Management of Atypical Glandular Cells (AGC) on Pap Smear

Initial Evaluation and Diagnosis

The National Comprehensive Cancer Network (NCCN) recommends that all patients with AGC require immediate colposcopy with endocervical curettage (ECC) and HPV DNA testing as the initial evaluation 1, 2, 3
AGC is associated with clinically significant lesions in 45% of patients, including cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), cervical cancer, and endometrial/ovarian/fallopian tube cancers 2, 3
3% to 17% of women with AGC have invasive cancer 2, 3
HPV DNA testing alone is not appropriate for initial triage of AGC 1, 2
Repeating cervical cytology is not appropriate for initial triage of AGC 1, 2

For patients ≥35 years or any age with risk factors, the NCCN recommends adding endometrial biopsy to colposcopy + ECC + HPV DNA testing 1, 2, 3, 4
Endometrial cancer risk factors include obesity, unopposed estrogen replacement therapy, polycystic ovarian syndrome, tamoxifen therapy, anovulation, hereditary nonpolyposis colorectal cancer syndrome (HNPCC), and abnormal bleeding 1, 2, 4

If colposcopy/biopsy reveals CIN I with negative ECC, the NCCN recommends conservative management with repeat cytology every 6 months until 2 consecutive negatives, or HPV DNA testing at 12 months 1, 5
If CIN II or III is identified, the NCCN recommends loop electrosurgical excision procedure (LEEP) or Cold Knife Conization (CKC) 1, 5
If AIS or "AGC favor neoplasia" is identified, the NCCN recommends CKC, which is preferred over LEEP, and follow-up with endometrial sampling and referral to a gynecologic oncologist 1, 5

The NCCN explicitly states that HPV testing alone should never be relied upon for AGC triage, as it may miss glandular lesions that are HPV-negative or in hard-to-sample areas 1, 2
Repeating cytology as initial management should never be done, as it delays diagnosis of potentially invasive disease 1, 2
Endometrial biopsy should never be skipped in patients ≥35 years, as it may miss endometrial cancers 1, 2

Transvaginal ultrasound is recommended to assess the endometrium when endometrial sampling is technically difficult or yields insufficient tissue in postmenopausal patients with AGC and abnormal uterine bleeding. 6

If transvaginal ultrasound cannot fully visualize the endometrium because of patient‑related factors, magnetic resonance imaging with diffusion‑weighted sequences should be used to delineate the endometrial cavity and help differentiate benign from malignant lesions. 6

In postmenopausal women presenting with AGC and abnormal uterine bleeding, endometrial adenocarcinoma is the most serious potential diagnosis and must be ruled out through appropriate imaging and tissue sampling. 6

Pelvic pressure symptoms in this population may suggest an underlying structural abnormality; therefore, imaging (ultrasound or MRI) should be considered when initial colposcopic, endocervical, and endometrial biopsies are non‑diagnostic. 6