What does a result of Atypical Glandular Cells (AGC) on a Pap (Papanicolaou) smear indicate in a female patient between 21 and 65 years old with a history of cervical cancer screening?

What is AGC on a PAP Smear?

Atypical Glandular Cells (AGC) on a Pap smear is a cytologic finding that indicates abnormal glandular cells that cannot be definitively classified as benign or malignant, occurring in only 0.2% of cervical cytology samples, and is associated with clinically significant cervical or endometrial lesions—including high-grade dysplasia, adenocarcinoma in situ, or invasive cancer—in 38-56% of cases. 1, 2, 3

Clinical Significance and Risk Stratification

AGC represents a high-risk cytologic finding that demands immediate and comprehensive evaluation, as it carries substantially greater cancer risk than squamous abnormalities:

• Overall cancer risk: 3-17% of women with AGC have invasive cancer at diagnosis 2, 3
• Significant pathology: 38-56% of AGC cases are associated with clinically significant lesions including CIN 2/3, adenocarcinoma in situ (AIS), cervical adenocarcinoma, or endometrial/ovarian/fallopian tube cancers 1, 2, 3
• Cervical lesions: CIN is the most common underlying pathology, particularly in women younger than 35 years 1
• Endometrial lesions: 44% of significant lesions are endocervical in origin, while 56% are endometrial 3
• Asymptomatic presentation: 75% of patients with AGC are asymptomatic, including 67% of those with invasive endocervical adenocarcinoma and 56% with invasive endometrial adenocarcinoma 3

Mandatory Initial Evaluation

All patients with AGC require immediate colposcopy with endocervical sampling and HPV DNA testing—reflex HPV testing or repeat cytology alone is explicitly unacceptable as initial management. 1, 2, 4

The complete initial workup includes:

• Colposcopy with directed biopsies of any suspicious lesions after acetic acid application 2, 4
• Endocervical sampling using either endocervical curettage (ECC) or cytobrush 2, 4
• HPV DNA testing if not already obtained 1, 2, 4
• Endometrial sampling for women ≥35 years old OR any age with risk factors for endometrial cancer 1, 2, 4

Age-Based Endometrial Sampling Requirements

Endometrial biopsy, dilation and curettage (D&C), or hysteroscopy is mandatory for:

• All women ≥35 years old with AGC 1, 2, 4
• Women <35 years old with any of the following risk factors: 4
  • Unexplained vaginal bleeding
  • Chronic anovulation
  • Obesity
  • Unopposed estrogen therapy
  • Polycystic ovarian syndrome (PCOS)
  • Tamoxifen use
  • Hereditary nonpolyposis colorectal cancer syndrome (HNPCC)

Management Based on Initial Findings

If No Lesion Identified on Initial Evaluation

• HPV-positive patients: Repeat cytology combined with HPV DNA testing at 6 months 1, 4
• HPV-negative patients: Repeat cytology combined with HPV DNA testing at 12 months 1, 4
• HPV positivity predicts high risk: 20% of HPV-positive AGC patients have CIN 3 or cancer on biopsy 1

If Cervical Lesions Identified

• CIN 1 with negative ECC: Conservative management with repeat cytology every 6 months until 2 consecutive negatives, or HPV DNA testing at 12 months 2
• CIN 2 or CIN 3: Loop electrosurgical excision procedure (LEEP) or cold knife conization (CKC) 2
• Adenocarcinoma in situ (AIS) or "AGC favor neoplasia": Cold knife conization is preferred over LEEP, followed by endometrial sampling and referral to a gynecologic oncologist 2, 4

If Initial Evaluation is Negative or Unsatisfactory

A diagnostic excisional procedure may be required, especially if cytology review suggests an endocervical neoplastic process 1

Special Populations

Pregnant women should undergo identical initial evaluation except that endocervical curettage and endometrial biopsy are contraindicated 4

Critical Pitfalls to Avoid

• Never rely on HPV testing alone for AGC triage—it may miss glandular lesions that are HPV-negative or in hard-to-sample areas 2
• Never repeat cytology as initial management—this delays diagnosis of potentially invasive disease 2
• Never skip endometrial biopsy in patients ≥35 years, as it may miss endometrial cancers 2
• Never underestimate AGC findings—even with negative HPV testing, the risk of significant disease remains substantial 5
• Do not treat AGC like ASCUS—AGC carries far higher cancer risk and requires more aggressive initial evaluation 6