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Urology Update

The evolving landscape of diagnosing urothelial carcinoma: Refining pathways using noninvasive biomarker testing

Hematuria is one of the most common presenting complaints in primary, emergency and specialist care practices, accounting for 6% of new patient presentations seen by urologists.1 While it is most commonly attributable to benign causes, hematuria can signal the presence of underlying urothelial carcinoma (UC), an association that underscores the importance of meticulous risk stratification and triage for further evaluation.

Currently, evaluation with cystoscopy and imaging is the mainstay for definitive evaluation for UC. This algorithm represents a potential barrier to a complete work-up, given hesitation amongst providers and patients to undergo potentially nondiagnostic procedures. The resulting delays in diagnosis and initiation of treatment could result in disease progression and worse prognoses in patients who do have cancer. A noninvasive test that is sensitive enough to detect most urothelial cancers — but specific enough to clear those who are cancer free — would represent a potential game changer in urologic oncology.

“There is an unmet need for an accurate noninvasive urinary biomarker test that can rule out patients without cancer and identify patients at greatest risk of UC,” said Jay Raman, MD, FACS, professor and chair of the Department of Urology at Penn State Health Milton S. Hershey Medical Center.

“Such a test would have high clinical utility by reducing the diagnostic burden on individuals without UC and prioritizing evaluation for those at risk of more advanced UC.”

Fortunately, such a test may very well be within reach for providers worldwide. An international team of investigators led by Raman recently conducted a robust study to validate the Cxbladder (Cxb) family of tests designed by Pacific Edge Limited, a New Zealand cancer diagnostics company. The tests combine clinical and phenotypic data with genomic biomarkers in urine to stratify patients based on the risk of having UC. The investigators examined the Cxb tests in a U.S. patient cohort, which resulted in a promising “report card” for Cxb, as summarized in a recent publication in the Journal of Urology.2

The Cxb family includes three unique tests: 1) Cxb Triage (CxbT), which has a high negative predictive value for identifying low-risk patients who may avoid unnecessary invasive investigations; 2) Cxb Detect (CxbD), which is highly sensitive and specific for identification of patients who require further work-up for UC; and 3) Cxb Resolve (CxbR), which has high accuracy for segregating test-positive patients likely to have high-impact tumors (HIT) with greater biologic aggressiveness.

Raman and colleagues performed a two-part study to determine diagnostic performance and then assessed the team’s newly designed algorithm — which combined all three tests — to determine which UC cases warranted further evaluation.

Evaluating the diagnostic performance of CxbR alone for identifying HIT

The first part of the analysis was performed in a cohort of 863 hematuria patients presenting in Australia, New Zealand and the United States. CxbR was found to have sensitivity of 92.4% and specificity of 93.8% for identifying patients with HIT who were considered higher priority for subsequent investigative testing.

Validating the efficacy of a new proposed algorithm incorporating all three tests (CxbT, CxbD and CxbR) to diagnose UC as confirmed by histopathologic sampling

In this part of the analysis, the proposed Cxb algorithm whereby positive tests reflexed to additional tests (CxbT+ >> CxbD+ >> CxbR) was validated in a cohort of 548 hematuria patients in the United States. The researchers report that sequential Cxb tests correctly ruled out further work-up in 87.6% of patients (negative predictive value of 99.4%). In both studies, all patients with HIT were correctly assigned to prioritize evaluation. Only three low-grade tumors were missed.

Raman said these study findings present additional resources to improve the diagnostic yield for patients with hematuria. Specifically, the Cxb family of tests demonstrates high sensitivity and specificity with potential incremental diagnostic yield (4.8-fold higher) than that obtained with conventional testing, based on stratification as recommended by commonly used society guidelines.

“Cxb’s high level of clinical resolution to rule out patients without UC and prioritize others is likely to reduce referral time and enable specialist resources to be focused on patients most likely to have UC, providing a clinically meaningful benefit and reducing the cost of care,” Raman concluded. “A positive result prioritizes patients for work-up, potentially obviating the need for flexible cystoscopy and fast-tracking patients for transurethral resection of the bladder tumor.”

The full study manuscript is available in the Journal of Urology.

A head-and-shoulders photo of Jay D. Raman, MD

Jay D. Raman, MD

Chair, Department of Urology
Professor, Department of Urology
Professor, Department of Surgery, Penn State Cancer Institute
Head, Robotic Surgery
Phone: 717-531-8887
Fellowship: Urology, University of Texas Southwestern Medical Center, Dallas
Residency: General Surgery, New York-Presbyterian Weill Cornell Medical Center, New York; Urology, New York-Presbyterian Weill Cornell Medical Center, New York
Medical School: Weill Cornell Medicine/Cornell University, New York
Connect with Jay D. Raman, MD, on Doximity


  1. Yafi FA, Aprikian AG, Tanguay S, Kassouf W. Patients with microscopic and gross hematuria: practice and referral patterns among primary care physicians in a universal health care system. Can Urol Assoc J. 2011;5(2):97-101. doi:10.5489/cuaj.10059
  2. Raman JD, Kavalieris L, Konety B, et al. The Diagnostic Performance of Cxbladder Resolve, Alone and in Combination with Other Cxbladder Tests, in the Identification and Priority Evaluation of Patients at Risk for Urothelial Carcinoma. J Urol. 2021;206(6):1380-1389. doi:10.1097/JU.0000000000002135

The Department of Urology at Penn State Health offers expert diagnosis and treatment of diseases and conditions involving the urinary tract. Our fellowship-trained surgeons and skilled advanced practice providers offer individualized care for cancer, kidney stones, infertility, impotence and other complex urologic concerns.

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