What is the clinical significance of squamous, urothelial (transitional), and renal tubular epithelial cells found on urine microscopy?

Clinical Significance of Epithelial Cells in Urine

The presence of epithelial cells in urine primarily serves as a marker of specimen contamination rather than disease, with squamous cells indicating contamination from the distal urethra or genitourinary tract, while renal tubular epithelial cells may indicate upper urinary tract pathology requiring further evaluation. 1

Squamous Epithelial Cells

Squamous epithelial cells are the most common type seen in routine urinalysis and typically indicate specimen contamination rather than pathology. 1

• These cells originate from the distal urethra, bladder trigone, or cervicovaginal region during collection 1, 2
• When significant squamous cells appear alongside >10 WBCs or mixed bacterial flora, this strongly suggests specimen contamination rather than true pathology 2
• If clinical suspicion for urinary tract infection remains high despite contamination, obtain a catheterized specimen rather than treating based on the contaminated sample 1, 2
• Clean-catch specimens have 27% contamination rates versus only 4.7% for catheterized specimens 1
• Proper perineal cleansing before collection reduces contamination from 23.9% to 7.8% 1

Important Caveat

While squamous cells usually indicate contamination, atypical squamous cells in urine are rare and may indicate underlying malignancy including squamous metaplasia of the urothelium, cervicovaginal squamous intraepithelial lesions, or even endometrial adenocarcinoma with squamous differentiation 3. Careful evaluation of squamous cell morphology is warranted when cells appear atypical 3.

Urothelial (Transitional) Epithelial Cells

Urothelial cells arise from the urinary tract lining anywhere from the renal pelvis to the proximal two-thirds of the urethra, and when atypical, may indicate urothelial neoplasia requiring cytologic evaluation. 1

• More than 90% of urothelial tumors originate in the urinary bladder, 8% in the renal pelvis, and 2% in the ureter and urethra 4
• The International Consultation on Urologic Disease (ICUD) recommends standardized reporting using terminology similar to the Bethesda System for atypical urothelial cells 1
• Atypical urothelial cells should be substratified into two classes: (1) atypical urothelial cells of undetermined significance, and (2) atypical urothelial cells that cannot rule out high-grade carcinoma or favor neoplasm 1
• Voided urinary cytology is recommended in all patients who have risk factors for transitional cell carcinoma 4
• If malignant or atypical/suspicious cells are identified on cytology in patients with hematuria, cystoscopy is required 4

Renal Tubular Epithelial Cells (RTECs)

Renal tubular epithelial cells contain nephron-specific proteins and indicate upper urinary tract pathology, making their identification clinically significant. 1

• RTECs are clinically relevant and their differentiation from other epithelial cell types is important 5
• Most laboratories do not routinely differentiate epithelial cells into the three subtypes (squamous, transitional, and renal tubular) despite the clinical importance of RTECs 5
• When RTECs are present, evaluate for kidney disease by obtaining serum creatinine, calculating eGFR using the 2021 CKD-EPI equation (without race factor), spot urine protein-to-creatinine ratio, and examining for dysmorphic RBCs and casts 2
• Direct microscopic examination by trained personnel is essential for accurate identification, as automated urinalysis alone is insufficient 2

Practical Algorithm for Interpretation

1. Assess collection method first: Determine if specimen was clean-catch, catheterized, or bag collection 1
2. Quantify squamous epithelial cells: If abundant squamous cells with mixed bacterial flora are present, consider the specimen contaminated 1, 2
3. Recollect if contaminated and clinical suspicion remains: Use catheterization for reliable results (95% sensitivity, 99% specificity) 2
4. Evaluate urothelial cells for atypia: If atypical cells are present, obtain formal cytologic evaluation and consider cystoscopy 4, 1
5. Investigate RTECs thoroughly: If renal tubular cells are identified, evaluate kidney function and proteinuria 2