Abnormal Pap with Negative HPV: Significance and Management
An abnormal Pap test with negative high-risk HPV testing indicates a lower risk of high-grade cervical disease compared to HPV-positive abnormalities, but the specific management depends critically on the degree of cytologic abnormality—with high-grade lesions requiring immediate colposcopy regardless of HPV status, while low-grade abnormalities can be managed more conservatively with repeat testing. 1
Understanding the Clinical Significance
The combination of an abnormal Pap with negative HPV represents a discordant result that occurs in approximately 5% of screened women 2. This finding carries important prognostic implications:
Women with normal cytology and negative HPV have substantially decreased risk of high-grade lesions compared to those with abnormal cytology alone, with a negative predictive value that supports extended screening intervals 3
However, an abnormal Pap test—even with negative HPV—still requires appropriate follow-up, as it indicates cellular abnormalities were detected at the time of testing 3
The risk stratification depends on the specific cytologic abnormality: ASCUS, LSIL, ASC-H, HSIL, or atypical glandular cells (AGC) each carry different risks and require different management approaches 1
Management Algorithm Based on Cytologic Grade
For ASCUS (Atypical Squamous Cells of Undetermined Significance) with Negative HPV:
Repeat HPV testing or cotesting in 12 months is recommended rather than immediate colposcopy 1
If severe inflammation is present, treat the underlying infection (trichomoniasis, bacterial vaginosis, candidiasis, chlamydia, or gonorrhea) and repeat testing after 2-3 months 1
The risk of CIN3+ after HPV-negative ASCUS is higher than after negative cotesting but below the threshold for immediate colposcopy 3
For LSIL (Low-Grade Squamous Intraepithelial Lesion) with Negative HPV:
If negative HPV testing or cotest occurred within the previous 5 years, repeat HPV test with or without Pap in 1 year instead of immediate colposcopy 1
For older women (≥30 years) with HPV-negative LSIL, management can be the same as HPV-negative ASCUS due to decreased risk with age 3
Most LSIL cases resolve spontaneously, especially in younger women, as HPV infections are typically transient and cleared by the immune system within 1-2 years 4
For HSIL or ASC-H with Negative HPV:
Colposcopy is mandatory regardless of HPV status—these findings carry significant risk of high-grade disease 1, 5
Never delay colposcopy based on negative HPV results for high-grade abnormalities 1, 5
Treatment or colposcopy is indicated for all women with high-grade squamous lesions, regardless of HPV result 3
For AGC (Atypical Glandular Cells) with Negative HPV:
Colposcopy with endocervical sampling is required for all AGC regardless of HPV status 1
For women ≥35 years with AGC, endometrial sampling is recommended even with negative HPV, as this may indicate endometrial pathology unrelated to HPV 1
AGC may represent endocervical or endometrial pathology that is not HPV-related 1
Important Clinical Considerations
Non-HPV Causes of Abnormal Cytology:
Severe inflammation from infections (trichomoniasis, bacterial vaginosis, candidiasis, chlamydia, gonorrhea) can produce atypical squamous cells without HPV present 1
HIV-infected women have 10-11 times higher rates of abnormal cervical cytology compared to the general population, even in the absence of HPV, due to immune dysfunction 1
The degree of immune dysfunction (lower CD4 counts) correlates with increased abnormal cytology independent of HPV status 1
Technical and Sampling Issues:
Specimens reported as unsatisfactory should be repeated, as they cannot reliably exclude disease 1
Even Pap tests reported as satisfactory and negative but lacking a transformation zone component can be managed without early repeat if HPV is negative, as risk for CIN3+ is not increased 3
Critical Pitfalls to Avoid
Never use HPV results alone to determine management of high-grade cytologic abnormalities (HSIL, ASC-H)—these require colposcopy regardless of HPV status 1
Do not extend screening intervals without appropriate negative follow-up testing 5
Women with previous abnormal Pap smears or history of cervical dysplasia require more frequent surveillance even with negative HPV 1
HIV-infected women with symptomatic disease require more frequent Pap smear surveillance regardless of HPV status 1
Follow-Up After Initial Management
Once appropriate management is completed and subsequent testing normalizes:
Women can return to routine screening intervals once they have negative HPV tests or normal co-testing results 4
For women ≥30 years with normal Pap tests and negative HPV tests, screening intervals can be extended to 3 years (or 5 years with co-testing), provided subsequent tests have been normal 4
Prior LSIL is NOT a contraindication to routine co-testing or extended screening intervals once follow-up testing normalizes 4