Atypical Squamous Cells (ASC) in Urine: Clinical Significance and Management
ASC in urine is a rare but clinically significant finding (occurring in only 0.15-0.3% of specimens) that warrants careful evaluation, as it carries a 25-31% risk of underlying malignancy, particularly squamous cell carcinoma of the bladder, urothelial carcinoma with squamous differentiation, or gynecologic malignancies. 1, 2
What ASC Represents
ASC refers to keratinizing squamous cells with abnormal features including:
- Large, hyperchromatic smudgy nuclei
- High nuclear-to-cytoplasmic ratio
- Abnormal nuclear or cytoplasmic shapes
- Densely orangeophilic cytoplasm 1
The diagnosis of ASC is made when there is insufficient qualitative or quantitative evidence for a definitive carcinoma diagnosis, but the cells are too atypical to be considered benign. 1
Risk Stratification Based on ASC Grade and Context
The risk of high-grade malignancy varies significantly based on two critical factors:
Grade of Squamous Atypia
- High-grade squamous atypia: 92% risk of malignancy 2
- Low-grade squamous atypia: 70% risk of malignancy 2
- Reactive changes or koilocytosis: 0% risk of malignancy 2
Presence of Accompanying Urothelial Cell Abnormality (UCA)
- ASC with accompanying UCA: 94% risk of malignancy 2
- ASC without accompanying UCA: 37% risk of malignancy 2
- When UCA is present, both low-grade and high-grade squamous atypia carry >90% risk of malignancy 2
Differential Diagnosis
Malignant Causes (31% of cases)
- Squamous cell carcinoma of the bladder (most common malignant cause) 1
- Urothelial carcinoma with squamous differentiation 3, 1
- High-grade cervical squamous cell carcinoma (6% of malignant cases in women) 1
- Endometrial adenocarcinoma with squamous differentiation (rare) 4
Benign Causes (69% of cases)
- Vaginal contamination in women (most common benign cause) 1
- Squamous metaplasia of the urothelium 4
- Exfoliation from distal urethra in men 1
- Reactive/inflammatory processes 1
Critical Management Algorithm
Immediate Actions
- Document the grade of squamous atypia and presence/absence of accompanying urothelial abnormalities in the cytology report 2
- Obtain detailed clinical history:
For Women with ASC
- Perform pelvic examination to exclude cervical squamous cell carcinoma 1
- Consider gynecologic evaluation even in absence of gynecologic symptoms, as cervical SCC can present with ASC in urine 1
Urologic Evaluation
Cystoscopy with biopsy is mandatory for:
Consider cystoscopy even when ASC are rare in the specimen, as 51% of malignancies showed only rare ASC in urine 2
Follow-up Strategy
- Prolonged clinical and histologic follow-up is essential, as ASC may precede a de novo diagnosis of malignancy or be the first sign of recurrence 1
- Serial urine cytology may be appropriate for low-risk patients (reactive changes only) with negative initial workup 2
Common Pitfalls to Avoid
- Do not dismiss ASC as contamination without proper evaluation, particularly when high-grade atypia or accompanying UCA is present 2
- Do not assume benign etiology based solely on absence of urinary symptoms, as malignancies can be asymptomatic 1
- Do not limit evaluation to urologic assessment in women—always consider gynecologic sources 1
- Do not overlook rare ASC in the specimen, as most malignancies (51%) present with only rare atypical cells 2
- Recognize that necrotic debris accompanying ASC may indicate malignancy in either bladder or non-bladder locations 3
Key Clinical Context
ASC in urine is fundamentally different from the Bethesda terminology for cervical cytology (ASC-US, ASC-H), which refers to cervical Pap test findings. 5 The presence of ASC in urine specifically indicates abnormal keratinizing squamous cells that require urologic and potentially gynecologic investigation rather than cervical cancer screening protocols.