CHOLESTEATOMA - A MOLECULAR AND CELLULAR PUZZLE

Hypothesis: There are at least three possible molecular models of chol esteatoma pathogenesis. Cholesteatoma may arise as a result of 1) the induction of a preneoplastic or neoplastic transformation event; 2) a defective wound-healing process; and/or 3) a pathologic collision of t he host inflammatory response, normal middle ear epithelium, and a bac terial infection. Background: There have been a number of speculations concerning the factors that foster the development of cholesteatoma. Before resolving the molecular basis for the pathogenesis of cholestea tomas, it is important to present and test plausible models that could explain how a cholesteatoma becomes invasive, migratory, hyperprolife rative, aggressive, and recidivistic. Methods: The authors evaluated b y various techniques (e.g., immunohistochemistry, flow cytometry, and image analysis) a large number of cholesteatomas of all types (e.g., p rimary and secondary acquired, recurrent, and congenital) and a range of normal tissues (tympanic membrane, canal wall skin, and postauricul ar skin) for the expression of various proteins (e.g., p53, ectopeptid ases, tryptase) and for the presence of DNA aneuploidy. Results and Co nclusions: The authors' published and unpublished studies to date supp ort several suppositions concerning the pathology of cholesteatomas. F irst, cholesteatoma epithelium behaves more like a wound-healing proce ss than a neoplasm. The available evidence to date does not indicate t hat cholesteatomas have inherent genetic instability, a critical featu re of all malignant lesions. Second, the induction of hyperproliferati ve cells in all layers of the cholesteatoma epidermis implicates a pot ential idiopathic response to both internal events as well as external stimuli in the form of cytokines released by infiltrating inflammator y cells. Third, the presence of bacteria may provide a critical link b etween the cholesteatoma and the host, which prevents the cholesteatom a epithelium from terminating specific differentiation programs and re turning to a quiescent state in which it becomes minimally proliferati ve, nonmigratory, and noninvasive. Fourth, none of our data suggest th at there are any obvious molecular or cellular differences among the v arious types of cholesteatomas (e.g., primary and secondary acquired, recidivistic, and congenital). Continued research should delineate the precise molecular and cellular dysfunction involved in the pathogenes is of cholesteatomas and how this knowledge can be useful in the clini cal management of cholesteatomas.