What is urine cytology?

What is Urine Cytology

Urine cytology is a laboratory test that examines exfoliated cells from the urinary tract (obtained from voided urine, bladder washings, or brushings) under a microscope to detect malignant or atypical urothelial cells, primarily used to identify high-grade bladder cancer and carcinoma in situ. 1

Purpose and Clinical Application

• Primary target: Urothelial (transitional cell) carcinomas, which are the most commonly detected malignancies in patients with microscopic hematuria 1
• Best performance: Detects almost all high-grade urothelial neoplasms with sensitivity ranging from 52.2% to 87.08% for high-grade tumors 2, 3
• Adjunct to cystoscopy: Particularly useful for detecting carcinoma in situ (CIS), which may be missed on visual inspection alone 1
• Surveillance role: Essential for monitoring all patients with urothelial neoplasms and can decrease the frequency of cystoscopy when used consistently 4

Specimen Collection Methods

The International Consultation on Urologic Disease (ICUD) recommends documenting both the anatomic site (bladder, urethra, ureter, or renal pelvis) and collection technique in the diagnostic report 1:

• Voided urine: Most useful type for routine diagnostic interpretation; freshly voided, randomly collected specimens are preferred 4
• Bladder washings/barbotage: May yield more and better preserved cells, but no significant difference in sensitivity or specificity compared to voided specimens 3
• Brushings: Alternative collection method for targeted sampling 1

Important caveat: Patients should not be catheterized solely to obtain diagnostic material 4

Diagnostic Performance Characteristics

Sensitivity and Specificity

• Overall sensitivity: 38.0% to 57.7% 5, 3
• High-grade tumors: Sensitivity improves to 78.3-87.08% after multiple samples 5, 2
• Specificity: 94.9% to 98.3% 5, 3
• Positive predictive value: 90.6% 3
• Negative predictive value: 78.6% to 98.7% 5, 3

Likelihood Ratios

• Positive likelihood ratio: 7.67 (moderate ability to increase post-test probability) 5
• Negative likelihood ratio: 0.35 (moderate ability to decrease post-test probability) 5

Reporting System and Diagnostic Categories

The ICUD recommends a standardized reporting format modeled after the Papanicolaou Society guidelines, similar to the Bethesda System for cervical cytology 1:

Diagnostic Categories for Epithelial Cell Abnormalities:

• Atypical urothelial cells of undetermined significance: Follow with repeat urine cytology 1
• Atypical urothelial cells, cannot rule out high-grade carcinoma or atypical urothelial cells, favor neoplasm: Require endoscopic evaluation 1
• Low-grade urothelial carcinoma: Lacks specific criteria; most cases included in atypical category 1
• High-grade urothelial carcinoma: Well-defined malignant features 1

Note: The Paris System for Reporting Urinary Cytopathology, proposed by the International Academy of Cytology in 2013, provides updated consensus guidelines 1

Clinical Indications

When to Order Urine Cytology:

• Risk-based approach: Recommended in all patients with risk factors for transitional cell carcinoma (smoking, occupational exposures, age >40, pelvic radiation) 1
• With hematuria: Can be useful adjunct to cystoscopy, especially for carcinoma in situ 1
• Surveillance: Monitoring patients with known urothelial neoplasms 4, 6
• Positive cytology with normal cystoscopy: Requires evaluation of upper tracts and prostate in men; ureteroscopy may be considered 1

AUA Guideline Recommendations:

• Strong recommendation (Grade C evidence): Do NOT routinely use urine cytology to decide whether to perform cystoscopy in low/negligible-risk or high-risk patients 5
• Intermediate-risk patients: Cytology may assist in informing cystoscopy decisions; negative cytology reduces post-test probability to 0.4% 5

Technical Considerations

Specimen Processing:

• Preservation: Refrigeration required to prevent bacterial growth and cellular degeneration; alcohol preservation unnecessary unless prolonged storage needed 4
• Processing methods: Membrane filtration displays cytologic details best; computer-programmed cytocentrifuge most popular 4
• Staining: Papanicolaou staining optimal for recognizing cytologic details; Romanovsky dyes less desirable 4

Diagnostic Criteria:

• Nuclear:cytoplasmic ratio: Cells with ratios of 1:2 or less should not be interpreted as malignant regardless of nuclear anaplasia 4
• Papillary aggregation: Not a reliable feature of low-grade neoplasia 4

Limitations and Pitfalls

• Low sensitivity for low-grade tumors: Cytologic interpretation of low-grade transitional cell neoplasia requires expertise; these cells lack many features of malignancy 4, 6
• Cannot replace cystoscopy: None of the currently available urinary markers can replace cystoscopy but are helpful for specific diagnostic problems 3
• Treatment effects: Alkylating agents (Cytoxan, thio-TEPA, mitomycin C) produce characteristic but nonspecific changes that rarely mimic carcinoma 4
• Differential diagnosis: Reactive/regenerative/reparative changes from urinary stones can almost always be distinguished from neoplasia using appropriate criteria 4

Adjunct Technologies

• FDA-approved biomarkers: Fluorescence in situ hybridization (FISH) or nuclear matrix protein 22 may be considered for monitoring recurrence 1
• Flow cytometry and image analysis: Used in selected centers; routine use awaits further refinements 4