Hippo Pathway Dysregulation in Thymic Epithelial Tumors (TETs): Associations with Clinicopathological Features and Patients’ Prognosis

Thymic epithelial tumors (TETs) display heterogeneous histology and often unpredictable clinical behavior. The Hippo signaling pathway has been implicated in tumorigenesis, but its role in TETs remains poorly characterized. We performed the first comprehensive immunohistochemical analysis of core and upstream Hippo pathway components-YAP1, active YAP (AYAP), TAZ, LATS1, MOB1A, MST1, SAV1, and TEAD4-in 77 TETs. Associations with clinicopathological parameters and survival were explored. We observed widespread expression of Hippo components in TETs with significant associations among molecules and differences in subcellular localization and expression in normal tissue. Early stage TETs showed higher nuclear YAP1 (<i>p</i> = 0.032) and AYAP (<i>p</i> = 0.007), while cytoplasmic MST1 (<i>p</i> = 0.002), LATS1 (<i>p</i> = 0.007), MOB1A (<i>p</i> = 0.033) and TEAD4 (<i>p</i> < 0.001) correlated with advanced stage. Cytoplasmic MST1 (<i>p</i> = 0.014), LATS1 (<i>p</i> < 0.001) and TEAD4 (<i>p</i> = 0.005) were associated with histological aggressiveness. Cytoplasmic TEAD4 overexpression was associated with poorer overall survival (log-rank, <70% versus ≥70%, <i>p</i> = 0.003). Our findings provide novel insights into the differential regulation and compartmentalization of Hippo components in TETs. While indolent tumors show features that are consistent with partial Hippo inactivation, more aggressive phenotypes exhibit reduced nuclear YAP/TAZ and altered TEAD4 compartmentalization, suggesting a context-dependent Hippo signaling state. Cytoplasmic TEAD4 emerges as a potential adverse prognosticator, indicating involvement in non-canonical or Hippo-independent mechanisms.