Clear Cell Carcinoma With Enteroblast-Like Differentiation Involving Multiple Gynecologic Sites: An Integrated Clinicopathologic, Whole-Exome, and Transcriptomic Analysis

Abstract

Clear cell carcinoma with enteroblastic differentiation arising in the female genital tract is exceptionally rare, and its pathogenesis, diagnostic features, and therapeutic implications remain poorly understood. We report a rare case in a 67-year-old woman with tumor involvement of the cervix, uterine cavity, fallopian tubes, and ovaries, and highlight the value of multi-site sequencing for resolving tumor origin and biological heterogeneity. Histologically, the tumor exhibited a fetal intestinal-like morphology with glycogen-rich clear cytoplasm. Immunohistochemistry revealed positive staining for HNF1β, with variable immunoreactivity for Glypican-3 and SALL4. Multi-site whole-exome sequencing revealed marked inter-lesional genomic heterogeneity, divergent clonal evolution, and a molecular phylogenetic pattern supporting the fallopian tube as the most likely primary site. RNA sequencing further demonstrated a more immunogenic microenvironment in the fallopian tube lesion, characterized by increased infiltration of CD4⁺ T cells and B cells and a higher immunophenoscore, suggesting potential sensitivity to immunotherapy. Comparison with previously reported cases also helped define immunophenotypic features of diagnostic relevance. Collectively, this case underscores the value of integrating clinicopathologic evaluation with multi-site whole-exome and transcriptomic sequencing to refine diagnosis, infer tumor origin, and identify potential therapeutic opportunities in this rare gynecologic tumor subtype.