Risk Assessment of Precancers and Cancers in Women with Atypical Glandular Cells of Endocervical, Endometrial, and Unknown Origin

Objective: To assess the risk of precancers high-grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ (AIS) and atypical endometrial hyperplasia (AEH) and cancers squamous cell carcinoma (SCC) and adenocarcinoma (ADC) in women with atypical glandular cells (AGC) cytology. Methods: A total of 1,028 women diagnosed with abnormal cervical glandular cytology from January 2019 and December 2023 were enrolled. Of these, 670 underwent both HPV genotyping and cervical biopsy. Results: Participants were classified into three groups: AGC-EC (endocervical), AGC-EM (endometrial), and AGC-NOS (unknown origin). AGC-EC was more prevalent than AGC-EM and AGC-NOS among younger women (cutoffs at 40 and 50; P < 0.0001 and < 0.0001) and in the HPV-positive group (P = 0.001). In the HPV-positive group, AGC-EC and AGC-NOS lesions were primarily endocervical, with significantly higher incidences of HSIL+, SCC, and AIS+ compared to the HPV-negative group (P = 0.00021, 0.047, < 0.0001 for AGC-EC; P ≤ 0.0001, = 0.004, < 0.0001 for AGC-NOS). However, hrHPV status did not significantly affect the incidence of endometrial and extrauterine lesions. Stratified by age, AGC-NOS's ECA and EUC were more common after age 65 (P = 0.028 and 0.001), and AGC-EM's AEH+ and EMC also increased significantly after 65 (P = 0.001, 0.000401). Moreover, for AGC-EM, older women (≥ 50) had significantly higher rates of AEH+ and EMC compared to younger groups (P < 0.05). Conclusion: Distinct cytological categories of AGC exhibit differential age and HPV-related risk profiles. AGC-EC and AGC-NOS in HPV-positive women indicate a higher risk of cervical neoplasia, highlighting the importance of HPV testing in triaging these cases. In contrast, AGC-EM is predominantly linked to endometrial pathologies in older women, especially those aged ≥ 50. These findings underscore the necessity of age- and subtype-specific evaluation strategies to optimize early detection of glandular and extrauterine malignancies in AGC patients.