What are the possible causes of an abnormal Pap (Papanicolau) smear result with no detected Human Papillomavirus (HPV)?

Reasons for Abnormal Pap Smear with Negative HPV

Abnormal Pap smear results without HPV detection can occur due to non-HPV causes of cellular changes, including inflammation, infection, immune dysfunction, inadequate sampling, or less commonly, glandular abnormalities and non-HPV-related neoplasia.

Non-HPV Infectious and Inflammatory Causes

• Severe inflammation from other infections can produce atypical squamous cells without HPV present, including trichomoniasis, bacterial vaginosis, or candidiasis 1
• 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 1

Immune Dysfunction and HIV

• 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
• HIV-infected women with symptomatic disease require more frequent Pap smear surveillance regardless of HPV status 1

Sampling and Technical Issues

• Inadequate or unsatisfactory specimens may yield false-negative HPV results while showing cellular abnormalities on cytology 2
• A negative HPV cotest in the setting of an unsatisfactory Pap test may reflect inadequate sampling rather than true HPV absence 2
• Specimens reported as unsatisfactory should be repeated, as they cannot reliably exclude disease 1

Glandular Cell Abnormalities

• Atypical glandular cells (AGC) may represent endocervical or endometrial pathology that is not HPV-related 3
• AGC requires colposcopy with endocervical sampling regardless of HPV status 3
• For women ≥35 years with AGC, endometrial sampling is recommended even with negative HPV, as this may indicate endometrial pathology 3

Low-Risk HPV Types and Testing Limitations

• Low-risk HPV types (6/11) can cause cellular changes including ASCUS and LSIL but are not detected by high-risk HPV testing 4
• Standard HPV testing targets only high-risk oncogenic types (particularly 16 and 18), missing low-risk types that can still cause cytologic abnormalities 4
• HPV testing has imperfect sensitivity and may miss some high-risk infections, particularly with low viral loads 5

Hormonal and Atrophic Changes

• Perimenopausal and postmenopausal women can have atrophic changes that mimic dysplasia on cytology without HPV infection 4
• Estrogen deficiency causes cellular changes that may be interpreted as atypical squamous cells 4

Clinical Management Algorithm

For ASCUS with negative HPV:

• Repeat HPV testing or cotesting in 12 months is recommended rather than immediate colposcopy 3
• If inflammation is present, treat underlying infection and repeat testing after 2-3 months 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 3

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 3, 6
• Do not delay colposcopy based on negative HPV results for high-grade abnormalities 6

For AGC with negative HPV:

• Colposcopy with endocervical sampling is required for all AGC regardless of HPV status 3
• Endometrial sampling is needed for women ≥35 years 3

Important Caveats

• HPV testing should not replace cytology as a stand-alone screening test, particularly in low-resource settings where combined testing detects more precancerous lesions 4
• The negative predictive value of HPV testing for HSIL is high (99.6%) but not absolute, meaning some high-grade lesions can occur without detectable HPV 2
• Women with previous abnormal Pap smears or history of cervical dysplasia require more frequent surveillance even with negative HPV 1
• Never use HPV results alone to determine management of high-grade cytologic abnormalities (HSIL, ASC-H), as these require colposcopy regardless of HPV status 3, 6