[Clinicopathological and molecular genetic characteristics of embryonal rhabdomyosarcoma with divergent...

Objective: To investigate the clinicopathological and molecular genetic features of embryonal rhabdomyosarcoma with heterologous neuroectodermal differentiation (ERMS-HND). Methods: A retrospective analysis was performed on 17 patients with ERMS-HND diagnosed from January 2021 to December 2025 at the Foshan Hospital of Traditional Chinese Medicine, Foshan, China. The clinicopathological, immunohistochemical, and molecular genetic characteristics were evaluated. Results: Among the 17 ERMS-HND patients, 15 were male and 2 were female. Their age was 24.0 (12.0, 46.5) months, ranging from 0.5 months to 22 years. Fourteen patients were children aged ≤5 years. The pelvic/genitourinary region was the most frequently involved site (8/17). All cases exhibited biphasic differentiation. The mesenchymal component was predominantly embryonal rhabdomyosarcoma (ERMS, 16/17). The neuroectodermal component encompassed the spectrum of neural crest differentiation, including neuroblastoma in 12 cases, ganglioneuroma/ganglion cells in 2 cases, composite ganglioneuroblastoma in 1 case, and Schwann cell differentiation in 2 cases. In addition to the classic configuration, two distinctive architectural patterns, namely micronest and inverted, were identified. The mesenchymal component uniformly expressed desmin, MyoD1, and Myogenin. The neuroblastoma component was mostly positive for synaptophysin (SYN), neuron-specific enolase (NSE), chromogranin A (CgA), and CD56, whereas the Schwann cell differentiation expressed only S-100 and/or SOX10. Only 2 cases showed focal PHOX2B positivity. RAS mutations were detected in 3 cases (HRAS mutation in 1 case and NRAS mutations in 2 cases). The tumor cells were all negative for FOXO1, PAX3 and PAX7. Case 17 showed no PRC2 alterations, NF1 inactivation, or CDKN2A/2B deletion, but retained H3K27me3 expression in Schwann cell areas, in contrast to the loss of H3K27me3 observed in malignant triton tumor. Conclusions: The neuroectodermal component of ERMS-HND encompasses the complete spectrum of neural crest-derived differentiation. S-100 and SOX10 are key and reliable markers for confirming the neuroectodermal component, while negativity of neuroendocrine markers such as SYN does not exclude this differentiation. Unlike malignant triton tumors, Schwann cell differentiation in this tumor does not exhibit loss of H3K27me3. Low PHOX2B expression in the neuroblastoma component may serve as an important marker for the differential diagnosis.