Intravenous leiomyomatosis: molecular analysis of 17 cases

Intravenous leiomyomatosis (IVL) is a rare smooth muscle tumour with a benign histology but with a quasi-malignant intravascular growth. In this study, we investigated the molecular alterations in 17 IVL cases composed of concurrent uterine leiomyoma (n=12), uterine IVL (n=17) and extra-uterine IVL (n=12). We found that eight tumours had a somatic MED12 mutation (c.130G>A, p.G44S, n=7; c.131G>C, p.G44A, n=1). The frequency of MED12 mutations was significantly higher in concurrent uterine leiomyoma (6/12, 50%) than in uterine (0/17, 0%) and extra-uterine IVL (2/12, 16.7%). The frequency of HMGA2 over-expression or MED12 low-expression was not significantly different among uterine leiomyoma, IVL and extra-uterine IVL (p>0.05). Short tandem repeat (STR) analysis indicated that one uterine and two extra-uterine IVL tumours from three patients were microsatellite instability positive (MSI+) whereas loss of heterozygosity (LOH) was found in one uterine leiomyoma, three uterine and three extra-uterine IVL tumours from five patients. LOH was more frequently seen in uterine/extra-uterine IVL tumours (6/20, 30%) than in the concurrent leiomyomas (1/7, 14.3%) (p<0.05). MED12 mutation, MSI and LOH were discordant between uterine and extra-uterine IVL in all patients. These findings suggest that IVL harbours distinct molecular pathogenesis from common uterine leiomyomas. Uterine IVL and extra-uterine tumours may represent an independent origin rather than uniclonal dissemination from a single tumour. Further investigations are warranted to explore the underlying key molecular events in the pathogenesis of IVL.