Uterine Leiomyosarcoma (ULMS)

Overview

Uterine leiomyosarcoma (ULMS) is a malignant smooth-muscle tumor of the uterus, distinct from the more common endometrial carcinomas. On OncoTree it is a child of Uterine Sarcoma/Mesenchymal Tumor (USMT) and a subtype of leiomyosarcoma (LMS). It carries a poor prognosis despite multimodal treatment. ULMS is distinguished from soft tissue LMS (STLMS) by its distinct genomic risk profile.

Cohorts in the corpus

  • 238 ULMS cases (177 primary at presentation, 61 metastatic) from MSKCC, profiled by MSK-IMPACT (341–505 genes); 15 with sequential tumors. Median age 54 years. Dataset: lms_msk_2024. PMID:38488807

Recurrent alterations

  • TP53 — mutations (55%) and deletions (16%); point mutations (not deletions) are prognostically significant in ULMS; truncal clonal event. PMID:38488807
  • RB1 — mutations (13%) and deletions (39%); co-occurs with PTEN deletions (P<0.01). PMID:38488807
  • ATRX — mutations (32%); co-occurs with TP53 mutations (P<0.05); prognostically significant in ULMS risk model. PMID:38488807
  • PTEN — deletions/mutations (18%); co-occurs with RB1 deletions (P<0.01). PMID:38488807
  • CDKN2A — deletions in 10% (more common than in STLMS at 2.6%). PMID:38488807
  • MED12 — recurrent mutations in 15% (much more common than in STLMS at 1%). PMID:38488807
  • TMB: median 3 mut/Mb; 98% of cases <10 mut/Mb. PMID:38488807
  • MET500 metastatic cohort identified a novel GREB1-NR4A3 activating fusion in uterine leiomyosarcoma; ULMS was sequenced as part of the 42/500 soft-tissue sarcoma cases within the cohort. PMID:28783718
  • ULMS (n=27) was molecularly distinguishable from STLMS by iCluster, with PI3K/AKT/MTOR pathway alterations in 84% and ESR1 target-gene hypomethylation supporting a hormonal-axis difference; STLMS had significantly higher PD-L1 (CD274) expression than ULMS (p=4e-5) PMID:29100075

Subtypes

  • Three-tier genomic risk model for disease-specific survival (primary, n=177): PMID:38488807
    • High risk: TP53 mutation + ATRX mutation or chr20q amplification (n=50, median DSS 52 months, 5-year DSS 41%).
    • Intermediate: TP53 mutation, ATRX mutation, or amp20q (n=66, median DSS 92 months).
    • Low: none of above (n=61, median DSS 157 months; global log-rank P=0.00012).
  • Most molecular alterations are early clonal events persisting through disease progression. PMID:38488807
  • ULMS vs. STLMS distinction: ATRX mutations more common in ULMS (32% vs. 10%), MED12 mutations unique to ULMS (15% vs. 1%), RB1 deletions more common in ULMS (39% vs. 24%). PMID:38488807

Therapeutic landscape

  • Genomic risk stratification using TP53, ATRX, and chr20q status provides superior or comparable prognostic information relative to tumor size; recommended for routine clinical NGS interpretation. PMID:38488807
  • IHC for TP53 and ATRX may serve as surrogate biomarkers for settings without NGS access. PMID:38488807
  • Risk stratification could inform decisions on neoadjuvant or adjuvant therapy. PMID:38488807

Sources

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