Albino A P, Kimmelman C P, Parisier S C
Department of Otolaryngology/Head and Neck Surgery, The Manhattan Eye, Ear, and Throat Hospital, New York, New York 10021, USA.
Am J Otol. 1998 Jan;19(1):7-19.
There are at least three possible molecular models of cholesteatoma 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 the host inflammatory response, normal middle ear epithelium, and a bacterial infection.
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 cholesteatomas, it is important to present and test plausible models that could explain how a cholesteatoma becomes invasive, migratory, hyperproliferative, aggressive, and recidivistic.
The authors evaluated by various techniques (e.g., immunohistochemistry, flow cytometry, and image analysis) a large number of cholesteatomas of all types (e.g., primary and secondary acquired, recurrent, and congenital) and a range of normal tissues (tympanic membrane, canal wall skin, and postauricular skin) for the expression of various proteins (e.g., p53, ectopeptidases, tryptase) and for the presence of DNA aneuploidy.
The authors' published and unpublished studies to date support several suppositions concerning the pathology of cholesteatomas. First, cholesteatoma epithelium behaves more like a wound-healing process than a neoplasm. The available evidence to date does not indicate that cholesteatomas have inherent genetic instability, a critical feature of all malignant lesions. Second, the induction of hyperproliferative cells in all layers of the cholesteatoma epidermis implicates a potential idiopathic response to both internal events as well as external stimuli in the form of cytokines released by infiltrating inflammatory cells. Third, the presence of bacteria may provide a critical link between the cholesteatoma and the host, which prevents the cholesteatoma epithelium from terminating specific differentiation programs and returning to a quiescent state in which it becomes minimally proliferative, nonmigratory, and noninvasive. Fourth, none of our data suggest that there are any obvious molecular or cellular differences among the various 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 pathogenesis of cholesteatomas and how this knowledge can be useful in the clinical management of cholesteatomas.
胆脂瘤发病机制至少有三种可能的分子模型。胆脂瘤可能由于以下原因产生：1）癌前或肿瘤转化事件的诱导；2）有缺陷的伤口愈合过程；和/或3）宿主炎症反应、正常中耳上皮和细菌感染之间的病理性碰撞。
关于促成胆脂瘤发展的因素有许多推测。在解决胆脂瘤发病机制的分子基础之前，提出并测试能够解释胆脂瘤如何变得具有侵袭性、迁移性、过度增殖性、侵袭性和复发性的合理模型很重要。
作者通过各种技术（如免疫组织化学、流式细胞术和图像分析）评估了大量各种类型的胆脂瘤（如原发性和继发性后天性、复发性和先天性）以及一系列正常组织（鼓膜、耳道壁皮肤和耳后皮肤）中各种蛋白质（如p53、外肽酶、类胰蛋白酶）的表达以及DNA非整倍体的存在情况。
作者迄今为止已发表和未发表的研究支持了一些关于胆脂瘤病理学的假设。首先，胆脂瘤上皮的行为更像是伤口愈合过程而非肿瘤。迄今为止的现有证据并未表明胆脂瘤具有所有恶性病变的关键特征——内在遗传不稳定性。其次，胆脂瘤表皮各层中过度增殖细胞的诱导意味着对内部事件以及浸润性炎症细胞释放的细胞因子形式的外部刺激存在潜在的特发性反应。第三，细菌的存在可能在胆脂瘤与宿主之间提供关键联系，这阻止了胆脂瘤上皮终止特定分化程序并恢复到最小增殖、非迁移和非侵袭性的静止状态。第四，我们的数据均未表明各种类型的胆脂瘤（如原发性和继发性后天性、复发性和先天性）之间存在任何明显的分子或细胞差异。持续的研究应阐明胆脂瘤发病机制中涉及的精确分子和细胞功能障碍，以及这些知识如何在胆脂瘤的临床管理中发挥作用。
