Transforming Growth Factor β and Wound Healing in Human Cholesteatoma

Objective: Cholesteatoma is a nonmalignant, destructive lesion of the temporal bone that gradually expands and causes complications by the erosion of the adjacent bony structures. The consequences can be as severe as facial paralysis and intracranial complications. Until now, surgery has been the only treatment of choice. The pathogenesis of cholesteatoma remains controversial. Current concepts postulate that cholesteatoma may be a wound-healing process, although formal proof is lacking as of yet. Several reports provide evidence for the involvement of transforming growth factor (TGF)beta in both normal and abnormal wound healing. Study Design: The expression of TGF beta, the activated form of its intracellular effector, phosphorylated-Sma-Mad (pSmad)2, its natural inhibitor, Smad7, and target gene extra domain A-positive fibronectin (EDA-FN) were examined. Methods: Quantitative immunohistochemical analysis was performed using an image analysis system. Results: In 12 cholesteatoma and control samples, protein expressions showed consistent relationships among TGF beta, nuclear pSmad2, and Smad7. We found concordant expressions of TGF beta and nuclear pSmad2 in cholesteatoma epithelium and its control. Epithelia] Smad7 expression was significantly reduced in cholesteatoma when compared with control epithelium (P = .04). In cholesteatoma extracellular matrix (ECM), a significantly increased TGF beta, and nuclear pSmad2 was demonstrated (P < .01). Smad7 expression in the ECM was comparable in cholesteatoma and its control. EDA-FN deposition in cholesteatoma ECM was excessive, whereas EDA-FN expression was absent in controls. Conclusion: Our results confirm reports of in vitro experiments and support the concept that cholesteatoma behaves as a chronic wound healing process.