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Molecular-Based Immunohistochemical Algorithm for Uterine Leiomyosarcoma Diagnosis.

Amir Momeni-Boroujeni1, Elham Yousefi2, Ridin Balakrishnan1

  • 1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|February 14, 2023
PubMed
Summary

Uterine leiomyosarcoma (LMS) diagnosis can be improved using immunohistochemical (IHC) markers targeting common genomic alterations identified by next-generation sequencing (NGS). This molecular-based IHC approach aids in distinguishing LMS from other smooth muscle tumors.

Keywords:
genomic landmarksgenomic profilingimmunohistochemistryuterine leiomyosarcoma

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Area of Science:

  • Gynecologic Oncology
  • Molecular Pathology
  • Genomics

Background:

  • Morphologic assessment of uterine leiomyosarcoma (LMS) is challenging.
  • Current diagnostic immunohistochemical (IHC) analysis for uterine LMS is lacking.
  • Genomic alterations in uterine LMS are not fully characterized for diagnostic use.

Purpose of the Study:

  • To identify common genomic alterations in uterine LMS using next-generation sequencing (NGS).
  • To develop and validate an IHC-based diagnostic algorithm for uterine LMS.
  • To assess the utility of IHC markers as surrogates for genomic alterations in uterine smooth muscle tumors.

Main Methods:

  • Targeted NGS was performed on 167 uterine LMS samples to identify genomic alterations.
  • IHC analysis was applied to test and validation cohorts including LMS, STUMP, and leiomyomas.
  • Pathologists blinded to NGS data interpreted IHC results, assessing concordance.

Main Results:

  • 94% of LMS showed ≥1 genomic alteration in key genes (TP53, RB1, ATRX, PTEN, CDKN2A, MDM2); 80% had ≥2 alterations.
  • An IHC panel (p53, Rb, PTEN, ATRX) identified abnormalities in 81% of LMS in the test cohort.
  • IHC results showed excellent concordance with NGS data (κ=0.941) and among pathologists (κ=0.97).

Conclusions:

  • Uterine LMS exhibits specific genomic landmark alterations.
  • Molecular-based IHC markers can serve as reliable surrogates for these genomic alterations.
  • A diagnostic algorithm using IHC may improve the evaluation of challenging uterine smooth muscle tumors.