What is the recommended follow-up interval for a Pap smear in a patient with Atypical Squamous Cells of Undetermined Significance (ASC-US) and a negative Human Papillomavirus (HPV) test result?

From the Guidelines

For a patient with Atypical Squamous Cells of Undetermined Significance (ASC-US) on Pap smear but negative HPV testing, the recommended follow-up is a repeat co-testing (both Pap and HPV test) in 3 years. This recommendation is based on the most recent and highest quality evidence available, which suggests that the risk of precancer and cancer after an HPV-negative ASC-US result is higher than that after negative cotesting, but still relatively low 1. The American Cancer Society and other organizations have updated their guidelines to reflect this new evidence, recommending a 3-year follow-up interval for women with ASC-US and negative HPV results 1.

The negative HPV test is reassuring because most cases of cervical cancer are caused by persistent high-risk HPV infection. Without the presence of high-risk HPV, the abnormal cells found on the Pap test are less likely to progress to more serious conditions. ASC-US represents minor cellular changes that often resolve on their own without treatment. If the patient has other risk factors such as immunosuppression or previous history of high-grade lesions, more frequent follow-up might be warranted, but for most patients with ASC-US/HPV-negative results, the 3-year interval is considered safe and appropriate.

Key points to consider in this recommendation include:

• The risk of CIN3 or greater (CIN31) after an HPV-negative ASC-US result is low, but higher than that of women with a negative cotest result 1
• The risk of cervical cancer is also higher in women with HPV-negative ASC-US results compared to those with negative cotest results 1
• The 3-year follow-up interval is recommended based on the analysis of over 1.1 million women from the KPNC data set 1 and additional analyses by Gage et al. 1

From the Research

Management of Atypical Squamous Cells of Undetermined Significance (ASC-US) with Negative HPV

• The management of ASC-US with negative HPV is a topic of interest in the field of cervical cancer screening.
• A study published in 2014 2 found that the 5-year risk of cervical intraepithelial neoplasia of grade 3 or higher (CIN3+) and cervical cancer after an HPV-negative/ASC-US result was closer to the risks after a negative Pap test result than after a negative cotest.
• The study suggests that women testing HPV negative/ASC-US should be managed similarly to women testing negative on Pap tests, with a recommended 3-year return for screening.
• Another study published in 2008 3 discussed the use of HPV DNA testing in the triage of equivocal smears, including ASC-US, and found that HPV DNA testing can be useful in identifying women at higher risk of cervical cancer precursors.
• However, the study also noted that there are still issues regarding how best to use HPV DNA testing in primary screening, and that the management of ASC-US with negative HPV should be individualized based on the patient's risk factors and medical history.

Risk of Progression to Dysplasia

• A study published in 2012 4 found that the risk of progression to dysplasia in women with ASC-US and positive HPV DNA testing varied by age, with the lowest risk among women between the ages of 41-50.
• Another study published in 1998 5 found that the sensitivity and specificity of repeat Pap smear and HPV DNA testing for detecting CIN 2/3 in women with ASC-US or low-grade squamous intraepithelial lesion (LSIL) Pap smear reports were variable, and that colposcopy examination was necessary to detect high-grade cervical precancerous lesions.
• A study published in 2019 6 found that the overall cervical intraepithelial neoplasia 2 and above (CIN2+) detection rate in women with ASC-US Pap test findings was 7.87%, and that the CIN2+ lesion was found in 13.98% of women with ASC-US Pap/HPV-positive test results, significantly higher than in women with ASC-US Pap/HPV-negative test results.

Recommendations for Follow-up

• Based on the available evidence, it is recommended that women with ASC-US and negative HPV should have a follow-up Pap test in 3 years, as suggested by the study published in 2014 2.
• However, the management of ASC-US with negative HPV should be individualized based on the patient's risk factors and medical history, and may involve more frequent follow-up or additional testing, such as colposcopy or HPV DNA testing.