Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease

Abstract

VGLL2-rearranged rhabdomyosarcomas (RMS) are rare low-grade tumors with only favorable outcomes reported to date. We describe 4 patients with VGLL2-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, TP53, CDKN2A/B, FGFR4) at relapse, but no recurrent events. RNA sequencing confirmed that high-grade tumors retained VGLL2 fusion transcripts and transcriptomic profiles consistent with VGLL2-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.

Spindle cell rhabdomyosarcomas: With TFCP2 rearrangements, and novel EWSR1::ZBTB41 and PLOD2::RBM6 gene fusions. A study of five cases and review of the literature

“…7,8 Only four reported cases developed metastasis, of which three showed high-grade morphology at relapse with genomic instability and alterations of different genes (in particular TP53, CDKN2A/B, and FGFR4). 42 Recently, Agaimy et al described a series of six cases with novel VGLL3 rearrangements with TCF12, EP300, and PPARGC1A being the fusion partners. Clinically, while these tumours occurred in adults, they again showed H&N predilection and appeared to follow an indolent course.…”

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

“…Recently, a case study with four VGLL2 rearranged tumors described three patients that had multi-metastatic spread, and two that died from disease. This study suggests that complete surgical resection is critical (however not always attainable) for long-term benefit, and that VGLL2 fusions are capable of aggressive disease 22 . Given that these tumors occur at a developmentally sensitive age, effective targeted therapies are critically needed to improve disease outcomes and ameliorate off-target effects from toxic and generalized therapies.…”

“…Clinically, VGLL2-NCOA2 tumors typically present between 0-1 year of age and have a spindle and sclerosing cellular morphology 4,8,18,20–22 . Fusion-driven congenital rhabdomyosarcomas generally have a favorable prognosis with successful surgery and chemotherapy 8 .…”

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

“…Clinically, VGLL2-NCOA2 tumors typically present between 0 and 1 year of age and have a spindle and sclerosing cellular morphology. 4 , 8 , 18 , 20 – 22 Fusion-driven congenital rhabdomyosarcomas generally have a favorable prognosis with successful surgery and chemotherapy. 8 However, non-resectable tumors are challenging to treat, and chemotherapy exposure carries a significant risk of short- and long-term adverse effects.…”

“…This study suggests that complete surgical resection is critical (but not always attainable) for long-term benefit, and that VGLL2 fusions are capable of aggressive disease. 22 Given that these tumors occur at a developmentally sensitive age, effective targeted therapies are critically needed to improve disease outcomes and ameliorate off-target effects from toxic and generalized therapies. Therefore, we set out to test the tumorigenic capacity of this fusion gene, define its oncogenic program, and identify potential therapeutic targets.…”