To present four cases of ERBB2-mutated hybrid nerve sheath tumors (HNSTs), characterize their clinical and molecular features, and explore implications for diagnosis, surveillance, and targeted therapy.

Hybrid nerve sheath tumors — tumors with both schwannoma-like and neurofibroma-like elements — are increasingly recognized within the non-NF2 schwannomatosis spectrum. Recent evidence suggests ERBB2 mutations may define a molecularly distinct subset, possibly independent of other SWN-defining alterations, and offering potential therapeutic targets.

We identified four patients at a single tertiary center who underwent next-generation sequencing of their nerve sheath tumor specimens and germline testing. Clinical course, imaging, molecular variant data, and treatment attempts (where applicable) were reviewed.

All four patients presented at relatively young age and demonstrated persistent tumor growth over time. All patients have severe phenotype with extensive spinal roots' and cranial nerve lesions. Two patients from the same family share the same pathogenic ERBB2 variant (c.1958C>G). All patients are under surveillance imaging including whole-body MRI surveillance +/- PET imaging and in one patient an off-label targeted therapy was initiated. The risk of transformation to malignant peripheral nerve sheath tumor (MPNST) in this subgroup remains unknown.

ERBB2-mutant hybrid nerve sheath tumors appear to represent a distinct molecular and clinical entity within schwannomatosis. Their identification may refine diagnostic classification and open avenues for targeted therapy. Further longitudinal studies are needed to delineate natural history and MPNST risk.