Fusion-negative Alveolar Rhabdomyosarcoma

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FUSION-NEGATIVE ALVEOLAR RHABDOMYOSARCOMA (ARMS): About 20% of cases with histologic features of ARMS lack PAX3- or PAX7-FOXO1A fusions. They may be:
  • true negatives
  • low expressors (carry mutations in rare cells)
  • cases with novel genetic mutations not detected by current methods
  • cases incorrectly diagnosed as alveolar RMS
Fusion-negative alveolar RMS are less aggressive clinically than fusion-positive cases and are more likely to have solid architecture (as shown in this image) in contrast to the classic alveolar pattern. Some true fusion-negative cases have mixed features of both alveolar and embryonal RMS. Some fusion-negative cases carry alternate fusions, including PAX3 with NCOA1, NCOA2 or FOXO4 as well as FOXO1-FGFR1.

Fusion-positive and fusion-negative alveolar RMS show different gene expression profiles. There is difference between the two groups with regards to an 11-gene DNA methylation status. In addition, myogenin immunoreactivity is different between fusion-positive and fusion-negative cases.

It has been suggested by some that FOXO1A fusion status should be tested on all RMS with alveolar and embryonal histology. Accurate diagnosis and differentiation between the two is critical from therapeutic standpoint.
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