Clinicopathological and molecular features of uterine smooth muscle tumours in patients with Li‐Fraumeni syndrome

AIMS: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome characterized by germline TP53 mutations and increased risk of various malignancies. While rare uterine leiomyosarcomas (LMS) have been reported, other uterine smooth muscle tumours (uSMT) have not been studied in this context. METHODS AND RESULTS: We describe clinicopathological features of uSMT from 10 LFS patients (four uSMT of uncertain malignant potential (STUMP), two leiomyomas with bizarre nuclei [LMBN] and four with only conventional leiomyomas [LM]) and next-generation sequencing results of eight tumours. Among six p53-aberrant tumours (four STUMPs, one LMBN, one LM) by immunohistochemistry (IHC), three STUMPs had biallelic TP53 inactivation and three uSMT (two STUMPs, one LMBN) had loss of fumarate hydratase (FH) by IHC with inactivating FH variants. One patient with a p53-aberrant, FH-deficient LMBN had a concurrent p53-wild-type, FH-proficient LM with a novel ACTG2::BRAF fusion. Two STUMPs with TP53 biallelic inactivation and intact FH had additional alterations, one with LMS features, including chromosome instability, ATRX, and RB1 alterations; the other with del(22q), CYLD, and ELOC mutations. The remaining two sequenced LM showed MED12 alterations, one with del(22q). No recurrences were seen in nine patients with follow-up and no LMS were diagnosed. CONCLUSION: 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.