Cholesteatoma The Theories The Pathophysiology of Cholesteatoma Maroun T. Semaan, MD, Cliff A. Megerian, MD* Otolaryngol Clin N Am 39 (2006) 1143–1159
CholesteatomaThe Theories
The Pathophysiology of Cholesteatoma Maroun T. Semaan, MD, Cliff A. Megerian, MD* Otolaryngol Clin N Am 39 (2006) 1143–1159
Definition
cystic lesion formed from keratinizing stratified squamous epithelium in the temporal bone
the matrix composed of epithelium that rests on the perimatrix
the resulting hyperkeratosis and shedding of keratin debris results in surrounding inflammatory reaction
Classification
Congenital
Acquired Primary Secondary
Congenital Cholesteatoma
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
Congenital cholesteatoma
Ongoing debate
Epithelial rest theory
Microperforation from chronic inflammation
Tos:
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
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
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
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
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
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
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’
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
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
Molecular models
Preneoplastic transformation events
Defective wound-healing process
Collision between host inflammatory response, normal middle ear epithelium, and bacterial infection
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
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
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
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
Summary
Complex pathogensis 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