SC
Surgical reports with Bosniak IIF category
Spalivieroet al (..)
☺ ☺
☺
☺
Loock et al (..)
☺ ☺
☺
☺

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Kostiukov et al (..)
☺ ☺
☺
☺
Song et al (..)
☺ ☺
☺
☺
AN
Kim et al (..)
☺ ☺
☺
☺
Pinheiro et al (..)
☺ ☺
☺
☺
Han et al (..)
☺ ☺
☺
☺
Mei et al (..)
☺ ☺
☺
☺
M

Goenka et al (..)
☺ ☺
☺
☺
Bata et al (..)
☺ ☺
☺
☺
Reese et al (..)
☺ ☺
☺
☺
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Boulma et al (..)
☺ ☺
☺
☺
Ho, Seo (..)
☺ ☺
☺
☺
TE

Radiological reports all with Bosniak IIF category

Israel, Bosniak (..)
☺

☺
☺

☺

☺
☺
EP

Israel, Bosniak (..)

Ascenti et al. (..)
☺

☺
☺
Clevert et al. (..)
☺

☺
☺
Quaia et al. (..)
☺

☺
☺
C

Gabr et al. (..)
☺

☺
☺

O’Malley et al. (..)
☺

☺
☺
AC

Weibl et al. (..)
☺

☺
☺

Hwang et al. (..)
☺

☺
☺
Smith et al. (..)
☺

☺
☺
Elmussarehet al. (..)
☺

☺
☺
Graumann et al. (..)
☺

☺
☺
El Mokadem et al. (..)
☺

☺
☺
Hindman et al. (..)
☺

☺
☺
Smith et al. (..)
☺

☺
☺
Weibl et al. (..)
☺

☺
☺
Ferreira et al (..)
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☺Low Risk;
High Risk; ? Unclear Risk

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