What is the next step in management for a female of reproductive age with a history of cervical intraepithelial neoplasia (CIN) 3, who is human papillomavirus (HPV) negative after a loop electrosurgical excision procedure (LEEP), and now presents with hematuria and epithelial squamous cells in her urine?

Management of Post-LEEP CIN 3 with HPV-Negative Status and Urinary Findings

The presence of hematuria and squamous epithelial cells in urine after LEEP for CIN 3 requires immediate cystoscopy to rule out bladder involvement, which would indicate stage IVA cervical cancer rather than residual CIN. 1

Immediate Diagnostic Evaluation

Cystoscopy is Mandatory

• Cystoscopy must be performed urgently when a patient with recent CIN 3 treatment presents with hematuria, as this suggests possible bladder mucosal infiltration that would upstage disease to at least stage IVA cervical cancer. 1
• The presence of squamous epithelial cells in urine after cervical procedures is particularly concerning, as these cells are not normally present in bladder mucosa and may indicate extension of cervical pathology. 1
• If bladder infiltration is confirmed histologically during cystoscopy, this represents stage IVA disease requiring immediate referral to gynecologic oncology for cervical cancer management protocols, not CIN follow-up. 1

Critical Distinction: CIN vs. Invasive Disease

• True CIN 3 is by definition non-invasive (preinvasive disease); any microinvasion (≤3mm stromal invasion) or frank invasion indicates cervical cancer, not CIN, and requires complete staging workup including cystoscopy. 1
• The LEEP specimen pathology must be carefully reviewed to confirm no invasion was present, as up to 7% of CIN 2/3 cases harbor occult microinvasive or invasive carcinoma. 2

Management Algorithm Based on Cystoscopy Results

If Bladder Involvement is Confirmed

• Immediate referral to gynecologic oncology for stage IVA cervical cancer management is required. 1
• Treatment shifts from excisional procedures to definitive chemoradiation therapy. 1
• Further excisional treatment (repeat LEEP or conization) is contraindicated once invasion is confirmed. 1

If No Bladder Involvement is Found

The hematuria and squamous cells may represent:

• Contamination from the cervix during clean catch collection
• Benign urinary tract pathology requiring separate urologic evaluation
• Post-LEEP healing changes

Proceed with standard post-LEEP CIN 3 surveillance protocols as outlined below. 3

Standard Post-LEEP Surveillance (If No Invasion Confirmed)

HPV-Negative Status is Reassuring

• The HPV-negative result is highly predictive of successful treatment, with studies showing 100% negative predictive value for high-grade lesions when HPV testing is negative 6 months post-treatment. 4
• Women who become HPV-negative after LEEP have essentially no risk of recurrent/persistent CIN, whereas 46-73% of those remaining HPV-positive develop recurrent disease. 3

Recommended Follow-Up Schedule

Follow-up should consist of cervical cytology at 6-month intervals or HPV DNA testing at 12 months post-treatment. 3

• For patients with negative margins on LEEP specimen: cervical cytology at 6 months OR HPV DNA testing at 12 months is recommended. 3, 2
• Continue surveillance with cytology every 6 months until 2-3 consecutive negative results are obtained. 3
• After 2 consecutive negative cytology results or 1 negative HPV test at 12 months, patients may resume regular screening schedules. 3

Margin Status Considerations

• If LEEP margins were positive for CIN 3: cervical cytology at 6 months with consideration of endocervical curettage (ECC) is recommended, and re-excision should be considered if invasion is suspected. 3, 2
• Up to 40% of LEEP procedures have positive margins, but most women with involved margins remain disease-free on follow-up. 3
• Positive margins are not an independent predictor of residual disease when adjusted for other factors. 3

Common Pitfalls to Avoid

• Never dismiss hematuria in a post-LEEP patient without cystoscopic evaluation, especially when squamous cells are present in urine, as this may represent occult invasive disease. 1
• Do not assume HPV-negative status alone excludes all risk; continued surveillance is mandatory as recurrent disease can occur years after treatment. 3
• Avoid hysterectomy as primary treatment for recurrent CIN 3; repeat excision is preferred unless other gynecologic indications exist. 3
• Do not perform repeat conization based solely on positive HPV testing without cytologic or colposcopic abnormalities. 2

Long-Term Risk Considerations

• The risk of invasive cervical cancer after treatment for CIN remains elevated compared to the general population for many years (5.8 per 1000 at 8 years vs. 0.08 per 1000 in general population). 3
• Recurrence rates for CIN after treatment range from 1-21%, with lesion size being an important determinant. 3
• Indefinite surveillance is required, as recurrent disease can manifest many years after initial treatment. 1