In a 48‑year‑old woman with a low‑grade squamous intraepithelial lesion (LSIL) on Pap smear and a negative high‑risk human papillomavirus (HPV) test, does she have a risk of high‑grade dysplasia or carcinoma?

Risk of High-Grade Dysplasia or Carcinoma in LSIL with Negative HPV

This patient has a very low but measurably elevated risk of high-grade dysplasia or carcinoma—approximately 0.5-1% over 5 years—which is roughly four times higher than a completely negative cotest but still does not warrant immediate colposcopy. 1

Understanding the Risk Profile

The combination of LSIL cytology with a negative high-risk HPV test creates a paradoxical clinical scenario that requires careful interpretation:

• The 5-year risk of CIN3+ in HPV-negative LSIL ranges from 0.48% to 1.1%, compared to only 0.11-0.27% after a completely negative cotest 1
• This represents approximately a four-fold increase in risk despite the negative HPV result 2, 1
• However, the absolute risk remains low—only 2-4% of women with HPV-negative LSIL develop CIN3 or carcinoma within 2 years 3
• For comparison, HPV-positive LSIL carries a much higher risk of 13-19% for CIN3+ over the same period 3

Why HPV-Negative LSIL Occurs

The existence of HPV-negative LSIL is controversial and likely represents several distinct scenarios rather than a true biological entity:

• Cytologic misinterpretation is common—LSIL has poor inter-observer reproducibility and may represent morphologic mimics rather than true dysplasia 4, 3
• False-negative HPV testing occurs in 12-32% of initially HPV-negative LSIL cases when retested at 6 months 3
• Sampling adequacy issues are more common in women with larger cervical os, potentially missing HPV-infected areas 3
• HPV-independent lesions such as adenocarcinoma in situ can produce abnormal cytology despite negative HPV testing 1
• Women with HPV-negative LSIL tend to be older (>35 years) with fewer sexual partners, suggesting a lower-risk population 3

Recommended Management Algorithm

Do not perform immediate colposcopy unless a visible cervical lesion is identified on examination 2, 1. Instead, follow this pathway:

Initial Step (at 12 months):

• Repeat cotesting (Pap + HPV) in 1 year rather than returning to routine 5-year screening 2, 1

Decision Points at Follow-Up:

If repeat cotest shows ANY of the following:

• Any cytologic abnormality (ASC-US or higher), OR
• Positive HPV result (regardless of cytology)
• → Refer immediately to colposcopy 2, 1

If repeat cotest is completely negative (HPV-negative AND cytology-negative):

• → Continue enhanced surveillance with cotesting every 3 years (not 5 years) 2, 1
• Do not revert to routine 5-year intervals after a single negative test 1

For Women ≥60-65 Years:

• Cannot discontinue screening based on HPV-negative LSIL alone 2
• Must achieve either 2 consecutive negative cotests or 3 consecutive negative Pap tests before stopping screening 2
• The most recent test must be within the prior 5 years 2

Critical Pitfalls to Avoid

Never assume the negative HPV test is fully reassuring when cytology shows LSIL—the four-fold increased risk compared to negative cotesting mandates enhanced surveillance 1

Avoid immediate colposcopy for HPV-negative LSIL in the absence of a visible lesion—this represents overtreatment given the low absolute risk and would subject the patient to unnecessary procedures 2, 1

Do not return to 5-year screening intervals after a single negative follow-up test—continued 3-year cotesting is required until adequate negative screening history is established 2, 1

Recognize that a negative colposcopy does not eliminate the need for continued surveillance because colposcopy has limited sensitivity (can miss significant lesions) 2

Be aware that 12-32% of initially HPV-negative LSIL cases become HPV-positive within 6 months, suggesting either false-negative initial testing or new infection 3

Evidence Quality and Nuances

The management recommendations are derived from high-quality ASCCP and NCCN guidelines reflecting strong consensus 2, 1. The ALTS trial provided robust data showing that HPV-negative LSIL likely does not represent a distinct biological entity but rather a heterogeneous group requiring surveillance 3. More recent cohort data from Kaiser Permanente Northern California (>1 million women) confirmed the elevated but still low absolute risk, supporting the 3-year cotesting interval rather than immediate colposcopy 1.