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

Abstract

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.