Prompt diagnosis of urothelial cell carcinoma (UCC) of the bladder and/or upper tracts is dependent on recognition of its early symptomatology—hematuria. Microhematuria (MH) can be widely prevalent in up to 31% of urine specimens.^1-3 The associated etiologies, however, are diverse and range from innocuous to lethal. Benign pathologies such as cystitis and urolithiasis represent the lion’s share of causes, while the incidence of genitourinary malignancies in all patients with MH is estimated at less than 1%.^4,5 The consequences of missed UCC, however, can be dire.

Accordingly, the AUA has periodically published diagnostic guidelines for MH, most recently in 2020.¹ Prior iterations advocated for cystoscopy and multiphasic cross-sectional abdominal imaging for patients ≥35 years old with MH (and in younger patients based on risk); the intensive workup is representative of the severity of a UCC diagnosis.³ The 2020 guidelines advocate a risk-stratified approach that serves to mitigate the invasiveness and risks of prior workups (infection, patient discomfort, radiation exposure, nephrotoxicity etc) by advocating alternative modalities such as ultrasound or permitting avoidance of cystoscopy in lower-risk patients (table 1).

Safely reducing procedure or imaging volumes also potentiates cost savings to health systems and patients alike. In our recent study, we aimed to quantify how the 2020 AUA hematuria guidelines may influence costs by modeling these changes in a large urban public health care system.⁶ By retroactively applying the 2020 guidelines, we risk-stratified nearly 4,000 patients with hematuria not explained by an alternative etiology (urinary tract infection, urolithiasis, prior urological malignancy etc) and modeled the recommended changes to diagnostic volumes. Using data from the CMS (Centers for Medicare and Medicaid Services) Medicare Physician Fee Schedule and Clinical Laboratory Fee Schedule for 2020 localized to the clinical study sites, cost data were calculated. For comparison, modeling was also performed based on the prior hematuria guidelines published in 2012.

Table 1. Summary of 2020 MH guidelines.

*Risk factors: irritative voiding symptoms, chronic indwelling Foley catheter, pelvic radiation, chemotherapy (eg cyclophosphamide), occupational exposures (eg rubber, petrols, dyes), relevant family history of malignancy and/or Lynch syndrome.
^†Guidelines recommend repeating urinalysis for low-risk patients in 6 months. If repeat urinalysis is positive, patient is re-risk-stratified. The 2012 MH guidelines recommended cystoscopy and CTU for patients ≥35 years with ≥3 RBCs/hpf. Patients <35 years were recommended to undergo workup if risk factors were present.

RBC, red blood cell. UA, urinalysis. RUS, renal ultrasound.

Total costs attributed to the study population were $1,905,236 (2012) vs $1,260,677 (2020), a cost savings of $644,558 using the new guidelines (see figure). Major cost savings were a consequence of performing 1,713 fewer computerized tomography urograms (CTUs) since these are not part of the new guidelines for low- and intermediate-risk patients. While this represented a 57% decrease in CTUs performed based on 2020 guidelines compared to 2012 guidelines, CTUs still made up 44% of total costs in 2020.

Targeting imaging as a major driver of costs is well elucidated in an analysis of national data sets conducted by Halpern et al.⁷ By comparing UCC detection methodologies, a protocol of cystoscopy and renal ultrasound was determined to be most cost effective without sacrificing diagnostic sensitivity. The incremental cost per cancer detected was $53,810 (per 10,000 patients), whereas a protocol of cystoscopy with computerized tomography detected only 1 additional UCC diagnosis, with an incremental cost per cancer detected of $6,480,484 (per 10,000 patients).

Figure. Total costs for workup after hematuria diagnosis, by guideline recommendations. Itemized costs for components of workup as recommended by AUA guidelines published in 2012 vs those published in 2020. Although the 2020 guidelines encapsulate a larger number of patients (3,789 vs 3,189), total costs and per-patient costs are lower based on the 2020 recommendations for subsequent diagnostic studies and procedures. Per-procedure costs based on CMS data are listed on the right. UA, urinalysis. RUS, renal ultrasound.

A significant barrier to effective diagnosis of UCC is poor referral rates to a urologist for workup. Hematuria is often diagnosed in primary care or emergency department settings, and patients are reliant on these providers to decide when hematuria warrants referral. This scenario is often made more complex by confounding factors such as urinary tract infections, kidney stones or benign prostatic enlargement. It is unclear to what degree primary care or emergency providers would be familiar with hematuria guidelines and effectively identify high-risk patients.

In reviewing the clinical outcomes in our study cohort, we found that a mere 12% of patients with hematuria were referred to the urology service, including only 17% of high-risk patients (table 2).⁶ Several large clinical studies report on poor urology referral rates for hematuria, with the most striking seen in a study by Loo et al in which only 2.5% of over 510,000 hematuria patients were seen by a urologist.^5,8,9 Certainly, further efforts should focus on identifying and eliminating barriers to urological evaluation.

Table 2. Rate of urology referrals with subsequent outcomes.

High-risk patients were referred to urology at significantly greater rates than intermediate- or low-risk patients. High-risk patients also underwent cystoscopy and upper-tract delayed-phase imaging at significantly greater rates. Ultimately, high-risk patients were diagnosed with UCCat significantly greater rates, as well. HiR, high risk. LiR, low risk. InR, intermediate-risk. MRU, magnetic resonance urogram.

With risk stratification ascribing less intense diagnostic workups to lower-risk patients, the question of whether this will result in missed disease is valid. Woldu et al examined a multinational cohort of patients with hematuria and retrospectively risk-stratified these patients according to the 2020 guidelines.¹⁰ Upon review, 98% of bladder cancer cases were high risk, while only 0.4% were low risk. Similarly, in our study, all patients with UCC were either intermediate-risk (16%) or high-risk (84%) cases. Risk stratification appears to appropriately identify patients at greatest risk for malignancy, but the benefits of this process—namely detecting malignancy while limiting workup morbidity and cost—are hindered by modest referral rates.

In summary, the 2020 AUA MH guidelines continue to provide effective diagnostic instruction by prioritizing more invasive and costly workups for the patients at greatest risk for UCC. In particular, reserving computerized tomography imaging for high-risk patients can drive dramatic cost savings without loss of diagnostic performance. Realization of these benefits is reliant on correct adoption of the guidelines, which will require coordination between referring providers and urologists. Otherwise, patients will continue to undergo invasive and costly procedures without demonstrated improvements to UCC diagnosis.