Platinum Priority – Review – Urothelial CancerEditorial by Vignesh T. Packiam, Daniel A. Barocas and Stephen A. Boorjian on pp. 599–600 of this issueNon-visible haematuria for the Detection of Bladder, Upper Tract, and Kidney Cancer: An Updated Systematic Review and Meta-analysis
Introduction
Haematuria is a common indication for a referral to an urologist, as its presence may indicate urinary tract stones, an infection, or cancer [1]. Visible haematuria (VH; ie, gross haematuria or macrohaematuria) is accepted as an indication to investigate, given the risks of significant pathology [2], [3], [4], [5], [6], [7]. In contrast, the need to investigate persons with non-visible haematuria (NVH; ie, microscopic haematuria) is contentious [8], [9], [10]. This reflects the high prevalence of NVH in the general population (estimated 20% in men over 60 yr) [11], contrasting definitions (eg, dipstick positive [and extent of positivity] or urine microscopy), and the low risk of underlying urological malignancies. Consequently, current guidelines differ regarding age thresholds and patient risk profiles that warrant investigation, and mode of evaluation [1], [2], [4], [12]. For example, the American Urological Association (AUA) recommends investigating persons over the age of 35 yr with three or more red blood cells (RBCs) per high-power field (HPF) [2], the UK’s National Institute for Health and Care Excellence (NICE) advocates investigation of persons with NVH only in those over 60 yr with either dysuria or an elevated white cell count [4], and the National Board of Health and Welfare of Sweden does not recommend investigating patients with NVH at all [5].
Unconstrained investigation of patients with NVH carries significant individual and public health implications with associated clinical and financial risks and benefits [1], [13]. Diagnostic tests such as cystoscopy and multidetector computed tomography with a urographic phase are costly, invasive, and uncomfortable, and carry risks of infection, contrast-medium–related toxicity, and radiation exposure. Up to 95% of urological evaluations of patients with NVH are negative for malignancy [14]. Conversely, many patients with urinary tract cancer are initially referred for NVH, and delays in diagnosis of these cancers lead to worse outcomes [13], [15], [16]. Two prospective studies found that haematuria screening in asymptomatic individuals is associated with lower-stage cancers at diagnosis (when compared with registry data) and so may improve survival [11], [17], [18]. Furthermore, a multicentre study of patients diagnosed with bladder cancer (BC) found that those who presented with NVH had a lower rate of muscle-invasive disease than those who presented with VH [19]. Of note, a contrasting multicentre study reported the opposite effect [20].
Given conflicts regarding the requirement and form of testing in individuals with NVH, we aimed to systematically review the literature for the most up-to-date evidence regarding the utility of NVH in the diagnosis of BC, upper tract urothelial carcinoma (UTUC), and kidney cancer (KC). We report the rate of cancers detected in individuals evaluated for NVH and the potential utility of cytology as an additional test in this setting, to provide an overview of the evidence to facilitate clinical decision making and help identify research necessary to advance this field.
Section snippets
Systematic review
A systematic review of original articles was performed using PubMed/Medline in April 2018 and updated in May 2019. We used the following search terms: (((((((((((((hematuria[MeSH Terms]) OR microscopic haematuria) OR microscopic hematuria) OR haematuria) OR dipstick haematuria) OR dipstick hematuria) OR urine dip haematuria) OR urine dip hematuria) OR non-visible haematuria) OR non-visible hematuria) OR non visible haematuria) OR non visible hematuria)) AND ((("Urologic
Evidence synthesis
We found 1529 articles, of which 78 full-text manuscripts were included in the systematic review and 40 in the meta-analysis (reporting on 19 193 persons; Table 1, Table 2, and Supplementary Fig. 1). The participants in the studies were predominantly patients with NVH who were referred from primary care to secondary care for evaluation.
In total, 11 studies enabled the calculation of sensitivity and specificity of urine cytology for UC in patients with NVH, of which seven (reporting on 2425
Conclusions
We provide a large contemporary systematic review and meta-analysis on NVH for the diagnosis of bladder and upper tract cancers. NVH can be small volume and intermittent in nature in urological cancers. Confirmation of NVH on repeated samples before more extensive evaluation risks missing clinically significant cancers. Patients with dipstick positive haematuria aged ≥40 yr, who have had potential precipitating causes excluded (eg, treatment for UTI), should undergo an evaluation. Evaluation
References (95)
- et al.
Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline
J Urol
(2012) - et al.
Microhematuria assessment an IBCN consensus—based upon a critical review of current guidelines
Urol Oncol
(2016) - et al.
Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes
Eur Urol
(2016) - et al.
Who should be investigated for haematuria? Results of a contemporary prospective observational study of 3556 patients
Eur Urol
(2018) - et al.
A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice
J Urol
(2000) - et al.
A community study of bladder cancer screening by the detection of occult urinary bleeding
J Urol
(1992) - et al.
Home screening for hematuria: results of a multiclinic study
J Urol
(1992) - et al.
Strategies for asymptomatic microscopic hematuria: a prospective study of 1,034 patients
J Urol
(1990) - et al.
Tumor characteristics of urothelial carcinoma on multidetector computerized tomography urography
J Urol
(2010) - et al.
Upper tract urothelial cancer
Eur J Radiol
(2018)
Diagnostic performance of ultrasound for macroscopic hematuria in the era of multidetector computed tomography urography
Can Assoc Radiol J
Can renal and bladder ultrasound replace computerized tomography urogram in patients investigated for microscopic hematuria?
J Urol
A new diagnostic algorithm for the evaluation of microscopic hematuria
Urology
Computerized tomography tailored for the assessment of microscopic hematuria
J Urol
Utility of urine cytology in the workup of asymptomatic microscopic hematuria in low-risk patients
Urology
Long-term outcome of patients with a negative work-up for asymptomatic microhematuria
Urology
Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years’ follow-up
Urology
Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018
Eur Urol
Stratifying risk of urinary tract malignant tumors in patients with asymptomatic microscopic hematuria
Mayo Clin Proc
The role of tobacco smoke in bladder and kidney carcinogenesis: a comparison of exposures and meta-analysis of incidence and mortality risks
Eur Urol
Are patients with hematuria appropriately referred to Urology? A multi-institutional questionnaire based survey
Urol Oncol
What is evaluation of hematuria by primary care physicians? Use of electronic medical records to assess practice patterns with intermediate follow-up
Urol Oncol
Gender disparities in hematuria evaluation and bladder cancer diagnosis: a population based analysis
J Urol
Preferences for cancer investigation: a vignette-based study of primary-care attendees
Lancet Oncol
EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016
Eur Urol
What contributions do languages other than English make on the results of meta-analyses?
J Clin Epidemiol
Performance of computed tomographic urography for the detection of bladder tumors in patients with microscopic hematuria
Actas Urologicas Espanolas
Prospective comparison of computerized tomography and excretory urography in the initial evaluation of asymptomatic microhematuria
J Urol
Prospective external validation of a bladder cancer detection model
J Urol
Multidetector computerized tomography urography as the primary imaging modality for detecting urinary tract neoplasms in patients with asymptomatic hematuria
J Urol
Guideline of guidelines: asymptomatic microscopic haematuria
BJU Int
Recommendations for the improvement of bladder cancer quality of care in Canada: A consensus document reviewed and endorsed by Bladder Cancer Canada (BCC), Canadian Urologic Oncology Group (CUOG), and Canadian Urological Association (CUA), December 2015
Can Urol Assoc J
Suspected cancer: recognition and referral | Guidance and guidelines | NICE
Time to abandon testing for microscopic haematuria in adults?
BMJ
Japanese guidelines of the management of hematuria 2013
Clin Exp Nephrol
Hematuria: a problem-based imaging algorithm illustrating the recent Dutch guidelines on hematuria
AJR Am J Roentgenol
Suspected cancer: recognition and referral | Guidance and guidelines
Haematuria guidelines
The British Association of Urological Surgeons Limited
Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults
Dipstick haematuria and bladder cancer in men over 60: results of a community study
BMJ
Cost-effectiveness of common diagnostic approaches for evaluation of asymptomatic microscopic hematuria
JAMA Intern Med
Importance of occult haematuria found at screening
Br Med J (Clin Res Ed)
A delay in radical nephroureterectomy can lead to upstaging
BJU Int
Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations
Urology
Bladder tumours detected on screening: results at 7 years
Br J Urol
Microscopic haematuria at time of diagnosis is associated with lower disease stage in patients with newly diagnosed bladder cancer
BJU Int
Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement
Syst Rev
Cited by (38)
A 25-year perspective on evaluation and understanding of biomarkers in urologic cancers
2021, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :The clinical needs for having a noninvasive marker/test for BC have remained the same for the last 25 years. Some of the first large-scale hematuria screening trials were conducted to detect significant pathologies including BC by Edward Messing and colleagues [59–63]. Unlike PCa, due to low prevalence of BC in the general population (0.001%) and in people >50 years of age (0.67% to 1.13%), screening the whole population for BC would result in too many false-positive results (each requiring an expensive workup), even when using an ideal marker [14,16,17,61,63,64].
Clinical management of microscopic haematuria in 2021
2021, Progres en Urologie - FMC