Julieta E. Barroeta

“Atypical Glandular Cells” on Cervical Cytology: Correlation Between Glandular Cell Component Volume and Histological Follow‐Up

ABSTRACT Background Atypical glandular cells (AGC) in cervical cytology, as defined by the Bethesda System, indicate nuclear atypia beyond reactive changes but without definitive features of malignancy. Although clinically significant because it prompts follow‐up procedures, no quantitative threshold exists for AGC diagnosis. This study evaluated whether the volume of glandular cell clusters (GCC), regardless of atypia, influences AGC interpretation and may contribute to unnecessary sampling. Methods Following IRB approval, all cervical cytology cases diagnosed as AGC between January 2014 and June 2024 were retrieved, along with 100 random negative for intraepithelial lesion or malignancy (NILM) cases, and were manually re‐screened with quantification of glandular cell clusters (GCC) defined as a group of ≥ 6 cohesive glandular cells irrespective of origin (endocervical versus endometrial) and the results were correlated with follow‐up findings including endocervical and endometrial sampling. Results Of 301 AGC cases, 186 cases had slides available for review and follow‐up data; two were excluded due to unsatisfactory quality. Eight cases were reclassified as unsatisfactory because of insufficient squamous cells and absence of atypia, most of which exhibited high GCC (mean 59). Notably, 140 cases (76.6%) showed no significant glandular pathology on follow‐up, and in 111 cases (60.6%) the follow‐up was negative. Overall, increased GCC correlated significantly with AGC interpretation compared to NILM cases ( p  = 0.01), even when histologic follow‐up was negative. Conclusion Higher GCC volumes may influence AGC diagnoses, even in cases lacking true cytologic atypia, potentially leading to unnecessary interventions. Greater awareness of this tendency and adherence to established cytologic criteria may improve diagnostic precision within the AGC category.

Expertise in Gynecological Pathology Impacts Diagnosis of Atypical Glandular Cell Category in Cervical Cytology

Objectives The Pap test is effective for detecting squamous neoplasia, but the interpretation of atypical glandular cell (AGC) remains challenging because of its rarity, complex cytologic features, and interobserver variability. Although AGC represents a small proportion of Pap test diagnoses, it often leads to extensive follow-up. This study aimed to assess whether gynecologic pathology expertise improves diagnostic accuracy and reduces unnecessary interventions in AGC interpretation. Methods A retrospective review of AGC cases diagnosed between 2014 and 2024 at the authors’ institution was conducted. Among 107,615 Pap smears, 301 (0.28%) were initially classified as AGC. Of these, 221 had slides available for review, and 184 had adequate histologic follow-up. Cases were re-evaluated by a cytopathologist with additional gynecologic pathology training, blinded to clinical information, and reclassified according to the Bethesda System. Results Reclassification identified 62 cases as AGC, 1 as adenocarcinoma in situ, and 4 as adenocarcinoma. The remaining 117 cases were reassigned to other diagnostic categories. The malignancy rate increased from 39.1% to 53.9%, and the positive predictive value for significant histologic findings was 59.7%. Cytology-histology concordance improved from 26.6% to 64.1% (p = .002). Conclusions Gynecologic pathology expertise enhanced the diagnostic accuracy of AGC, improved malignancy detection, and significantly increased cytohistologic correlation. While decreasing sensitivity, it increases positive predictive value of AGC interpretation. These findings highlight the value of specialized training and the need for a specific, criteria-based approach to minimize unnecessary follow-up and optimize patient care.

Integrated Analysis of Ovarian Juvenile Granulosa Cell Tumors Reveals Distinct Epigenetic Signatures and Recurrent TERT Rearrangements

Abstract Purpose: Adult granulosa cell tumor (AGCT) is characterized by the somatic FOXL2 p.C134W mutation, and recurrences have been associated with TERT promoter and KMT2D-truncating mutations. Conversely, the molecular underpinnings of the rare juvenile granulosa cell tumor (JGCT) have not been well elucidated. To this end, we applied a tumor-only integrated approach to investigate the genomic, transcriptomic, and epigenomic landscape of 31 JGCTs to identify putative oncogenic drivers. Experimental Design: Multipronged analyses of 31 JGCTs were performed utilizing a clinically validated next-generation sequencing (NGS) panel targeting 580 cancer-related genes for genomic interrogation, in addition to targeted RNA NGS for transcriptomic exploration. Genome-wide DNA methylation profiling was conducted using an Infinium Methylation EPIC array targeting 866,562 CpG methylation sites. Results: We identified frequent KMT2C-truncating mutations along with other mutated genes implicated in the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, in addition to previously reported hotspot AKT1 and DICER1 mutations. Targeted transcriptome sequencing revealed recurrent TERT rearrangements (13%) involving partners CLPTM1L or DROSHA, and differential gene expression analysis showed FGFR1 upregulation in the TERT non-rearranged JGCTs under direct promoter control. Genome-wide DNA methylation rendered a clear delineation between AGCTs and JGCTs at the epigenomic level, further supporting its diagnostic utility in distinguishing among these tumors. Conclusions: This is the largest comprehensive molecular study of JGCTs, where we further expand our current understanding of JGCT pathogenesis and demonstrate putative oncogenic drivers and TERT rearrangements in a subset of tumors. Our findings further offer insights into possible targeted therapies in a rare entity.