In 2022, over 600,000 individuals worldwide were diagnosed with bladder cancer, making it the ninth most common type of cancer in the world1. In the United States, an estimated over 83,000 individuals will be diagnosed with bladder cancer in 2024, comprising 4.2% of all new cancer diagnoses2. The majority of bladder cancer diagnoses are of the urothelial carcinoma subtype with between 70 and 80% of the urothelial subtype diagnosed as non-muscle invasive bladder cancer (NMIBC)3,4. NMIBC is typically associated with high rates of disease recurrence, potential progression to muscle invasive disease, and a significant impact on patient quality of life4,5. Muscle-invasive bladder cancers (MIBC) are significantly more aggressive than NMIBC with a 5-year survival of around 60%6. Due to its propensity to metastasize, MIBC is often managed with systemic therapy in addition to surgical management with radical cystectomy or alternative bladder preservation therapies4,7,8. Most patients with bladder cancer initially present with asymptomatic microscopic hematuria or gross hematuria. The resulting diagnostic work-up is dependent on the patient’s risk of bladder cancer and alternative benign causes for the hematuria and classically employs a combination of cystoscopy and urinary tract imaging9,10.

Cystoscopy remains the gold standard in the initial diagnosis and surveillance of bladder cancer. Modern cystoscopy practice predominantly employs a flexible camera that is inserted into the urethra and uses white light to visualize the urinary bladder and evaluate for bladder cancer. However, this white light cystoscopy can miss small papillary bladder tumors or flat urothelial tumors such as carcinoma in situ (CIS)9,11. To better identify these types of lesions, enhanced cystoscopy methods have grown in popularity. Narrow-band imaging cystoscopy employs two short wavelength light beams that penetrate into bladder tissue and assist in visualizing capillaries to better visualize the vascular networks in urothelial tumors12,13. Blue-light cystoscopy or fluorescent based photodynamic cystoscopy starts with intravesical administration of hexaminolevulinate. The hexaminolevulinate leads to accumulation of photoactive porphyrins in the mitochondria of bladder tumors. When exposed to the blue light employed during cystoscopy, this tissue fluoresces and leads to improved detection of tumors missed on white light flexible cystoscopy14,15. With the improved performance of these enhanced cystoscopic techniques, the American Urological Association (AUA) recommends employing these techniques when surveilling patients with a history of NMIBC who have a normal white light cystoscopy, but a positive urine cytology16.

From the first microscopic descriptions in the 1800s of cancer cells present in urine, urine cytology has evolved into a standard testing methodology in the evaluation for bladder cancer4,17. Currently, the AUA does not recommend the use of urine cytology in the initial evaluation for microhematuria, but does recommend for urine cytology to be performed in patients with risk factors for CIS or patients with persistent microhematuria and prior negative evaluations18. The AUA does not recommend the initial use of urine cytology due to its test performance as a test with primarily a high specificity, yet relatively lower sensitivity4. Urine cytology exhibits better performance characteristics for high-grade urothelial carcinoma (HGUC) when compared to low-grade urothelial carcinoma (LGUC). Urine cytology’s performance with LGUC has a sensitivity of 10-43.6% compared to a sensitivity of 50-85% for HGUC19. This is in comparison to the specificity of urine cytology, which has been reported as high as 99.8% in patients with non-visible hematuria20.

With its high specificity, urine cytology assessment is most frequently employed to surveil patients with history of high-grade bladder cancer as an adjunct screening tool along with surveillance cystoscopy21. While the majority of local recurrences of bladder cancer will be identified on routine surveillance cystoscopy, lesions that are more challenging to visualize (like CIS) or areas which are difficult to access, like the upper urinary tract, can still be diagnosed with urine cytology. Patients that receive urinary diversion following radical cystectomy for MIBC can also provide specimens for cytologic evaluation to evaluate for recurrent disease19.

In 2013, a standardized classification of urine cytology interpretation was proposed and later developed into The Paris System for Reporting Urinary Cytology (TPS). The intention of this system was to maintain urine cytology’s diagnostic excellence in identifying HGUC, in addition to reducing the number of atypical diagnoses that are issued on urine cytology specimens. TPS has since been adopted throughout the world as the standardized method of evaluating urine cytology17,22. A meta-analysis of TPS showed that the implementation of TPS led to a better correlation with histologic biopsy of bladder lesions and a reduction of atypical diagnoses23. TPS stratifies urine cytology interpretations into the following categories: non-diagnostic, negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells (AUC), suspicious for high-grade urothelial carcinoma (SHGUC), and high-grade urothelial carcinoma (HGUC). Each of these categories is associated with a certain risk of high-grade malignancy (ROHM), and this risk of malignancy is essential for clinicians to understand when interpreting urine cytology results and determining follow-up management for patients19.

Urine cytology also remains a useful tool in the management of patients with bladder cancer when leveraged as a mechanism to evaluate for recurrence of high-grade disease. TPS has provided cytopathologists with a standardized interpretation guide for urine cytology specimens and generated a standardized language for the reporting of these results. However, it is equally important to understand how the urologist takes TPS interpretations and makes clinical management decisions based on the risk stratification for high-grade malignancy placed in each category. This article reviews the current landscape of urine cytology interpretations using TPS and integrates a urologist’s perspective on clinical context and management of each of the TPS diagnostic categories.