








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Renal cell carcinoma, stage shift, RCC 
screening tools, risk-stratified screening

None declared. Received on July 15, 2022 
Accepted on September 20, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(6):371–385

DOI: 10.48083/XBCX3386

2022 WUOF/SIU International Consultation on 
Urological Diseases: Kidney Cancer Screening  
and Epidemiology 

Sabrina H. Rossi,1 Hajime Tanaka,2 Juliet A. Usher-Smith,3 Jean-Christophe Bernhard,4  
Yasuhisa Fujii,2 Grant D. Stewart1

1 Department of Surgery, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom 2 Department of Urology, Tokyo 
Medical and Dental University Graduate School, Tokyo, Japan 3 The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge School of 
Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom 4 Hôpital Pellegrin - CHU de Bordeaux, Université de Bordeaux, Bordeaux, France

Abstract

The incidence of renal cell carcinoma (RCC) has risen worldwide over the past few decades, and this has been 
associated with a stage shift. Survival outcomes of RCC depend largely on the stage at diagnosis. Although overall 
mortality has stabilized or declined in most countries, survival remains poor in late-stage disease, suggesting early 
detection may improve overall survival outcomes. A number of potential candidate screening tools have been 
considered (including urinary dipstick, blood- and urine-based biomarkers, ultrasound, and computed tomography 
[CT]), though it may be that a combination of these approaches may be optimal. Ultimately, the sensitivity and 
specificity of the chosen screening tool will determine the rate of false positives and false negatives, which must be 
minimized. One of the key challenges is the relatively low prevalence of the disease, which might be overcome by 
performing risk-stratified screening or screening for more than one condition (such as combined lung and kidney 
cancer screening). Both approaches have been shown to be acceptable to the general public, and they may maximize 
the efficiency of screening while reducing harms. Indeed, quantifying benefits and harms of screening is key 
(including the impact on overdiagnosis and quality of life). Whether screening for RCC will lead to a stage shift and 
the impact on survival are the decisive missing pieces of information that will determine whether the screening 
program might be adopted into clinical practice (along with feasibility, acceptability, and cost-effectiveness).

Epidemiology and Risk Factors for RCC

Incidence and Risk Factors
Renal cell carcinoma (RCC) RCC is the 9th most frequently diagnosed cancer in men and the 14th most common in 
women globally, accounting for 2.2% of all new cancer diagnoses (Table 1)[1]. The incidence of RCC demonstrates 
geographic variability (Figure 1)[2,3]. The International Agency for Research on Cancer (IARC), established in 1965 
by the World Health Assembly, provides comprehensive information on global cancer epidemiology by aggregating 
data from 343 population-based cancer registries in 65 countries[4]. The registry data is currently available online at 
the Global Cancer Observatory as the GLOBOCAN database[2]. According to the GLOBOCAN 2020 report, the age-
standardized incidence of kidney cancer is highest in Northern America, followed by Europe, Oceania, Latin America 
and the Caribbean, Asia, and Africa (Figure 1). The incidence of RCC has generally increased over time in both sexes, 
and is predicted to continue to rise over the next 15 years, although there is some variability across countries[2,3]. 

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The geographic distribution and rising incidence of 
RCC have been partially attributed to variation in risk 
factors for the disease as well as differences in healthcare 
delivery systems, as detailed below[5–7].

A number of modifiable and nonmodifiable risk 
factors for RCC have been identified (Table 2). The aging 
population and rising prevalence of certain risk factors 
(such as obesity, hypertension, and diabetes) contrib-
ute to increasing rates of the disease[5–7]. In addition, 
increased incidental detection reflects the widespread 
use of abdominal imaging. For example, in the United 
States, it is estimated that 43% of individuals aged 65–85 
years on Medicare undergo either thoracic or abdominal 
computed tomography (CT) in a 5-year period, and for 
every 1000 CT scans performed there are 4 additional 
nephrectomies[8]. Additionally, 2 studies have shown a 
statistically significant increase in the number of renal 
cancers detected among newly insured patients second-
ary to widening access to care through expansion of 
healthcare insurance[9,10].

Incidental detection has also contributed to a stage 
shift (i.e., detection of disease at an earlier stage), which 
was noted until the mid-2000s and has subsequently 
stabilized[11–13]. Clinical stage I tumors accounted 
for 43% of all kidney cancers diagnosed in 1993; the 
percentage increased to 57% in 2004[11] and leveled off 
around 70% after 2007, although the size of localized 
tumors continued to decline[12]. Overall, between 1993 
and 2004, 50.6%, 26.7%, and 22.7% of kidney cancer 
patients were diagnosed with stage I, stage II or III, and 
stage IV, respectively[11]. In contrast, between 2004 and 
2015, 70.3%, 10.5%, 8.3%, and 11.0% of patients were 
diagnosed with stage I (including 47.5% stage Ia and 
22.8% stage Ib), stage II, stage III, and stage IV, respec-
tively, highlighting a significant increase of stage I as 
well as a decrease of stage IV RCC[12].

Mortality
The crude mortality rate of kidney cancer was 13th in 
men and 14th in women (Table 1; Figure 2)[1]. Europe 
has the highest age-standardized mortality rate, 
followed by Northern America/Oceania, Latin America 
and the Caribbean, Asia, and Africa (Figure 2). The age-
standardized rate and the cumulative risk for kidney 
cancer death have been stabilizing in many countries, 
and have declined particularly in Europe and Northern 
America during the past one to 2 decades in both 
sexes[2,14]. Survival outcomes of RCC depend largely 
on the stage at diagnosis. The most recent report based 
on the National Cancer Database in the United States 
showed that the 5-year survival rate was 93%, 70%, and 
13% in patients with localized, regional, and distant 
RCC, respectively[15]. In this report, the mortality 
data were collected by the National Center for Health 
Statistics[15]. Similar survival outcomes were also 
observed in the United Kingdom; 5-year survival was 
87% in stage I compared to 12% in stage IV RCC[16]. 
The decline in kidney cancer mortality may, therefore, 
be related to earlier diagnosis, as well as improved 
treatment strategies and recent advances in systemic 
therapy[12,17].

Population Screening
Rationale for Screening
The relatively large proportion of patients with RCC 
who are diagnosed at a late, advanced, or metastatic 
stage due to the absence of symptoms and the poor 
survival in this group are the main drivers for the need 
to improve the early detection of RCC. Initiatives to raise 
public awareness of hematuria have not been successful 
in improving detection of RCC[18], suggesting that 
a more systematic identification approach may be 
necessary. Screening for RCC has the potential to 
improve survival outcomes by enabling earlier diagnosis 
and treatment[19,20]. No randomized controlled trials 
(RCTs) of screening for RCC have been performed and 
due to insufficient evidence, international urology and 
oncology associations have yet to publish guidelines 
on this topic[21–27]. Screening and early detection 
of RCC have been identified as a key research priority 
in 3 independent priority-setting initiatives[28–31], 
and patient groups have been vocal in their desire to 
champion this agenda[32]. The “sojourn time,” also 
known as the “preclinical period,” refers to the length 
of time during which an individual with RCC has not 
yet received a diagnosis, and would therefore benefit 
from early detection via screening. Cancers with very 
short or very long sojourn times are not ideal screening 
candidates. Imaging studies have suggested the sojourn 
time for RCC is between 3.7 and 5.8 years[33]. Scelo 
et al. demonstrated raised kidney injury molecule-1 
(KIM-1) plasma levels up to 5 years prior to RCC 

Abbreviations 
AAA abdominal aortic aneurysm
ASR age-standardized rate
AUC area under the curve
BMI body mass index
ccRCC clear cell renal cell carcinoma
chRCC chromophobe renal cell carcinoma
CT computed tomography
ctDNA circulating tumor DNA
KIM-1 kidney injury molecule-1
NV nonvisible 
RCC renal cell carcinoma
RCT randomized controlled trial
SRMs small renal masses

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TABLE 1. 

Age-standardized rate and cumulative risk of kidney cancer incidence and mortality (GLOBOCAN 2020 report)[1] 

 Incidence Mortality

 
ASR, per  
100 000a

Cumulative  
risk, %b

ASR, per  
100 000a

Cumulative  
risk, %b

Worldwide

Male 6.1 1.45 2.5 0.81

Female 3.2 0.76 1.2 0.39

Both sexes 4.6 1.06 1.8 0.57

Europe

Male 13.1 2.78 4.5 1.41

Female 6.4 1.36 1.7 0.58

Both sexes 9.5 1.96 2.9 0.91

Northern America

Male 16.1 3.23 3.0 0.95

Female 8.6 1.69 1.3 0.45

Both sexes 12.2 2.39 2.1 0.67

Latin America and the Caribbean

Male 6.3 1.37 2.8 0.79

Female 3.3 0.74 1.3 0.37

Both sexes 4.7 1.02 2.0 0.55

Oceania

Male 12.4 2.83 3.0 1.05

Female 5.4 1.27 1.3 0.51

Both sexes 8.8 2.00 2.1 0.75

Asia

Male 3.8 0.89 2.0 0.61

Female 1.9 0.45 0.90 0.30

Both sexes 2.8 0.65 1.4 0.44

Africa

Male 2.1 0.48 1.4 0.43

Female 1.5 0.24 0.98 0.21

Both sexes 1.8 0.34 1.2 0.30

ASR: age-standardized rate. 
aThe age-standardized rate (ASR) was adjusted to the world standard population.  
bThe cumulative risk was the probability of kidney cancer development or death in a lifetime defined as 0–74 years.
Source: Reprinted from GLOBOCAN 2020 report, Global Cancer Observatory, Cancer Today. Ferlay J, Ervik M, Lam F, et al., eds. Age-standardized rate and 
cumulative risk of kidney cancer incidence and mortality. World Health Organization, International Agency for Research on Cancer, Copyright 2022 [1].

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FIGURE 1. 

Age-standardized rate of kidney cancer incidence  

FIGURE 2. 

Age-standardized rate of kidney cancer mortality  

Source: Reprinted from GLOBOCAN 2020 report, Global Cancer Observatory, Cancer Today. Ferlay J, Ervik M, Lam F, et al., eds. Age-standardized rate 
of kidney cancer incidence. World Health Organization, International Agency for Research on Cancer, Copyright 2022[1]. 

Source: Reprinted from GLOBOCAN 2020 report, Global Cancer Observatory, Cancer Today. Ferlay J, Ervik M, Lam F, et al., eds. Age-standardized rate 
of kidney cancer incidence. World Health Organization, International Agency for Research on Cancer, Copyright 2022[1].  

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TABLE 2. 

Modifiable and nonmodifiable risk factors for RCC 

Risk factor Relative risks (RRs) and comments

Modifiable factors

Smoking
Established risk factor for RCC[34–37]
RR 1.31 (95% CI, 1.22–1.40) for smokers versus nonsmokers[34]

Obesity
Established risk factor for RCC[35,37–39]
RR 1.77 (95% CI, 1.68–1.87) for obesity (BMI ≥ 30) versus a normal BMI[39]

Hypertension 
Established risk factor for RCC[37]
RR 1.70 (95% CI, 1.30–2.22) for patients with hypertension vs. those without hypertension[37]
Meta-analysis reported 67% increased risk in patients with hypertension[40]

Diabetes
Controversial whether diabetes is an independent risk factor for RCC due to potential confounders  
(smoking, obesity, and hypertension)[7,41]

Diet

Meat: potential risk factor for RCC; may be partially related to the carcinogens formed in the cooking 
process[42,43]
Fruit and vegetables: may be protective (particularly for cruciferous vegetables)[44,45] 
Alcohol: may be protective; an inverse relationship between moderate alcohol intake (< 60 g/day) and RCC risk  
is reported[46,47]

Occupation
Trichloroethylene: may modestly increase the risks of several cancers including RCC[48–50].  
Toxicity is officially acknowledged by the Environmental Protection Agency in the United States

Drug exposure
Acetaminophen and NSAIDs other than aspirin: significantly associated with an increased incidence  
of kidney cancer[51]
Aspirin: No increase in RCC incidence[51]

Nonmodifiable factors

Age
RCC incidence increases with age[14]
Global crude incidence, per 100 000 = 4.3 in 40–49 years, 10.8 in 50–59 years, 20.3 in 60–69 years,  
and 29.6 in 70–79 years[1]

Sex
RCC incidence shows 2:1 male predominance across the world[1] (Table 1)
May be related to various confounders including modifiable risk factors of RCC (smoking, obesity,  
or hypertension) as well as intrinsic biological variances

Race

Racial disparities between black and Caucasian has been highlighted
ASRs of kidney cancer incidence in black vs. white individuals,  
per 100 000 = 16.4 vs. 13.5 in males and 8.1 vs. 7.0 in females[2]
ASRs of kidney cancer incidence in black vs. white individuals,  
per 100 000 = 16.4 vs. 13.5 in males and 8.1 vs. 7.0 in females[2]

Family history RR 2.2-fold when patients have RCC history in any-degree relatives[52]
RR 4.3-fold when patients have RCC history in first-degree relatives[52]

ASR: age-standardized rate; BMI: body mass index; CI: confidence interval; NSAID: nonsteroidal anti-inflammatory drug; RCC: renal cell carcinoma.

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diagnosis[53], which is in keeping with the estimated 
sojourn time. Taken together, these studies suggest that 
there is a length of time during which asymptomatic 
patients might benefit from screening interventions. 
Any screening program for RCC, however, must be 
evaluated with the Wilson and Jungner criteria in 
mind[54], to minimize risks to the general population 
while maximizing benefits for individuals. The Wilson 
and Jungner criteria serve as guiding principles and a 
framework to evaluate potential screening programs 
and assess their utility and feasibility within the existing 
health service[54].

Screening Modality
A successful screening strategy relies on a screening 
tool that is accurate, reliable, acceptable to the public, 
and scalable (i.e., can be rolled out on a population level 
by the existing health service). A number of screening 
approaches have been considered, each with advantages 
and disadvantages, although the ideal screening tool has 
yet to be identified.

Urinary Tests
Urinary tests represent an ideal tool due to their 
noninvasive nature, ease of collection and storage, and 
acceptability by the general public[55]. This strategy 
could involve either a point-of-care test (such as dipstick 
for hematuria) or laboratory test (urinary biomarkers). 
Dipstick tests are cheap, readily available, and require 
minimal training; however, color changes may be 
open to subjective interpretation. Nonvisible (NV) 
hematuria is defined as blood in the urine detected by 
urinary dipstick or microscopy, which is not visible to 
the naked eye (as opposed to visible hematuria, which is 
macroscopic)[63]. The main concerns are the nonspecific 
nature of NV hematuria for RCC, the high number of 
incidental findings, and the unacceptably high rate of 
false positives and false negatives[20,64]. Therefore, 
screening for RCC based around dipstick-detected 
NV hematuria is not currently recommended (though 
there may be benefits for bladder cancer detection)[65]. 
The vast majority of patients diagnosed with RCC will 
not have hematuria, meaning there would be a large 
number of false negatives. The prevalence of hematuria 
in RCC is 35% (prevalence 17.5% visible and 17.5% 
nonvisible hematuria), compared to 94% in bladder 
and ureter urothelial cancers[66]. The prevalence of NV 
hematuria may be as high as 20% to 30% in the general 
population[64,67]; however, < 1% of individuals with NV 
hematuria are found to have RCC and 5% are found to 
have bladder cancer[63]. Conversely, urinary dipstick 
may identify a large number of nonmalignant urological 
diseases that are associated with NV hematuria 
(including renal stones, cysts, etc.) as well as medical 
diseases associated with proteinuria or glycosuria (renal 
disease, diabetes, infection, etc). The high volume of 

individuals requiring further investigation and the high 
number of incidental findings preclude this as a cost-
effective screening strategy for RCC.

Urinar y biomarkers would represent the ideal 
screening tool; however, to date none are validated 
or approved for use in clinical practice[68]. A number 
of different analytes have been considered, including 
urinary proteins, cell-free tumor DNA, microRNAs, 
and exosomes. Perhaps the most well-studied group 
is urinary proteins, including aquaporin-1, perili-
pin-2, carbonic anhydrase-9, Raf-kinase inhibitory 
protein, nuclear matrix protein-22, 14–3–3 Protein 
β/α, and neutrophil gelatinase-associated lipocalin[68]. 
Aquaporin-1 and perilipin-2 have been evaluated in a 
prospective study of 720 patients undergoing screen-
ing CT, 80 healthy controls, and 19 patients with RCC. 
In this cohort, these 2 biomarkers used in combina-
tion achieved an area under the curve (AUC) of > 0.99 
for RCC[69]. Although these 2 proteins may be good 
markers for clear cell renal cell carcinoma (ccRCC) and 
papillary renal cell carcinoma (pRCC), levels are low or 
negative in chromophobe renal cell carcinoma (chRCC), 
meaning that screening would miss these cancers[19]. 
Further prospective validation in an independent cohort 
is warranted.

Blood Tests
Blood-based tests represent anot her potentia l ly 
useful option due their relative public acceptability 
and presumed relatively low cost. Analytes similar to 
those identified in urine may be used, such as proteins, 
circulating tumor DNA (ctDNA), microRNAs, and 
exosomes. KIM-1 is a glycoprotein that reflects injury 
to the proximal convoluted tubule of the kidney (from 
which ccRCC and pRCC are derived). KIM-1 blood levels 
may be elevated 5 years prior to a diagnosis of RCC[53]. 
One of the main disadvantages is the low specificity 
of KIM-1 (levels may be elevated in kidney injury). 
Furthermore, KIM-1 levels are not elevated in patients 
with renal tumors derived from the distal nephron (e.g., 
chRCC and collecting duct RCC), limiting applicability 
as a screening tool. Cancer screening using ctDNA has 
recently received significant media attention and has 
entered large-scale validation studies[70–72]. A number 
of studies have been published evaluating ctDNA for the 
simultaneous detection of multiple cancer subtypes with 
the aim of pan-cancer screening[70,73–75]. Although 
initial reports evaluating mutations[76] and methylation 
patterns[74] in ctDNA suggested that patients with RCC 
may have lower levels of ctDNA than those with other 
malignancies, more recent reports evaluating DNA 
methylation appear more promising[77]. Nuzzo et al.[77] 
evaluated ctDNA methylation using cell-free methylated 
DNA immunoprecipitation and high-throughput 
sequencing (cfMeDIP–seq) in a case-control study. The 

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study cohort included 99 ctDNA samples from patients 
with RCC (of which 33% were from patients with stage 
I–II disease), 21 samples from patients with stage IV 
bladder cancer, and 28 healthy controls. The overall 
AUC for the detection of RCC was 0.99, suggesting 
ctDNA may be detected in patients with RCC across the 
spectrum of disease severity, raising the possibility that 
in future this could potentially be used to enable earlier 
disease detection.

Unfortunately, thus far, neither urine- nor blood-
based biomarkers have achieved sufficient sensitivity and 
specificity required for implementation in clinical prac-
tice. Further research on minimally invasive biomarkers 
as a screening tool, in prospective cohorts, is warranted.

Ultrasound
Ultrasound is perhaps the most well-studied screening 
method for RCC, with a number of observational studies 
published in the 1990s and early 2000s[78–85]. The main 
drawback is that accuracy is dependent on operator 
experience, anatomical factors (including obesity and 
overlying bowel gas), and lesion size. There is a potential 
for false negatives, as ultrasound can detect 85% to 100% 
tumors > 3 cm in size, but only 67% to 82% of tumors of 
2–3 cm in size[86,87]. Advantages of ultrasound include 
the relative acceptability by the general public, as it is 
pain-free and noninvasive (compared to blood tests). 
Ultrasound is widely available, does not involve ionizing 
radiation, and is relatively inexpensive compared to 
CT. Furthermore, focused renal ultrasound may be 
performed, imaging the kidneys alone rather than 
the entire abdomen, therefore reducing the time and 
cost of the scan and avoiding incidental detection of 
indeterminate lesions in other abdominal organs, which 
may require additional investigation with associated 
costs. Another potential advantage is the opportunity 
to combine screening for renal cancer with the existing 
abdominal aortic aneurysm (AAA) screening program, 
currently underway in a number of countries[88–90].  
A combined approach would reduce the overall cost of the 
screening intervention and maximize cost-effectiveness, 
although currently AAA is only recommended for men 
and not women. To the best of our knowledge, Malaeb et 
al.[85] is the first and only study to explore the combined 
screening of RCC and AAA, demonstrating this is 
a feasible approach that is well tolerated by patients. 
Although this study is promising, none of the ultrasound 
studies were randomized in nature, meaning the impact 
of the intervention on survival remains unknown.

Computed Tomography
Use of CT has increased in recent decades due to 
technological advances (enabling increased resolution, 
reduced scanning times, and lower radiation dose), 
increasing availabilit y and reducing costs[8,91]. 

Contrast-enhanced CT is the gold-standard diagnostic 
imaging technique to evaluate small renal masses 
in patients with suspected RCC (e.g., if a mass is 
identified on ultrasound or there is visible hematuria). 
Contrast uptake can enable the differentiation between 
benign and malignant disease, and visualization of 
tumor and vessel anatomy that can guide operative 
management approaches. However, the utility of 
contrast-enhanced CT as a screening tool in the general 
population is limited by the use of contrast (which may 
be nephrotoxic), the relatively high radiation dose, and 
cost, particularly given the low prevalence of RCC. 
However, low-dose unenhanced CT has the advantage of 
providing less radiation dose and no contrast.

Whole-body CT has been proposed as a potential 
screening tool for the combined detection of multiple 
malignant and nonmalignant diseases (e.g., abdomi-
nal cancers, AAA, etc.). Although a number of studies 
have been performed, the main drawback of performing 
whole-body scans is the high number of incidental find-
ings, false positives, and findings of unknown clinical 
potential. For example, Millor et al.[92] reviewed 6516 
whole-body screening CTs (which included unenhanced 
chest CT, enhanced abdominal CT, cardiovascular, 
and bone assessments). Fewer than 2% of individuals 
had normal scans, meaning that > 98% had to undergo 
further investigations with significant costs, burden to 
the health service, and anxiety for the individual. Only 
1.5% of individuals were found to have a malignancy  
(35 of 96 were RCC). As a result, whole-body CT to 
screen for kidney cancer as a standalone test in an 
unselected population is unlikely to be a cost-effective 
strategy at present[93], though in future automated 
interpretation of imaging features using machine learn-
ing may increase the accuracy and feasibility of this 
strategy[95]. An alternative approach is to add low-dose 
noncontrast abdominal CT scans to the low-dose unen-
hanced chest CT scans currently being investigated for 
lung cancer screening. The Yorkshire Kidney Screening 
Trial (NCT05005195), currently underway, is a novel 
study and the first to evaluate the added benefit of 
screening for RCC by extending the low-dose chest CT 
to image the kidneys in 55–80-year-old smokers and 
ex-smokers undergoing lung cancer screening enrolled 
in the Yorkshire Lung Screening Trial[95]. It is postu-
lated that combined lung and kidney cancer screening 
may maximize cancer detection rates while reducing 
costs.

Screening Population
The ideal population to whom screening for RCC should 
be offered is unknown. Meta-analyses have estimated 
that screening 1000 individuals using ultrasound would 
identify between 1 and 2 patients with RCC[78], while 
using CT would identify between 1 and 3 (the pooled 

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prevalence of RCC is 0.17% (95% CI 0.09–0.27%) 
and 0.21% (95% CI, 0.14–0.28%) in ultrasound and 
CT respectively)[33,78]. One of the main challenges 
is the relatively low prevalence of RCC. Indeed, a 
health economic analysis of screening for RCC using 
ultrasound identified prevalence of RCC as the greatest 
determinant of cost-effectiveness[96].

Risk-stratified screening may enable more efficient 
identification of RCC, focusing on high-risk individuals 
and therefore maximizing benefits while reducing costs 
and harms for those at low risk. A systematic review of 
risk-prediction models for RCC[97] identified 11 models 
that report performance measures and could potentially 
be used. Fewer than 20% (2 of 11) had been validated in 
an external population, highlighting one of the limita-
tions of current models. The most commonly included 
factors were sex, age, smoking status, body mass index 
(BMI), and hypertension, which is consistent with the 
known data on risk factors for RCC. However, none of 
these risk factors are specific for RCC. Only one study 
considered genetic risk (i.e., single-nucleotide polymor-
phisms) and biomarker studies were characterized by a 
high risk of bias. The models identified in the system-
atic review were externally validated in > 450 000 partic-
ipants within the UK Biobank cohort[98]. Five models 
had reasonable calibration and discrimination, with an 
area under the receiver operating characteristic curve 
between 0.61 and 0.72. All the models performed less 
well in women, compared to men. Additionally, although 
the models were better at identifying individuals at high 
risk for RCC than age and sex alone, the improvement 
was small. Risk-prediction models for RCC based on 
genetic factors performed poorly compared to the best 
genetic risk models for other cancers, suggesting more 
research on this topic is needed[99]. Future incorpo-
ration of biomarkers into risk scores could improve 
performance.

Screening Implementation and  
Public Acceptability
If screening is demonstrated to improve disease-specific 
survival, it is crucial to consider implementation within 
the existing healthcare delivery system. The cost of 
screening is not limited to the intervention itself, but 
includes the associated costs of investigating incidental 
findings and the cost of treatment of diagnosed 
conditions. The cost-effectiveness of any screening 
intervention needs to be demonstrated prior to the 
screening program being accepted into clinical practice. 
Other important considerations are in regard to 
program delivery, including optimal screening location 
(e.g., primary care, secondary care, screening vans in 
public spaces), training an adequate workforce to deliver 

screening (e.g., ultrasound delivered by technicians 
vs. sonographers), and quality control (e.g., audit for 
laboratories undertaking biomarker work or facilities 
offering imaging).

Public acceptability of the program will also be key to 
ensure high attendance rates. A survey has shown that 
members of the general public would be “very likely” 
or “likely” to undergo each of the following screening 
tests: urine test, 94%; blood test, 90%; ultrasound, 90%; 
low-dose CT, 79%; and low-dose CT offered as part of 
lung screening, 95%[55]. In addition, 83% reported that 
tailoring the starting age of RCC screening based on a 
risk score incorporating phenotypic or genetic risk was 
acceptable, and 85% reported they would be more likely 
to attend screening if the risk score suggested they were 
high risk[100]. The high anticipated intention to attend 
screening and positive attitudes toward risk-stratified 
screening are promising.

Unknown Benefits and Harms
Although screening could have many potential benefits, 
there are still many unknowns that require further 
research (Table 3). Importantly, it is unclear whether 
screening would lead to increased RCC diagnoses 
(including a stage shift) in view of the high rates of 
incidental detection. Crucially, it is unknown whether 
screening leads to a survival benefit. Another main 
challenge relates to increased detection of small renal 
masses (SRMs, defined as < 4 cm in diameter), which are 
difficult to characterize and therefore may lead to false 
positives or overdiagnosis of indolent lesions (Table 4). 
Ultimately, being able to clearly determine which 
SRMs require further investigation or treatment and 
developing pathways for the management of patients 
with SRMs based on competing risks are essential before 
any RCC population-based screening program can be 
implemented.

As screening is offered to a large number of asymp-
tomatic individuals in order to detect only a small 
number of cancers, it is crucial to understand any 
quality of life (QoL) detriment associated with screen-
ing itself. None of the observational studies evaluating 
ultrasound screening for RCC assessed the impact on 
QoL[19]. There are a number of ways in which screening 
can cause harm (Table 4)[101–103]. These include phys-
ical harm, resulting from both the screening test and/
or follow-up procedures; psychological harm, includ-
ing increases in anxiety; treatment burden, including 
from subsequent invasive procedures and overdiagnosis; 
financial costs associated with travel and time off work 
to attend appointments and potential loss of earnings; 
social harm, resulting from social stigma or missing out 
on other activities; and dissatisfaction with health care.

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Future Directions
In summary, the incidence of RCC has risen worldwide 
over the past few decades, and this has been associated 
with a stage shift. Survival outcomes of RCC depend 
largely on the stage at diagnosis. Although overall 
mortality has stabilized or declined in most countries, 
survival remains poor in late-stage disease, meaning 
that early detection could improve overall survival 
outcomes. A number of potential candidate screening 
tools are currently being investigated, though it may 
be that a combination of these approaches may be 
optimal. Ultimately, the sensitivity and specificity of the 
chosen screening tool will determine the rate of false 

positives and false negatives, which must be minimized.  
One of the key challenges is the relatively low prevalence 
of the disease, which might be overcome by performing 
risk-stratified screening or screening for more than one 
condition (such as combined lung and kidney cancer 
screening). Both approaches have been shown to be 
acceptable to the general public, and they may maximize 
the efficiency of screening while reducing harms. 
Whether screening for RCC will lead to a stage shift and 
the impact on survival are the decisive missing pieces of 
information that will determine whether the screening 
program might be adopted into clinical practice (along 
with feasibility, acceptability, and cost-effectiveness).

TABLE 3. 

Research questions that remain to be addressed 

Unknowns Comments, challenges, and future direction

The ideal screening modality is unknown.
• Ideally a two-step approach would be adopted (such as for colorectal cancer screening), where 

an initial noninvasive test (e.g., urinary test) would be followed by a second, more advanced 
test (e.g., imaging).

The ideal screening population is unknown.

• The main challenge is the low prevalence of RCC, meaning that a large number of healthy 
individuals would have to be screened to identify only a small number of cases.

• Risk-prediction models may identify individuals at high risk, therefore maximizing cost-
effectiveness. However, existing models have a relatively low accuracy and are based on 
nonspecific risk factors.

Unknown whether screening for kidney cancer 
will translate into a survival benefit beyond 
length and lead time bias.

• No randomized controlled trials (RCTs) have been performed to date.
• Ultimately, an RCT would be needed to demonstrate a survival benefit; however, due to the low 

prevalence of RCC, this would necessitate hundreds of thousands of participants with long-
term follow-up, which is prohibitive.

Unknown whether screening 
will lead to increased detection and a stage 
shift (i.e., earlier detection) given high volume 
of abdominal imaging for other complaints and 
widespread incidental detection.

• It is estimated that 43% of individuals aged 65–85 years on Medicare in the United States 
undergo either a CT chest or CT abdomen over a 5-year period[8], meaning that it is unclear 
whether these individuals may benefit from further screening.

Unclear when to start screening and how often 
to screen. 

• No premalignant lesion has been identified for RCC.
• Thus far, studies have evaluated screening for RCC at a single time point rather than regular 

intervals[19].

Potential harms of screening and the impact on 
quality of life have not yet been fully quantified.

• See Table 4.

Unclear whether screening could be 
implemented in the current health service.

• Once the screening modality has been selected, further data will be needed on cost-
effectiveness (based on a trial), feasibility, public acceptability, and potential uptake.

Adapted from Rossi SH, T. Klatte J, Usher-Smith J, Stewart GD. Epidemiology and screening for renal cancer. World J Urol.2018;36(9):1341–1353. 
doi:10.1007/s00345-018-2286-7, under the Creative Commons License.

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TABLE 4. 

Potential harms of screening for RCC 
The following potential harms may depend on the screening modality that is ultimately chosen 

Potential harms Comment

False negatives
• False negatives are associated with real harms and anxiety to the individual.
• May erode public trust in the screening program and negatively affect attendance if the test is perceived  

to be inaccurate.

False positives

• Unfortunately, it is not possible to accurately differentiate benign from malignant SRMs using contrast-
enhanced CT, the gold standard imaging investigation[97,98].

• Renal biopsy is often under-utilised due to inadequate service provision, lack of expertise or low perceived 
clinical benefit. Biopsy is non-diagnostic in ~10% of cases[99] and it can be particularly difficult to distinguish 
oncocytoma from eosinophilic variants of chRCC and ccRCC.

• A meta-analysis demonstrated approximately 25% of renal biopsies reported as oncocytoma are found to 
be malignant following excision[100]. Erring on the side of caution, patients with SRM are often offered 
surgery and as a result, approximately 20%-30% are found to have benign disease post-operatively, meaning 
they underwent unnecessary surgery, with associated morbidity and potential long-term effects on renal 
function[101,102].

Overdiagnosis and overtreatment 
of renal tumors that would not 
affect survival

• It is not possible to distinguish aggressive from indolent SRMs, meaning that screening could identify a large 
number of individuals with SRMs who would not benefit from treatment.

• Increasing the use of active surveillance (which has been shown to be noninferior to primary intervention) 
especially in patients with comorbidities who may have a limited life expectancy, could reduce 
overtreatment[62].

• Recently, a growing number of observational studies are being performed that are increasing our 
understanding of the natural history of disease[62].

Incidental findings

• High cost of further investigations.
• May have indeterminate clinical potential and result in increased patient anxiety.
• However, imaging-based screening may identify additional conditions  

(such as other abdominal cancers or AAA) that could benefit patients.

Anxiety and worry • Resulting from both the screening test and/or follow-up procedures.

AAA: abdominal aortic aneurysm; ccRCC: clear cell renal cell carcinoma; chRCC; chromophobe renal cell carcinoma;  
CT: computed tomography; SRMs: small renal masses.

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