Delayed Diagnoses of Cervical Intraepithelial Neoplasia and Cancer After Negative Evaluation for Atypical Glandular Cell Pap Smear

Does Age Matter?

Anthony F. Valdini, MD, MS, FACP, FAAFP; Carolyn L. Augart, MD, FAAFP; Michelle Olivieri, BBA


J Low Genit Tract Dis. 2013;17(4):390-396. 

In This Article

Abstract and Introduction


Objective: At initial evaluation, 1 in 6 women with atypical glandular cells (AGCs) on Pap smear has cervical intraepithelial neoplasia (CIN) or cancer. Years later, a greater-than-expected incidence of "significant delayed diagnoses" has been reported in women who had negative initial evaluation results. This study aimed to test the premise that AGC represents a lesser future risk for CIN 2/CIN 3/carcinoma in situ (CIS) and cancer after negative evaluation results in a population diagnosed at a young age (<35 years).

Materials and Methods: Cohort study consists of 43,000 community health center patients who had 83,542 Pap smears (1997–2010); 213 were diagnosed with AGC, and 117 met inclusion criteria. Completed evaluation was consistent with American Society for Colposcopy and Cervical Pathology guidelines without finding CIN 2/CIN 3/CIS or cancer. Follow-up lasted for longer than 1 year. Categorical data were evaluated with χ2.

Results: During the follow-up period that averaged for 85.3 months, the cohort had 4.5 mean Pap smears and reported 46 cytological diagnoses of low-grade squamous intraepithelial lesions, 3 diagnoses of high-grade squamous intraepithelial lesions, and 10 repeated diagnoses of AGCs. Two CIN 2/CIN 3/CIS lesions, 1 cervical cancer, and 1 endometrial intraepithelial neoplasia were confirmed on biopsy. Average age of patients at index Pap smear was 34.2 years (range = 15–64 years). Compared with a published report where the average age at index Pap smear was 41.5 years, our cohort developed a total of 4.3% significant delayed diagnoses versus 10.8% (significant difference, p = .046).

Conclusions: During a 7-year follow-up, this cohort of 117 women with AGC and negative initial evaluation findings developed fewer significant delayed diagnoses than expected when compared with an older reported group and had no new extragynecological cancers. Age seems to be a risk factor for delayed diagnoses in patients with AGC.


Atypical glandular cells (AGCs) are an uncommon yet potentially dangerous Pap smear diagnosis. AGC occurs in less than one-half percent of all Pap smears,[1] yet is associated with high-grade lesions or cancer in at least 1 in 6 women on initial workup.[2–5] In addition to high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ, and cancer of the endometrium, very rarely, extrauterine cancer (ovarian, colon, or breast) has been discovered on evaluation for an AGC index Pap.[6,7] Because of the frequent association of AGC with high-grade lesions at the time of abnormal Pap smear finding, it is recommended that women with a Pap smear diagnosis of AGC receive further investigation.

The 2006–2007 "Initial Workup of Women with Atypical Glandular Cells" suggested by the American Society for Colposcopy and Cervical Pathology (ASCCP) includes colposcopy with endocervical sampling, human papillomavirus (HPV) DNA testing for high-risk oncogenic types and endometrial sampling in patients older than 35 years or in women at risk for endometrial neoplasia, such as those with unexplained vaginal bleeding or conditions suggesting chronic anovulation. If the AGCs are described on pathology review as "atypical endometrial cells," then endometrial and endocervical sampling are recommended, with colposcopy to follow if no endometrial pathological result is found.[8]

Recently, in addition to the initial pathological examination discovered on workup of the index Pap smear, an increased incidence of cancers and high-grade lesions has been reported, years later, in women with a history of AGC. This increased incidence of delayed diagnoses of neoplasia and cervical intraepithelial neoplasia (CIN) occurred in women who had negative initial evaluation findings and included cancers of the breast and colon in addition to those of the cervix and endometrium.[9]

To add to the emerging literature on the natural history of AGC and significant delayed diagnoses, defined as cancer or histological CIN 2 or higher diagnosed at least a year after initial AGC evaluation, we present a series of women who were diagnosed with AGC at a younger age than those previously reported.[5,9] The series includes a subset of women who had repeated AGC Pap smears—a risk factor for future CIN 2/CIN 3/carcinoma in situ (CIS), compared with a single AGC Pap smear.[2,9] In addition, we report on the cohort's covariables of race and tobacco use, both of which may be associated with risk for delayed diagnoses. Most studies of delayed diagnoses in patients with AGC do not include these variables, and when rarely described, they are incomplete.