Molecular evidence of a clonal relationship of synchronous/multifocal gastric‐type lesions of the female genital tract

Abstract Synchronous/multifocal gastric‐type lesions (SMGLs) of the female genital tract are heterogeneous diseases that are rare and challenging to diagnose. The core issue is distinguishing between multiple primaries and multifocal metastases from a single lesion. This is vital for staging, prognosis, and treatment decisions, especially when metastases mimic primary and early lesions at the relevant sites. Traditional morphological diagnosis often faces a paradoxical situation on this key issue and cannot quantitatively evaluate the correlations among multiple foci. Here, six cases of SMGL were collected, two of which exhibited pagetoid dissemination within the genital tract, with all lesions being noninvasive. A total of 24 samples were subjected to whole‐exome sequencing. By inference based on overlapping genetic variations, base substitution mutation patterns, composition and similarity of COSMIC signatures, clonality indices, and the construction of evolutionary trees, it was inferred that the multiple foci in each patient were clonally related, indicating that all cases were metastatic. The follow‐up duration ranged from 7 to 62 months (median: 24.5 months). Four patients died of disease (median survival time: 24.5 months, range: 8–47 months), including one patient who had no invasive lesions at initial diagnosis; two patients experienced recurrences at 17 and 40 months, respectively. These results imply that even if all foci exhibit the appearance of in situ or premalignant changes histologically, they may actually be aggressive. Hence, for SMGLs, before opting for conservative treatment, comprehensive clinical assessment, appropriate surgical extent, adequate sampling, and careful microscopic examination are crucial. Clonal analysis should also be conducted where necessary to avoid undertreatment due to understaging. The study further explored the genomic traits of SMGLs involving more than two sites. © 2025 The Pathological Society of Great Britain and Ireland.