The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria


  • See referenced original article on pages 2641-50,this issue.

Urothelial bladder cancer is the fourth most common cancer diagnosed in males and the fifth most common cancer overall.1 Bladder cancer is typically diagnosed due to the presence of blood in the urine, but around 25% of patients already have muscle-invasive or metastatic disease at the time of diagnosis.1 Further compounding the problem in detection of bladder cancer is the fact that only 10% of patients with visible (“gross”) hematuria and 2% to 5% of patients with microscopic hematuria have bladder cancer.2, 3 Although these risks are not insignificant, identifying which patients have cancer is difficult because most patients with bladder cancer are asymptomatic at presentation. Furthermore, there is a very high prevalence of microscopic hematuria ranging from 9% to 18% in apparently normal individuals.2, 4, 5 If one were to evaluate every person with hematuria then there would be a very high rate of unnecessary testing.

The American Urologic Association best practice policy states “that patients at high-risk for bladder cancer (especially those with a history of smoking or chemical exposure) should be considered for a full urologic evaluation after one properly performed urinalysis documenting the presence of at least 3 red blood cells per high powered field.”4 “An initial finding of microscopic hematuria on urinary dipstick should be confirmed by microscopic evaluation of the urinary sediment.”4 “Patients in whom a carefully performed history suggests a ‘benign’ cause of their microscopic hematuria should undergo a repeated urinalysis after 48 hours. The evaluation for high risk patients should include cystoscopy, cytology and upper tract imaging.”6 A separate review of clinical practice recommendations for microhematuria recommended a repeat urinalysis for patients and no further evaluation if microscopic hematuria is absent on repeated testing in low-risk patients. If patients have risk factors for bladder cancer such as cigarette smoking or exposure to toxins then further evaluation with upper tract imaging and cytology and cystoscopy are recommended, especially for patients over the age of 50.7

There are few studies on the compliance of primary care physicians with these recommendations. These reports, which include surveys and reviews of hospital records, suggest that many patients, especially those with microscopic hematuria, do not get referred for evaluation by urologists.8-11 One possible way to improve early detection of bladder cancer is to identify individuals at higher risk for bladder cancer and select them for more thorough evaluation. Although age, gender, ethnicity, and smoking can identify some increase in risk, they are not sufficiently discriminating in predicting who has bladder cancer.12 Urine-based tumor markers may serve as adjunct noninvasive tests that will identify individuals at higher likelihood for bladder cancer. An extensive review of the literature and meta-analysis comparing bladder tumor markers with cytology found that urine-based bladder tumor markers were more sensitive than cytology, especially for low-grade and low-stage tumors but suffer from a lower specificity.13 Although there are several commercially available urine markers for detection of bladder cancer, their use is sporadic and not currently recommended by guideline panels.14, 15

The study by Abogunrin et al16 evaluates the impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria. This is a case-control study that focuses primarily on patients with gross hematuria. The study found that markers in combination improve prediction of bladder cancer presence over clinical variables such as age and smoking. Although such reports are promising, there are still numerous hurdles before proof of clinical utility. First, the test needs to be performed in a prospective fashion in all patients with hematuria. The case-control design enriches the population with cancer cases and increases the positive predictive value of the test. A population of patient with gross hematuria would more likely have around 10% cancer incidence and not 50%. As such, there is usually a decrease in specificity when larger populations of patients with gross hematuria are evaluated. Second, the test would need to be evaluated in patients with microscopic hematuria because they represent a much larger percentage of all patients with hematuria, and the risk for cancer is lower for patients with microscopic hematuria than gross hematuria. One might argue that regardless of a marker test, every patient with gross hematuria should be evaluated due to risk of the high risk of malignancy. The ability to identify which 2% of patients with microhematuria have cancer would be far more valuable. Third, the test may not be easily reproducible among other labs, and this would need to be verified in a multicenter study. Finally, the issue of cost is critical in today's health care environment and cost-effectiveness of the test would need to be demonstrated.

Nonetheless, the authors should be commended on their efforts. The need is great to reduce mortality from bladder cancer. In the absence of newer chemotherapeutic drugs to treat metastatic disease, the greatest hope for reducing bladder cancer mortality is earlier detection prior to muscle invasion and development of metastatic disease. There are several groups working on incorporation of markers into diagnostic algorithms, and hopefully this approach will yield sufficient evidence to justify widespread utilization.17


No specific funding was disclosed.


I am performing scientific studies supported by Abbott Inc., Alere Inc., and Danone Inc.

Conflicts of interest: none.