Urine Cytology

Urine cytology examines cells shed from the lining of the urinary tract for malignant cells. The urothelium lines the renal pelvis, ureters, bladder and proximal urethra, and tumours at any of these sites shed cells into the urine.

It is used to diagnose and monitor urothelial carcinoma, and it complements cystoscopy, which remains the main test. It is most sensitive for high grade tumours and carcinoma in situ, and least sensitive for low grade papillary tumours, whose cells look almost normal.

The test needs a fresh voided sample, or a catheter or bladder wash specimen. The report is available in 2 to 5 days.

Sensitivity is about 80 to 90% for high grade urothelial carcinoma and only 10 to 20% for low grade tumours. Specificity is over 95%, so a positive report is reliable. Structured reporting categories class results by the risk of high grade disease.

Indications.

• Visible or non-visible haematuria, with cystoscopy and imaging, in adults at risk of bladder cancer (age over 40, smoking, occupational exposure).
• Surveillance after treatment of bladder cancer, particularly high grade disease and carcinoma in situ.
• Suspected carcinoma in situ (irritative voiding symptoms with sterile pyuria).
• Upper tract lesions seen on imaging, using ureteric washings and brushings.
• Monitoring of patients with high occupational risk (dye and rubber industries).
• Cytology of urinary diversions and neobladders.

Not indicated as a screening test for bladder cancer in healthy people, or as the only test for haematuria, since a negative result does not exclude a tumour.

Contraindications and precautions.

• Urinary tract infection and haematuria with heavy inflammation obscure cells, so infection is treated first where possible.
• Instrumentation, catheterisation and recent stone passage produce reactive and clumped cells, which can mimic malignancy.
• Intravesical BCG or chemotherapy in the past weeks causes changes that confuse interpretation.
• First morning urine is not used, because cells degenerate in concentrated urine overnight.
• A small volume reduces cell yield.

Preparation and technique.

The patient provides a freshly voided mid-stream sample, ideally the second void of the morning, with good hydration beforehand. A volume of 30 to 100 mL is requested. Collection is repeated on 3 days to raise the yield.

Catheterised specimens and bladder washes (barbotage with saline during cystoscopy) give more cells and better preservation. Ureteric washings and brushings are obtained during ureteroscopy.

The sample goes to the laboratory without delay, or is kept at 4°C, or placed in an alcohol based preservative to stop degeneration. The laboratory spins the sample, and makes slides by cytocentrifuge or liquid based preparation.

Normal appearances.

The sample shows scattered urothelial cells, small and with round nuclei, superficial umbrella cells (which can be large, with many nuclei), squamous cells from contamination, red cells and a few neutrophils. The background is clean.

Interpretation.

• Negative for high grade urothelial carcinoma: no cells with the features of high grade tumour. This does not exclude a low grade tumour.
• Atypical urothelial cells: changes beyond reactive but short of suspicion for high grade carcinoma. Repeat cytology and cystoscopy are used.
• Suspicious for high grade urothelial carcinoma: a few cells with definite features, and not enough for a firm diagnosis. Cystoscopy and biopsy follow.
• High grade urothelial carcinoma: cells with a high nuclear to cytoplasmic ratio, hyperchromatic irregular nuclei, coarse chromatin and clumping, often with a necrotic background.
• Low grade urothelial neoplasm: cells in papillary fragments with a fibrovascular core and mildly enlarged nuclei, with low reliability for diagnosis.
• Other findings: squamous carcinoma (in schistosomiasis), adenocarcinoma, metastatic cells (prostate, colon, lymphoma), BK polyomavirus decoy cells in immunosuppressed and transplant patients, viral inclusions, fungal elements, and Schistosoma haematobium eggs.
• Benign changes: stones, catheter effect, treatment effect (radiation, chemotherapy, BCG), and instrumentation cause atypia that mimics cancer.
• Unsatisfactory: too few cells or poor preservation.

Critical values and findings needing immediate action.

• A report of high grade urothelial carcinoma or suspicion of it: urgent cystoscopy, imaging of the upper tract, and biopsy.
• Positive cytology with a normal cystoscopy: upper tract imaging, random bladder biopsies and prostatic urethra sampling, since carcinoma in situ or upper tract tumour may be present.
• Visible haematuria with clots and retention: urgent urological care, irrespective of cytology.

Limitations and artefacts.

• Low sensitivity for low grade papillary tumours means a negative report must not delay cystoscopy.
• Degeneration of cells in voided urine, especially if delayed or stored at room temperature.
• Inflammation, stones, instrumentation and treatment effects cause false positives.
• Hyperchromatic cells may be degenerate, and the report may use the atypical category.
• A voided sample may not represent the upper tract, and upper tract washings are less accurate.
• Tests such as fluorescence in situ hybridisation, nuclear matrix protein and other markers have higher sensitivity for low grade tumours and lower specificity, and they are adjuncts to cytology and cystoscopy.
• Cytology cannot stage disease or show invasion.
• Reporting varies between pathologists, so use of a defined reporting scheme improves consistency.

Special groups.

• Men and women with haematuria and risk factors: a complete evaluation of the upper and lower tract, whatever the cytology.
• Patients with prior bladder cancer: serial surveillance depending on the risk of recurrence, and more frequent testing for high grade disease.
• Transplant and immunosuppressed patients: BK virus decoy cells are common and reflect viral reactivation.
• Patients with neurogenic bladder or long term catheters: higher risk of squamous cancer and chronic inflammation, with more reactive cells.
• Women: contamination by vaginal cells is common, and a catheter sample helps.
• Regions: schistosomiasis causes terminal haematuria and squamous cell carcinoma of the bladder, so cytology is combined with microscopy for eggs and with cystoscopy. Where cystoscopy is limited, cytology with ultrasound is used for initial triage, though sensitivity is lower for low grade tumours.

Follow up tests.

• Cystoscopy with biopsy.
• Imaging of the upper tract (CT urography, MR urography, ultrasound).
• Ureteroscopy with washings and brushings.
• Fluorescence in situ hybridisation and other urine markers.
• Random bladder and prostatic urethral biopsies for carcinoma in situ.
• Urinalysis, urine culture, and urine microscopy for schistosome eggs.
• BK virus PCR in transplant patients.
• Staging imaging after a malignant diagnosis.
• Repeat cytology at the surveillance interval.