What is the next step for a 36-year-old female with a Papanicolaou (Pap) test result showing atypical squamous cells of undetermined significance and atypical glandular cells, with a negative Human Papillomavirus (HPV) test?

From the Guidelines

For a 36-year-old female with a Pap test showing atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells (AGC) with negative HPV testing, the next step should be colposcopy with endocervical sampling. This procedure allows for direct visualization of the cervix and collection of tissue samples for further evaluation. The presence of atypical glandular cells is particularly concerning and warrants thorough investigation regardless of the HPV result, as they can indicate a significant squamous or glandular lesion up to 38 percent of the time 1. During colposcopy, the physician will apply acetic acid and iodine solutions to highlight abnormal areas and take targeted biopsies. Endocervical curettage should also be performed to evaluate the endocervical canal, as glandular abnormalities may represent more significant pathology including adenocarcinoma in situ or invasive adenocarcinoma, which can occur even with negative HPV testing 1.

Some key points to consider in the management of AGC include:

• The finding of AGC on cervical cytology is associated with a clinically significant lesion in 45% of patients, including CIN, cervical adenocarcinoma in situ (AIS), cervical cancer, and endometrial, ovarian, and fallopian tube cancers 1
• CIN is the most common finding; 3% to 17% of women have invasive cancer 1
• Reflex HPV DNA testing or repeat cytology is unacceptable as initial triage of atypical glandular cells–not otherwise specified (AGC-NOS), AGC–favor neoplasia, or adenocarcinoma in situ (AIS) 1
• If the initial evaluation of AGC is unremarkable, cytology and HPV testing should be repeated in six months if HPV testing is positive, and at 12 months if HPV testing is negative 1

The combination of ASCUS and AGC increases the risk of underlying significant pathology, making immediate colposcopic evaluation the appropriate management strategy rather than repeat cytology or observation. This approach is supported by the most recent guidelines, which emphasize the importance of thorough evaluation and follow-up for women with AGC, regardless of HPV status 1.

From the Research

Next Steps for Atypical Squamous Cells of Undetermined Significance and Atypical Glandular Cells

• The patient has a Papanicolaou (Pap) test result showing atypical squamous cells of undetermined significance and atypical glandular cells, with a negative Human Papillomavirus (HPV) test.
• According to the study 2, a diagnosis of atypical glandular cells of undetermined significance (AGUS) requires an aggressive workup because of the high rate of cancer and precancerous lesions.
• The evaluation should include:
  • Colposcopy with directed biopsies
  • Endocervical curettage
• Postmenopausal patients, those with irregular bleeding, and those with high-risk characteristics should also undergo endometrial biopsy 2, 3.
• The study 3 suggests that colposcopy and directed biopsy, endo-cervical curettage, and endometrial biopsy should be performed on all women with AGUS, especially those above the age of 40 years, menopause, or having abnormal vaginal bleeding.
• The study 4 found that a significant percentage of postmenopausal patients with AGUS were found to have clinically significant lesions on subsequent follow-up, including endometrial adenocarcinoma and high-grade squamous intraepithelial lesions.
• The study 5 found that age and prior history of squamous dysplasia can be useful in evaluating AGUS specimens, and that certain tissue fragment cytomorphologic features can be associated with specific histologic diagnostic categories.
• Although the patient has a negative HPV test, the study 6 suggests that high-risk HPV-positive status is associated with clinically significant disease, and that ASC-H is associated with a higher risk of cervical intraepithelial neoplasia (CIN) II/III.

Considerations for the Patient's Age and HPV Status

• The patient's age (36 years) and negative HPV status should be taken into consideration when determining the next steps for evaluation and management 5, 6.
• However, the presence of atypical glandular cells and atypical squamous cells of undetermined significance still requires further evaluation, regardless of the patient's age and HPV status 2, 3, 4.