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