39 (2006) 1143–1159
* Corresponding author.
E-mail address: Cliff.Megerian@uhhs.com (C.A. Megerian).
0030-6665/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.otc.2006.08.003 oto.theclinics.com
1144 SEMAAN & MEGERIAN
Congenital cholesteatoma
The first published description of a congenital cholesteatoma appeared in
1885, by Lucae [13]. Körner’s initial criteria [14] to distinguish acquired
from congenital cholesteatoma were revived half a century later by Derlacki
PATHOPHYSIOLOGY OF CHOLESTEATOMA 1145
the anterior aspect of the malleus handle or neck and that posterosuperior
cholesteatoma had an attachment to the posterior aspect of the malleus han-
dle and to the incudostapedial joint. This location was far from the anterior
tympanic annulus and the lateral wall of the eustachian tube where epithelial
rests are usually found. Furthermore, he speculated that if the site of origin
was the lateral eustachian tube wall and the area anterior to the tympanic
annulus, cholesteatoma would block the eustachian tube before extending
into the tympanic cavity and the area of the malleus handle, a finding
that has not been described previously. Therefore, he argued against the ep-
ithelial rest theory and explained the pathogenesis of congenital cholestea-
toma by the acquired inclusion theory (Fig. 1). This theory speculates that
keratinized squamous epithelium may be implanted or included into the
tympanic cavity during one of many pathological events affecting the tym-
panic membrane and middle ear in childhood. According to Tos, viable
Fig. 1. ‘‘Acquired’’ inclusion theory suggested by Tos. (A1, 2) The tympanic membrane re-
tracted and adherent to the malleus handle, malleus neck, or long process of the incus is loos-
ened and torn leaving a small cuff of viable keratinized epithelium adherent to the ossicles with
a small residual tear in the tympanic membrane. As the tear heals, the included epithelium leads
to formation of an inclusion cholesteatoma. (B1, 2) A tangential tear is created as the retracted
and adherent tympanic membrane is loosened from the underlying structure resulting in a rem-
nant of epithelial cells without a perforation of the tympanic membrane that results in an inclu-
sion cholesteatoma. (C1, 2) Microperforations of the traumatized retracted tympanic
membrane result in invasion of the basal membrane by epithelial cones. As the ear drum is sud-
denly loosened, these cones are left behind and included in the tympanic cavity. (D1, 2) Similar
to the previous mechanism, repeated inflammation of the tympanic membrane result in prolif-
erating epithelial cones that penetrate the basal membrane and proliferate into the subepithelial
space. These cones are included in the tympanic cavity as the drum is loosened and detached
from the underlying bony structures.
PATHOPHYSIOLOGY OF CHOLESTEATOMA 1147
did not stain for LEF-1. Thus, they concluded that the epidermoid forma-
tion precursor initially reported is likely the result of a tangential cut arti-
fact of a thickened actively growing epithelial bud from the tip of the
tubotympanic recess. Microscopically, they observed that as the anterosu-
perior tip of the meatal plate (precursor of the pars tensa) develops, by ges-
tational week 12, the epidermal interface becomes jagged, and by
gestational week 16, epidermal cells become encroached onto the fibroblasts
of the bilaminar collagen layer. As the fibroblasts become more condensed,
small clumps of epidermal cell become trapped within the condensed bila-
minar collagen layer.
Despite improvements in our understanding, the pathophysiology of con-
genital cholesteatoma continues to be controversial and actively debated.
Furthermore, many questions remain unanswered. These questions pertain
to the biological factors that predict aggressiveness, growth, and recidivism
of middle ear congenital cholesteatoma (Fig. 2).
Acquired cholesteatoma
Primary acquired cholesteatoma
The pathophysiology of acquired cholesteatoma is similarly controver-
sial. As previously eluded to, the precise pathogenesis of cholesteatoma
has been debated for more than two centuries. Four predominant theories
have fueled the debate: (1) invagination, (2) basal cell hyperplasia or papil-
lary ingrowth, (3) metaplasia, and (4) epithelial invasion.
The invagination theory is currently regarded as one of the primary
mechanism of the formation of primary acquired attic cholesteatoma.
Anatomic or pathological conditions that predispose to eustachian tube
Fig. 2. Site of origin and patterns of spread of congenital cholesteatoma according to (A) Tos
‘‘acquired’’ inclusion theory and (B) Teed-Michael’s epidermal rest theory.
PATHOPHYSIOLOGY OF CHOLESTEATOMA 1149
Fig. 3. Mucosal compartmentalization of the middle ear. The mucosal folds of the middle ear
cleft define the spaces that limit the boundaries of the retraction pockets. Knowledge of their
anatomy helps understand the formation and extension of primary acquired cholesteatoma
(black arrows). (1) superior incudal fold, (2) superior malleolar fold, (3) lateral incudal fold,
(4) anterior malleolar fold, (5) lateral malleolar fold, (6) posterior malleolar fold. ET, eustachian
tube orifice; HAC, hypotympanic air cells; RW, round window niche. Eustachian tube dysfunc-
tion results in formation of a retraction pocket. Often, a pars flaccida retraction pocket is
formed (star). As the pocket deepens and insinuates between folds, the self-cleaning mechanism
is altered and keratin accumulates.
1150 SEMAAN & MEGERIAN
Fig. 4. Patterns of spread of primary acquired cholesteatoma from an attic retraction pocket
(D). (A) Antrum, most common; (B) posterior mesotympanum, second most common; and
(C) anterior mesotympanum, least common.
PATHOPHYSIOLOGY OF CHOLESTEATOMA 1151
Summary
The pathophysiology of cholesteatoma continues to be debated widely.
Cholesteatoma is classified as congenital or acquired. Recent studies appear
to favor a possible common origin and overlap in the pathophysiology be-
tween both entities. Despite the growing evidence that the genesis, expan-
sion, and progression of cholesteatoma is a complex interaction between
anatomic, inflammatory, and regulatory factors of cellular proliferation
and differentiation, the exact mechanism responsible for the invasion, recid-
ivism, and destruction seen in this disease remains unknown.
PATHOPHYSIOLOGY OF CHOLESTEATOMA 1157
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