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<p>POLE-mutated endometrial carcinomas are typically associated with favorable prognosis, yet marked spatial heterogeneity may complicate biological and clinical interpretation. We report a unique triphasic carcinoma composed of endometrioid, dedifferentiated-like, and sarcomatoid-like components with distinct morphologic and immunophenotypic profiles. Multiregional sequencing demonstrated a shared pathogenic POLE V411L mutation across all components, confirming a common clonal origin. Progressive molecular divergence was observed, with subclonal MSH6 alteration in the endometrioid region, complete MSH6 loss and dramatic tumor mutational burden escalation in the dedifferentiated-like and sarcomatoid-like components, and acquisition of TP53 and ARID1A truncating mutations restricted to the sarcomatoid-like compartment. Despite high-grade transformation and stage IIC disease, microsatellite stability was maintained, supporting a POLE-driven hypermutator phenotype. This case provides direct morphologic and molecular evidence of spatial clonal evolution in a multiple-classifier endometrial carcinoma. The clinical implications of this spatial heterogeneity remain uncertain and warrant further investigation.</p>

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POLE-mutated endometrial carcinoma with extreme morphological and molecular heterogeneity: spatial clonal divergence in a multiple-classifier tumor

  • 期刊论文

  • 发表日期：

    2026年4月8日

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  • Antonio d’Amati,
  • Elisa De Paolis,
  • Valentina Iacobelli,
  • Francesca Addante,
  • Angelo Minucci,
  • Francesco Fanfani,
  • Angela Santoro,
  • Gian Franco Zannoni

摘要

POLE-mutated endometrial carcinomas are typically associated with favorable prognosis, yet marked spatial heterogeneity may complicate biological and clinical interpretation. We report a unique triphasic carcinoma composed of endometrioid, dedifferentiated-like, and sarcomatoid-like components with distinct morphologic and immunophenotypic profiles. Multiregional sequencing demonstrated a shared pathogenic POLE V411L mutation across all components, confirming a common clonal origin. Progressive molecular divergence was observed, with subclonal MSH6 alteration in the endometrioid region, complete MSH6 loss and dramatic tumor mutational burden escalation in the dedifferentiated-like and sarcomatoid-like components, and acquisition of TP53 and ARID1A truncating mutations restricted to the sarcomatoid-like compartment. Despite high-grade transformation and stage IIC disease, microsatellite stability was maintained, supporting a POLE-driven hypermutator phenotype. This case provides direct morphologic and molecular evidence of spatial clonal evolution in a multiple-classifier endometrial carcinoma. The clinical implications of this spatial heterogeneity remain uncertain and warrant further investigation.