Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings.

Cyrta, Joanna;Gauthier, Arnaud;Karanian, Marie;Vieira, Andre F;Pierron, Gaëlle;et.al.
(2021) American Journal of Surgical Pathology — Vol. 45, n° 6, p. 854-867 (2021)

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Authors
  • Cyrta, Joanna
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  • Gauthier, Arnaud
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  • Karanian, Marie
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  • Vieira, Andre F
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  • Brichard, BénédicteUCLouvain
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  • Pierron, Gaëlle
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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.
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Cyrta, J., Gauthier, A., Karanian, M., Vieira, A. F., Cardoen, L., Jehanno, N., Bouvet, M., Bouvier, C., Komuta, M., Le Loarer, F., Orbach, D., Rome, A., Minard-Colin, V., Brichard, B., Pluchart, C., Thebaud, E., Renard, M., Pannier, S., Brisse, H., et al. (2021). Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings. American Journal of Surgical Pathology, 45(6), 854-867. https://doi.org/10.1097/PAS.0000000000001702 (Original work published 2021)