<scp>CD73</scp> Expression Correlates With Malignant Progression in <scp>NF1</scp> ‐Associated Peripheral Nerve Sheath Tumors: Potential Role in Pathological Diagnosis

This study investigated the association between CD73 expression and malignant progression in NF1-associated peripheral nerve sheath tumors and evaluated its potential as a diagnostic marker. Histopathological differentiation of atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP) and low-grade malignant peripheral nerve sheath tumors (MPNST) in patients with NF1 remains challenging. Therefore, reliable adjunctive markers are needed to improve diagnostic accuracy. CD73 is an ectoenzyme with ecto-5'-nucleotidase activity. Recent studies have also suggested that CD73 may promote tumor invasion by facilitating extracellular matrix remodeling, independent of immune suppression. To investigate the role of CD73 in NF1-associated tumors, we analyzed CD73 expression in 57 NF1-associated tumors, including 39 benign neurofibromas (NF), 7 ANNUBP, and 11 MPNST, using immunohistochemistry and reverse transcription- quantitative PCR (RT-qPCR) in selected cases. Most tumors arose in the skin or subcutaneous tissue. Among the four histological subtypes of NF, solitary and diffuse types were mostly negative for CD73 expression (19/20 cases), whereas plexiform and mixed types, which are associated with a higher risk of malignant transformation, more frequently exhibited positive expression. Most ANNUBP cases (6/7 cases) demonstrated low or negative CD73 expression, whereas all MPNST cases were positive, with the majority showing high expression (9/11 cases). CD73 expression was significantly higher in MPNST than in solitary and diffuse types of NF and ANNUBP. RT-qPCR analysis consistently demonstrated a stepwise increase in NT5E(CD73) mRNA expression progressing from benign solitary and diffuse types of NF (0.74 ± 0.33) to ANNUBP (2.93 ± 0.57) and MPNST (9.26 ± 4.89). These findings suggest that CD73 expression increases in association with higher tumor grade and malignant progression in NF1-associated peripheral nerve sheath tumors and may serve as a useful adjunctive marker in pathological diagnosis, particularly in cases where distinguishing ANNUBP from MPNST is challenging.