Can Cervical Cancer Be Present with Abnormal Pap and Negative HPV?
Yes, cervical cancer can exist despite a negative HPV test, though this scenario is uncommon—the 5-year risk of high-grade precancer (CIN 3+) after an HPV-negative abnormal Pap ranges from 0.48% to 1.1% depending on the cytologic abnormality, which is approximately 4 times higher than after a completely negative cotest. 1, 2
Understanding the Risk Stratification
The absolute risk varies by the specific cytologic abnormality:
- HPV-negative ASC-US: 5-year CIN 3+ risk of 0.48–1.1%, which is significantly higher than the 0.11–0.27% risk after a negative cotest 1, 2
- HPV-negative LSIL: Similar elevated risk profile requiring enhanced surveillance 1
- The negative predictive value of HPV testing for HSIL is approximately 99.6%, meaning a small percentage of high-grade lesions can still be missed 3
Why This Discordance Occurs
Several biological and technical factors explain false-negative HPV results in the presence of cervical abnormalities:
- Cervical parakeratosis/hyperkeratosis is present in 87.8% of biopsy-proven LSIL cases with concurrent negative Pap tests, and causes an 83.3% HPV-negative rate by physically blocking access to infected cells 4
- Sampling inadequacy can result in insufficient cellular material for HPV detection, particularly when thick keratotic layers are present 4
- Non-HPV-related lesions including adenocarcinoma in situ and rare HPV-independent cancers can produce abnormal cytology without detectable HPV 5
- Approximately 14% of cytologically negative preparations associated with histologic HSIL contain no morphologically abnormal cells despite positive HPV, suggesting cytology has inherent sensitivity limitations 6
Recommended Management Algorithm
For Women ≥21 Years with HPV-Negative ASC-US:
The ASCCP recommends repeat cotesting (Pap + HPV) at 12 months rather than returning to routine 5-year screening 7, 1:
- If repeat cotest shows any cytologic abnormality (ASC-US or higher) OR positive HPV: refer immediately to colposcopy 7, 1
- If repeat cotest is negative for both: continue enhanced surveillance with cotesting every 3 years until adequate negative screening history is established 1
- Do not return to 5-year intervals after a single negative follow-up test 1
For Women ≥21 Years with HPV-Negative LSIL:
- Do not perform immediate colposcopy unless a visible cervical lesion is identified on examination 1
- Repeat cotesting in 1 year 1
- If repeat testing shows abnormality or positive HPV, proceed to colposcopy 1
- Continue 3-year cotesting intervals until adequate negative history is achieved 1
For Women ≥30 Years:
- The same management applies, but these women cannot discontinue screening at age 65 based on an HPV-negative abnormal result alone 1
- Must achieve either 2 consecutive negative cotests or 3 consecutive negative Pap tests before discontinuing screening 1
Critical Clinical Pitfalls to Avoid
- Never assume an HPV-negative result completely excludes disease when cytology is abnormal—the 4-fold increased risk compared to negative cotesting mandates enhanced surveillance 1, 2
- Do not perform immediate colposcopy for HPV-negative ASC-US or LSIL unless there is a visible lesion, as this represents over-treatment given the low absolute risk 7, 1
- Colposcopy has limited sensitivity for detecting all cervical lesions, so a negative colposcopic evaluation does not eliminate the need for continued surveillance 1
- Do not revert to 5-year screening intervals after HPV-negative abnormal cytology—3-year cotesting is required until adequate negative history is documented 1
- Be aware that thick keratotic plaques on the cervix should raise suspicion for sampling issues that could cause false-negative HPV results 4
Evidence Quality Considerations
The management recommendations are based on high-quality guidelines from ASCCP and NCCN 7, 1, supported by large prospective cohort data from Kaiser Permanente Northern California showing the elevated but manageable risk profile of HPV-negative abnormal cytology 2. The biological mechanisms explaining discordance are well-documented in pathology literature 4, 6, providing a strong rationale for the conservative but vigilant approach recommended by current guidelines.