Cholesteatoma is a cystic lesion formed from keratinizing stratified squamous epithelium in the temporal bone. It has a complex pathogenesis involving both congenital and acquired factors. Congenitally, it may arise from epithelial rests or microperforations. Acquired cholesteatomas develop primarily from invagination or secondarily from implantation, migration, or basal cell changes. Molecularly, cytokines released in response to bacteria promote bone erosion and development of cholesteatoma.

2. 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

3. Classification
 Congenital
 Acquired
 Primary
 Secondary

4. 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

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 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