Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease

<jats:p> <jats:italic toggle="yes">VGLL2</jats:italic>-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with <jats:italic toggle="yes">VGLL2</jats:italic>-rearranged RMS confirmed by molecular studies, who experienced local progression and distant metastases, including 2 with fatal outcomes. Tumors were diagnosed at birth (n=3) or at 12 months of age (n=1), and were all localized at initial diagnosis, but unresectable and therefore managed with chemotherapy and surveillance. Metastatic progression occurred from 1 to 8 years from diagnosis (median, 3.5 y). Three patients experienced multimetastatic spread and one showed an isolated adrenal metastasis. At initial diagnosis, 3 tumors displaying bland morphology were misdiagnosed as fibromatosis or infantile fibrosarcoma and initially managed as such, while 1 was a high-grade sarcoma. At relapse, 3 tumors showed high-grade morphology, while 1 retained a low-grade phenotype. Low-grade primary tumors showed only very focal positivity for desmin, myogenin, and/or MyoD1, while high-grade tumors were heterogenously or diffusely positive. Whole-exome sequencing, performed on primary and relapse samples for 3 patients, showed increased genomic instability and additional genomic alterations (eg, <jats:italic toggle="yes">TP53</jats:italic>, <jats:italic toggle="yes">CDKN2A/B</jats:italic>, <jats:italic toggle="yes">FGFR4</jats:italic>) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained <jats:italic toggle="yes">VGLL2</jats:italic> fusion transcripts and transcriptomic profiles consistent with <jats:italic toggle="yes">VGLL2</jats:italic>-rearranged RMS. High-grade samples showed a high expression of genes encoding cell cycle proteins, desmin, and some developmental factors. These 4 cases with distinct medical history imply the importance of complete surgical resection, and suggest that RMS-type chemotherapy should be considered in unresectable cases, given the risk of high-grade transformation. They also emphasize the importance of correct initial diagnosis.</jats:p>