HPV Genotype, AGC Categories, and Age-Stratified Immediate Prevalence of Precancers and Cancers in Women with Atypical Glandular Cells with or without Concurrent Squamous Abnormal Cytology

Abstract

Objectives: Limited data exists on Papanicolaou (Pap) tests involving atypical glandular cells (AGC) with or without concurrent squamous cell abnormalities (Sq), hindering the reproducibility of results. This study aims to stratify the risk of precancers and cancers based on distinct high-risk human papillomavirus (hrHPV) genotyping, AGC categories, and age groups among women with AGC with or without concurrent squamous cell abnormalities. Methods: This retrospective analysis examined Pap smear patient data from January 2019 to December 2023, including 54 AGC + Sq cases and 974 cases with AGC-Alone. Among these, 799 patients (including 43 AGC + Sq cases and 756 AGC-Alone cases) had HPV testing results, and 769 (including 43 AGC + Sq cases and 726 AGC-Alone cases) had subsequent histological follow-up data. Results: In the total cohort, 5.25% (54 cases) were AGC + Sq, and 94.75% (974 cases) were AGC-Alone. The detection rates of high-grade glandular lesions (AIS+/AEH+) and adenocarcinoma (AC) were significantly higher in AGC patients over 65 years compared to other age groups (p = 0.000444 and p < 0.0001, respectively), while no significant differences were observed for high-grade squamous lesions (HSIL+) (p = 0.791) or squamous carcinoma (SCC) (p = 0.909). The prevalence of AIS+/AEH+ was significantly higher in HPV-16 (28.6%) and HPV-18 (50.0%) positive groups compared to the HPV-negative (10.4%) and other hrHPV types positive groups (6.3%) (p < 0.0001). Notably, the AGC + Sq group exhibited a higher prevalence of isolated squamous lesions, as well as glandular lesions with concurrent squamous involvement, compared to the AGC-Alone group (p = 0.001). Additionally, increased AC risk was observed in older AGC + Sq women at the 50-year cutoff, although no significant association was found between HPV genotype and immediate histology in the AGC + Sq group. Conclusions: A comprehensive approach that incorporates cytological results, hrHPV status, and age offers more effective stratification of AGC patients, leading to more precise management. While hrHPV testing and age provide valuable insights, relying solely on hrHPV results for triaging AGC + Sq cases is inadequate.

Keywords: Atypical glandular cells; Papanicolaou (Pap) test; coexisting glandular and squamous cells abnormalities; histological follow-up; risk stratification.

Figure 1

Schematic Overview of Data Analysis Workflow.

Figure 2

Representative Cytologic and Histologic Findings in Two Cases of Abnormal Glandular Cells with Concurrent Squamous Abnormalities Confirmed by Histologic Follow-up. Case 1: Endocervical Adenocarcinoma (ECA) with High-Grade Squamous Intraepithelial Lesion (HSIL) (Cytologic diagnosis: AGC-FN/ASC-H) (Panels A-D): (A) AGC-FN, arrow indicates a tightly packed cluster of glandular cells with a high nuclear-to-cytoplasmic ratio, enlarged nuclei, and coarse chromatin. (B) HSIL, arrow highlights abnormal squamous cells with eosinophilic cytoplasm, hyperchromatic, enlarged nuclei, and irregular nuclear contours. (C) Endocervical adenocarcinoma, disorganized glands of varying shapes and sizes composed of columnar tumor cells. (D) HSIL, dysplastic changes involving more than two-thirds of the epithelial thickness, with loss of nuclear polarity and numerous koilocytic cells on the surface. Case 2: Endocervical Adenocarcinoma In Situ (AIS) with Low-Grade Squamous Intraepithelial Lesion (LSIL) (Cytologic diagnosis: AGC-FN/ASC-US) (Panels E-H): (E) AGC-FN, arrow indicates atypical glandular cells with a high nuclear-to-cytoplasmic ratio. (F) ASC-US, arrow points to squamous cells with enlarged nuclei. (G) AIS, abnormal endocervical glands adjacent to normal glands without stromal reaction. The neoplastic cells form stratified, crowded clusters with hyperchromatic nuclei and atypical mitoses at the luminal borders (arrow). (H) LSIL, mild nuclear polarity disorder involving the basal one-third of the epithelium, with variable nuclear sizes, mitotic figures, and surface koilocytic cells (arrow).

Figure 3

Histologic outcomes in women with atypical glandular cells (AGC) with or without concurrent squamous cell abnormalities. AGC + Sq group (A), AGC-alone group (B). Abbreviations: AC, adenocarcinoma; AEH: atypical endometrial hyperplasia; AGC, atypical glandular cell; AGC + Sq, atypical glandular cells with concurrent squamous cell abnormalities; AGC-alone, atypical glandular cells without concurrent squamous cell abnormalities; AIS, adenocarcinoma in situ; EH, endometrium hyperplasia without atypia; ECA, endocervical adenocarcinoma; EMC, endometrial carcinoma; EUA, Extrauterine adenocarcinoma; HSIL, high-grade squamous intraepithelial lesion; SCC, squamous cell carcinoma; LSIL, low-grade squamous intraepithelial lesion.