Chasing Ghosts, In Search of Origin and Common Pathways

BackgroundGhost cell tumors (GCTs) are rare neoplasms arising in ectodermal tissues of odontogenic, skin adnexal, and sellar locations, unified by the presence of anucleate ghost cells and Wnt pathway activation. Their histogenesis and broader stem and developmental signaling landscapes remain poorly understood. Here, we evaluate the expression of key stem and developmental markers in GCTs and related histologic controls to advance understanding of their ontogenetic overlap.MethodsImmunohistochemistry for β-catenin, LEF1, NOTCH1, SOX2, OCT3/4, and CD34 was performed on GCTs (ACP n=13, PMC n=9, COC n=1) and histologic controls papillary craniopharyngioma (PCP n=8), ameloblastoma (AMB n=10), and calcifying epithelial odontogenic tumor (CEOT n=1). Manual interpretation and digital quantification using QuPath were performed. Pairwise Wilcoxon signed-rank tests assessed differences in marker expression between tumor types.ResultsLEF1 and β-catenin were expressed in all GCTs and most AMB cases (9/10 and 8/10). A consistent hierarchy of LEF1>NOTCH1>SOX2 was identified across ACP, PMC, and AMB. NOTCH1 was expressed in 82% (9/11) of ACP and all evaluable PMC (8/8), with suprabasal predominance relative to basal-predominant LEF1. Despite comparable median LEF1 in AMB (28.1%) and ACP (29.6%), median NOTCH1 was low in AMB (2.7%). SOX2 was sparse across all tumors, supporting physiologic expression. OCT3/4, CD34, and all markers in CEOT were negative.ConclusionsACP and PMC co-express LEF1 and NOTCH1 in epithelial compartments, supporting a Wnt-on/Notch-on profile in GCTs, contrasting the Wnt-on/Notch-off profile of AMB. Basal and suprabasal distributions of LEF1 and NOTCH1 in PMC support recapitulation of normal hair follicle compartmental organization into the neoplastic state.