Theories of cholesteatoma

1. Cholesteatoma The Theories The Pathophysiology of Cholesteatoma Maroun T. Semaan , MD, Cliff A. Megerian , MD* Otolaryngol Clin N Am 39 (2006) 1143–1159

2. Definition cystic lesion formed from keratinizing stratified squamous epithelium in the temporal bone the matrix composed of epithelium that rests on the perimatrix t he resulting hyperkeratosis and shedding of keratin debris results in surrounding inflammatory reaction

3. Classification Congenital Acquired Primary Secondary

4. Congenital C holesteatoma Korner’s 1965: pearly white mass behind an intact TM in the absence of history of otitis or otorrhea , TM perforation, or previous otologic procedures Levenson 1986: presence of prior bouts of otitis media does not necessarily exclude the presence of congenital cholesteatoma

5. Congenital cholesteatoma Ongoing debate Epithelial rest theory Microperforation from chronic inflammation Tos :

6. Primary acquired cholesteatoma Represent the vast majority seen clinically Deep retraction pockets in which desquamated keratin deposits and does not migrate These retraction pockets are considered precursors to cholesteatomas Bacteria can infect the keratin matrix, forming biofilms leading to chronic infection and epithelial proliferation

7. Primary acquired cholesteatoma Invagination: Eustachian tube dysfunction causes negative middle ear pressure Fluctuating negative and positive pressures combined with inflammation can lead to loss of structural support and atelectasis Pars flaccida the most susceptible Retraction pocket may form leading to alteration of normal epithelial migration patterns

8. Primary acquired cholesteatoma basal cell hyperplasia or papillary ingrowth Papillary ingrowth of keratinizing epithelium into the lamina propria of the TM Basal lamina of the TM separates the connective tissue of the lamina propria from the keratinising epithelium of the lateral layer of the TM Breaks in the basal lamina in spontaneous and induced cholesteatoma

9. Primary acquired cholesteatoma Metaplasia Low cuboidal and simple squamous epithelium can be changed to stratified squamous epithelium in patients with chronic or recurrent ear infection Epithelial cells pluripotent and can differentiate into other cell types in the presence of inflammation Clinically there is little support for this theory

10. Primary acquired cholesteatoma epithelial invasion Epithelial pseudopods seen within the lamina propria which form epithelial cones and microcholesteatomas Inflammation in Prussaks space causes breaks in the basal lamina allowing epithelial invasion and cholesteatoma formation

11. Primary acquired cholesteatoma Sudhoff & Tos 2000 Proposed a combination of both theories 4 stages Retraction pocket stage Proliferation stage of retraction pocket Expansion stage of retraction pocket Bone resorption

12. Secondary acquired cholesteatoma Perforations from infection or trauma can cause cholesteatoma Posterior marginal perforation Epithelial cells migrate across a denuded surface ‘ contact guidance ’ and stop when they encounter another epithelial surface ‘ contact inhibition ’

13. Alternatively Primary acquired Eustachian tube dysfunction Poor aeration of the epitympanic space Retraction of the pars flaccida Normal migratory pattern altered Accumulation of keratin, enlargement of sac

14. Alternatively Secondary acquired Implantation – surgery, foreign body, blast injury Metaplasia – transformation of cuboidal epithelium to squamous epithelium from chronic infection Invasion/Migration – medial migration along permanent perforation of TM Papillary ingrowth – intact pars flaccida , inflammation in Prussack ’ s space, break in the basal membrane, cords of epithelium migrate inward

15. Molecular models Preneoplastic transformation events Defective wound-healing process Collision between host inflammatory response, normal middle ear epithelium, and bacterial infection

16. Preneoplastic transformation events Hyperproliferative keratinocytes Increased proliferation Decreased terminal differentiation Expression of epithelial markers in the basal and suprabasal layers ( cytokeratins –10,13,16, filaggrin , involucrin ); confirm they arise from pars flaccida and overlying EAC skin High expression of epidermal growth factor receptor, transforming growth factor Upregulation of p53

17. Defective wound-healing process Chronic inflammatory response around matrix (granulation/ perimatrix ) Infiltration of activated T-cells and macrophages Production of cytokines (TGF,TNF,IL-1,IL-2,FGF,PDGF) Causes increased migration and invasion of cholesteatoma epithelium and fibroblasts

18. Host inflammatory response Bacterial related antigens producing host inflammatory response may stimulate the migrating epithelium ’ s uncoordinated proliferation Granulation induces invasion of keratinocytes Granulation – contains proteases, acid phosphatases, bone resorption proteins, osteoclast-activating factors, prostaglandins Keratin implanted into mouse calvaria was shown by Chole , et. al., to activate osteoclasts and produce a localized inflammatory bone remodeling similar to cholesteatomas

19. Cytokines Cytokines TNF -alpha lysosomal enzymes, acid phosphatase (total and tartrate resistant), cathepsin B , leucyl aminopeptidase lysozyme together with non- lysosomal enzymes calpain I and II It is likely that TNF-alpha acts both directly by causing bone erosion and indirectly by stimulating the release of lysosomal enzymes. The non- lysosomal enzymes calpain I and II seem to participate in the bone erosion associated with cholesteatoma by their involvement in collagen destruction. bacterial endotoxin

20. Summary Complex p athogensis of cholesteatoma Congenital: Epithelial rests Microperforations Tos theory Acquired: Primary (invagination) Secondary (implantation, migration, basal cell hyperplasia, metaplasia, invasion) Molecular biology: Cytokines  bony erosion and development of cholesteatoma