The Largest Cohort Study of Intravenous Leiomyomatosis Reveals HMGA2 and Collagen Gene Alterations as Cooperative Drivers

Intravenous leiomyomatosis (IVL) is a rare, hormonally responsive smooth muscle neoplasm defined by nondestructive intravascular growth. Despite its distinct clinical behavior, the comprehensive molecular landscape of IVL has not been systematically characterized. We collected the clinicopathologic characteristics of 89 IVLs, 106 conventional uterine leiomyomas (cULMs), and 83 cellular leiomyomas (CLs). Using immunohistochemistry (IHC), we evaluated high mobility group AT-hook 2 (HMGA2) expression in 88 IVLs, 106 cULMs, and 83 CLs. We also assessed fumarate hydratase (FH) and 2-succinocysteine status by IHC in 82 IVLs. Fluorescence in situ hybridization was performed using the HMGA2 break-apart probe in 84 IVLs and the HMGA2/RAD51B fusion probe in 83 IVLs. We detected MED12 exon 2 hotspot mutations by Sanger sequencing in 79 IVLs. Whole-exome sequencing (WES) was performed in 10 IVLs. We found that IVL predominantly affected reproductive-aged women, most with a history of uterine trauma. HMGA2 expression was upregulated in 87.5% (77/88) of IVLs, with strong immunoreactivity in 40.9% (36/88) of IVLs. Half of IVLs harbored HMGA2 rearrangements, predominantly the HMGA2/RAD51B fusion. WES revealed frequent mutations in collagen (COL) gene family members (70.0%, 7/10), all co-occurring with HMGA2 upregulation. Conversely, MED12 exon 2 mutations (2.5%, 2/79) and FH deficiency (2.4%, 2/82) were rare events in this cohort. We propose that IVL pathogenesis likely involves synergistic interplay between dysregulated HMGA2 and COL gene family alterations within a permissive microenvironment influenced by hormones and uterine trauma. FH deficiency and MED12 exon 2 hotspot mutations appear infrequent in IVL and may not represent primary drivers of disease initiation.