Abnormal Pap Smear with Negative HPV: Clinical Considerations

Non-HPV Infectious and Inflammatory Causes

Severe inflammation from other infections, such as trichomoniasis, bacterial vaginosis, or candidiasis, can produce atypical squamous cells without HPV present, and women with severe inflammation should be evaluated for specific infectious processes, treated appropriately, and undergo reevaluation after 2-3 months 1
Chlamydia trachomatis and gonorrhea can cause cervical inflammation leading to reactive cellular changes that appear abnormal on cytology 2, 3

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 4, 5, 2, 3
The degree of immune dysfunction (lower CD4 counts) correlates with increased abnormal cytology independent of HPV status 4, 5
HIV-infected women with symptomatic disease require more frequent Pap smear surveillance regardless of HPV status 4, 5

Specimens reported as unsatisfactory should be repeated, as they cannot reliably exclude disease 4, 5

Atypical glandular cells (AGC) may represent endocervical or endometrial pathology that is not HPV-related, and AGC requires colposcopy with endocervical sampling regardless of HPV status 6
For women ≥35 years with AGC, endometrial sampling is recommended even with negative HPV, as this may indicate endometrial pathology 6

For ASCUS with negative HPV, repeat HPV testing or cotesting in 12 months is recommended rather than immediate colposcopy, and if inflammation is present, treat underlying infection and repeat testing after 2-3 months 6, 1
For LSIL 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 6
For HSIL or ASC-H with negative HPV, colposcopy is mandatory regardless of HPV status, as these findings carry significant risk of high-grade disease, and do not delay colposcopy based on negative HPV results for high-grade abnormalities 6, 7
For AGC with negative HPV, colposcopy with endocervical sampling is required for all AGC regardless of HPV status, and endometrial sampling is needed for women ≥35 years 6

Women with previous abnormal Pap smears or history of cervical dysplasia require more frequent surveillance even with negative HPV 4, 5
Never use HPV results alone to determine management of high-grade cytologic abnormalities (HSIL, ASC-H), as these require colposcopy regardless of HPV status 6, 7

Women who have a normal cytology result and a negative high‑risk HPV test have a markedly lower risk of developing high‑grade cervical lesions compared with women who have abnormal cytology, providing a negative predictive value that justifies extending screening intervals. [8][9]
Even when the HPV test is negative, the detection of any cytologic abnormality on a Pap smear signals the presence of cellular changes that require appropriate follow‑up. [10][11]

In HPV‑negative ASCUS, the risk of progression to CIN 3 + is higher than the risk after a completely negative cotest, but it remains below the threshold that would mandate immediate colposcopy. 12

For women aged 30 years or older with HPV‑negative LSIL, management can follow the same conservative pathway as HPV‑negative ASCUS because the risk of high‑grade disease declines with age. 12

All women with high‑grade squamous lesions should undergo colposcopic evaluation and receive treatment as indicated, regardless of a concurrent negative HPV result. 12

When a Pap test is reported as satisfactory and negative but does not include a transformation‑zone component, it may be safely observed without an early repeat if the HPV test is negative, because the risk of CIN 3 + is not increased. 12