CDX2 expression in malignant peripheral nerve sheath tumour: a potential diagnostic pitfall associated with PRC2 inactivation.

Aims: Malignant peripheral nerve sheath tumour (MPNST) is a soft tissue sarcoma that exhibits features of Schwann cell differentiation. Heterologous, often mesenchymal-type differentiation occurs in a subset of MPNST, while glandular morphology also is encountered in rare cases. We observed in MPNST unanticipated expression of CDX2, a transcription factor that regulates intestinal epithelial differentiation, and aimed to further characterize this phenomenon.

Methods/results: Expression of CDX2 was assessed by immunohistochemistry in a total of 32 high-grade MPNSTs lacking morphological evidence of epithelial differentiation, including twelve tumours (38%) that developed in the setting of neurofibromatosis and four (13%) in the setting of prior radiation therapy. CDX2 was expressed by 14 of 32 MPNSTs (44%), wherein immunoreactivity, varying from weak to strong, was present in 2-95% of neoplastic spindle cells (median 10%, mean 23%). Notably, CDX2 expression was limited to tumours with PRC2 inactivation (22/32; 69%), as evidenced immunohistochemically by diffuse loss of trimethylated histone H3K27. Analysing publicly available RNA-sequencing data from twelve MPNST cell lines, two of which are clonally related, we observed CDX2 expression in all six PRC2-inactivated cell lines, while CDX2 expression was negligible in six cell lines with intact PRC2, amounting to a 58-fold increase in CDX2 expression on average with PRC2 inactivation.

Conclusions: CDX2 is expressed in a subset of MPNSTs, even in the absence of morphological evidence of epithelial differentiation. CDX2 expression in MPNST is strongly associated with underlying PRC2 inactivation.