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A report on the 4th International Conference on cholesteatoma and mastoid surgery, Niigata, Japan, September 1992

From the Cholesteatoma Club grew this series of International Conferences on Cholesteatoma and Mastoid Surgery. The first was in Iowa, the second in Jerusalem, the third in Copenhagen and 360 delegates gathered in Niigata, Japan in early September 1992 for the 4th. The conference was divided into sessions some of which were clinical but most of which reported basic scientific investigation of cholesteatoma. There was an extensive video section, concerned mainly with surgical technique, and an excellent poster session. Representation from Europe and North America was not as strong as in Copenhagen but those who had made their way to Japan heard many high quality papers. The scientific sections were divided into bone resorption, immunology, animal experimentation, migration and cytokeratins and biochemistry. The bone resorption section was opened by a special lecture given by Professor Richard Chole, who began by emphasizing that the pathways which lead to bone resorption end with recruitment and activation of osteoclasts. The osteoclast is the only cell which has been observed to actively resorb bone. For 80 to 90 per cent of its life a cholesteatoma is apparently inactive and adjacent bone will be devoid of osteoclast activity. Osteoclasts make a transient appearance for one to three weeks during active bone resorption. In the animal model Professor Chole has shown that a sustained increase in middle ear pressure of as little as 4 mm mercury results in the recruitment of osteoclasts within two days. It is unlikely that pressure alone is the sole mediator of resorption in cholesteatoma. Activation of osteoclasts implies the localized production of cytokines. A number of papers dealt with the immunohistochemical localization of bone resorbing cytokines and hormones in cholesteatoma and related tissue. Both interleukin 1 (IL-1) and tumour necrosis factor (TNF) have been identified in the keratinizing epithelium, in granulation tissue (monocytes and macrophages) and at sites of bone resorption. In vitro studies to determine the possible interactions of various cytokines accompanied most of this work. It appears that IL-1 works synergistically with TNF and transforming growth factor and IL-6 may be involved in and support IL-1 and TNF induced bone resorption. IL-1 also stimulates the production of prostaglandin E2 by osteoblasts. Similar findings have been reported previously. It is possible to have severe inflammation and infection of the middle ear when all these cytokins are likely to be present, but with little or no clinical symptoms of bone resorption. With the presence of cholesteatoma bone resorption seems inevitable. Novel research on parathyroid hormone related protein (PTH-rP) was presented by Cheshire et al. from the United Kingdom. This recently recognized protein demonstrates potent bone resorbing activity and was shown by the British group to be produced by cholesteatoma cells both in vivo and in vitro. Attention at the conference was also focused on possible medical management of cholesteatoma in view of the presence of these mediators of inflammation. It is known that indomethacin inhibits prostaglandin synthesis and steroids impede the inflammatory reaction presumably through a similar mechanism. Bisphosphonates are powerful inhibitors of bone resorption and these compounds have a low toxicity and some are absorbed orally. They are selectively concentrated in bone where they interfere with the action of osteoclasts. It was suggested therefore that the use of all three of these drugs would be useful in the medical management of cholesteatomas where surgery is inadvisable, such as the very elderly or where active bone resorption is being observed, or where there will be a delay for planned surgery. Whether these drugs should be applied topically or systemically has yet to be determined. Most attention in recent years has been directed at keratinocytes element of cholesteatoma. Albino et al. proposed that a fundamental alteration in the biology of one or more of the constituents of cholesteatoma (keratinocytes or fibroblasts) may explain the neoplastic like behaviour of this tissue. This group looked at the fibroblasts and compared the invasive potential of fibroblast derived from cholesteatoma and non cholesteatoma skin using the Boyden chamber assay. Fibroblasts from cholesteatoma specimens were always invasive whereas those from normal ear specimens were not. They propose that such invasive fibroblasts may provide a contact guidance mechanism which may in part explain the invasive potential of the keratinizing epithelium. The immunology section offered little new but did reinforce the apparent importance of the increased numbers of Langerhan cells found in cholesteatoma. Close contact between these antigen presenting cells in the cholesteatoma matrix and T-helper cells in the associated connective tissue has been observed. Interestingly, some of these T-helper cells respond to antigens by secreting a variety of substances that can activate lymphocytes and macrophages with subsequent production of cytokines. Cholesteatoma debris itself has been shown to stimulate the production of TNF by human monocytes in vitro. In addition, evidence was presented that Langerhan cell con-