Uterine Leiomyosarcoma

uSMTs exhibit a broad morphologic spectrum in LFS, and multiple molecular alterations may drive tumorigenesis, including MED12, FH, TP53, RB1, ATRX, and a novel ACTG2::BRAF fusion. Although some may be incidental, uSMT in this setting appears enriched for atypical morphology, FH deficiency, and aberrant p53 expression, suggesting an interplay between p53 and FH pathways in tumorigenesis.

Histological subtype, stage, and coagulative necrosis were critical prognostic factors in uterine sarcoma. The findings suggest that vigilant pulmonary surveillance and further investigation into tailored therapeutic strategies may be warranted-including endocrine therapy for hormone-receptor-positive tumors, immunotherapy for high-grade ESS, and PARP inhibitors for uLMS. However, these hypotheses require thorough preclinical and clinical validation. Additionally, caution should be exercised to avoid overtreatment of chemotherapy in early-stage uLMS.

Histologic subtyping of unclassified sarcomas predicted prognosis and therapeutic response. We propose universal MMR IHC screening of (1) PRMS, (2) uterine LMS, (3) unclassified/UPS, and (4) any sarcoma in a patient with a personal or family history of Lynch syndrome.

In xenografts, atorvastatin suppressed ULMS tumor growth by ~50% with minimal toxicity, as evidenced by normal serum ALT and creatinine levels and preserved organ histology. These findings identify protein geranylgeranylation as a novel therapeutic vulnerability in ULMS and support statin repurposing as a promising treatment strategy.

A novel p53-aberrant endometrial glandular lesion, occurring in young patients with LFS, likely represents an unusual form of endometrial atypical hyperplasia, rather than serous carcinoma. In morphologically benign tissues, aberrant p53 expression in numerous discrete foci or diffusely across nearly all cells should prompt consideration of an underlying g-TP53 mutation.

P2, N=96, Active, not recruiting, City of Hope Medical Center | N=72 --> 96

IRS4 fueled cancer dependency through PI3K-Akt activation, and domain analysis revealed the PH and PTB domains, which have a predicted drug pocket, to be dispensable, suggesting degradation-based modalities. These data reveal IRS4 as a target in IRS4-expressing cancers and suggest inhibitory approaches.

Inflammation and immunity play a pivotal role in the pathogenic mechanism of ULMS. Our study findings suggest that CALCRL can serve as an immune-inflammatory biomarker for ULMS, providing a new perspective for exploring the development and diagnosis of ULMS.

PLAG1-rearranged uterine mesenchymal tumours demonstrate notable morphologic heterogeneity, predominantly presenting as myxoid leiomyosarcoma. We recommend using the integrated diagnostic term 'PLAG1-rearranged uterine mesenchymal tumour with features of [specific morphology]' to capture both the genetic alteration and histologic spectrum, accompanied by a comment regarding the limited experience and potential for recurrence.

P2, N=30, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting

ATRX mutational status may serve as a potential biomarker for prognosis and therapeutic stratification. Future clinical trials investigating epigenetic therapies could offer novel treatment strategies for ATRX-deficient sarcomas.

In cultured LMS cells, proliferation correlated with increased nuclear smoothelin positivity. These findings suggest that smoothelin is linked to proliferative capacity in SMTs, and its altered subcellular distribution may have potential utility in the pathological evaluation of SMTs.