Abstract:

Hybrid nerve sheath tumors combine the features of more than one benign peripheral nerve sheath tumors, specifically combinations of neurofibroma, schwannoma, and perineurioma. These rare benign tumors have a wide anatomical distribution, with a higher prevalence in superficial rather than deep tissue. The most common subtype is hybrid schwannoma/perineurioma, followed by neurofibroma/schwannoma. In two recent studies, recurrent VGLL3 gene fusion was identified in a subset of hybrid nerve sheath tumors, suggesting that they are a distinct entity rather than a variant of classic benign nerve sheath tumors. These studies reported VGLL3 gene fusion in 18 out of 25 (70%) hybrid schwannoma/perineurioma cases, while none of the three tested neurofibroma/schwannoma cases were positive, and no neurofibroma/perineurioma cases were studied for this fusion. In our study, we examined clinicopathologic and immunohistochemical features, as well as VGLL3 rearrangement status using a break-apart FISH probe (3p12.1) in 7 cases of dermal-based hybrid nerve sheath tumors (subcutaneous-based tumors were excluded). Our control group comprised two subcutaneous hybrid nerve sheath tumors cases that were positive for the fusion and three negative cases (plexiform schwannoma, pleomorphic dermal sarcoma, and undifferentiated spindle cell sarcoma). By reviewing morphology and immunohistochemistry, we identified 5 schwannoma/perineurioma cases and 2 neurofibroma/perineurioma cases. Patients, aged 38 to 81 years, with a female predominance (5/7), presented with tumor sizes ranging from 0.3 cm to 1.2 cm, primarily located in extremities (4/7), followed by the head and neck (2/7), and trunk (1/7). All seven cases tested negative for VGLL3 rearrangement. Our findings contrast with previous studies, possibly due to the difference in anatomical locations; lesions originating from small peripheral nerves in subcutaneous soft tissue may possess distinct genetic profiles compared to the less common lesions arising from smaller nerve twigs in the dermis. Additionally, differences in sensitivity between our break-apart FISH probe and RNA-sequencing techniques used in prior studies may contribute to the variation. Another aspect to consider is defining the hybrid lesions; although they are generally defined as a mixture of two seemingly distinct cell populations – alternating Schwann cells and perineurial cells – distinguishing between these two populations may not be obvious without immunohistochemistry, making the classification less straightforward.