Elsevier

European Urology

Volume 77, Issue 5, May 2020, Pages 583-598
European Urology

Platinum Priority – Review – Urothelial Cancer
Editorial by Vignesh T. Packiam, Daniel A. Barocas and Stephen A. Boorjian on pp. 599–600 of this issue
Non-visible haematuria for the Detection of Bladder, Upper Tract, and Kidney Cancer: An Updated Systematic Review and Meta-analysis

https://doi.org/10.1016/j.eururo.2019.10.010Get rights and content

Abstract

Context

Non-visible haematuria (NVH) is a common finding and may indicate undiagnosed urological cancer. The optimal investigation of NVH is unclear, given the incidence of cancer and the public health implications of testing all individuals with this finding.

Objective

We review contemporary literature to determine the association of NVH with the diagnosis of bladder cancer (BC), upper tract urothelial carcinoma (UTUC), and kidney cancer (KC).

Evidence acquisition

A systematic review of original articles in English was completed in May 2019. Meta-analyses for the diagnostic accuracy of NVH and urine cytology were performed.

Evidence synthesis

We screened 1529 articles and selected 78 manuscripts that fulfilled our inclusion criteria for narrative synthesis. Forty manuscripts were eligible for a meta-analysis (reporting 19 193 persons). The likelihood of a urological cancer in patients with NVH increased with age (<1% in those aged <40 yr), male sex, and cigarette smoking. Less than 1% of patients are found to have a urological cancer after a negative NVH evaluation. Cancer detection rates in individuals evaluated for NVH ranged from 0% to 16% for BC in 37 studies, 0% to 3.5% for UTUC in 30 studies, and 0% to 9.7% for KC in 29 studies. Substantial statistical heterogeneity was present for the meta-analysis of detection rates.

Conclusions

We present an up-to-date review of the association of NVH with the diagnosis of BC, UTUC, and KC. Individuals with dipstick positive haematuria aged ≥40 yr, who have had potential precipitating causes excluded, should undergo an evaluation. Re-evaluation of patients with unremarkable initial investigations should be performed in high-risk patients or if new symptoms occur.

Patient summary

One in five people have microscopic traces of blood in their urine. This is an important indicator of urological cancer. Investigating all patients is uncomfortable and expensive. We evaluate the risk of cancer and estimate risks to groups of individuals.

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

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