The Laryngoscope
C 2014 The American Laryngological,
V
Rhinological and Otological Society, Inc.
Contemporary Review
Etiopathogenesis of Acquired Cholesteatoma: Prominent Theories
and Recent Advances in Biomolecular Research
Chin-Lung Kuo, MD
Objective: To review recent biomolecular advances in etiopathogenesis of acquired cholesteatoma.
Data Sources: MEDLINE via OVID (to March 2014) and PubMed (to March 2014).
Review Methods: All articles referring to etiopathogenesis of acquired cholesteatoma were identified in the above databases, from which 89 articles were included in this review.
Results: The mechanisms underlying the etiopathogenesis of acquired cholesteatoma remain a subject of competing
hypotheses. Four theories dominate the debate, including theories of invagination, immigration, squamous metaplasia, and basal
cell hyperplasia. However, no single theory has been able to explain the clinical characteristics of all cholesteatoma types: uncoordinated hyperproliferation, invasion, migration, altered differentiation, aggressiveness, and recidivism. Modern technologies
have prompted a number of researchers to seek explanations at the molecular level. First, cholesteatomas could be considered
an example of uncontrolled cell growth, capable of altering the balance toward cellular hyperproliferation and enhancing the
capacity for invasion and osteolysis. Second, the dysregulation of cell growth control involves internal genomic or epigenetic
alterations and external stimuli, which induce excessive host immune response to inflammatory and infectious processes. This
comprises several complex and dynamic pathophysiologic changes that involve extracellular and intracellular signal transduction
cascades.
Conclusions: This article summarizes the existing theories and provides conceptual insights into the etiopathogenesis of
acquired cholesteatoma, with the aim of stimulating continued efforts to develop a nonsurgical means of treating the disorder.
Key Words: Connexin 26, cytokines, etiology, microRNA, pathogenesis.
Laryngoscope, 125:234–240, 2015
INTRODUCTION
Acquired cholesteatoma is a well-demarcated nonneoplastic lesion in the temporal bone that arises from
an abnormal growth of keratinizing squamous epithelium.1 Acquired cholesteatoma is locally invasive and
capable of causing middle ear destruction.2 Due to the
likelihood of fatality resulting from intracranial complications, acquired cholesteatoma remains a cause of morbidity and death for individuals who lack access to
advanced medical services. Despite substantial research
into the disorder, the etiopathogenesis of acquired cholesteatoma has yet to be clearly elucidated. Furthermore, given the fact that no viable nonsurgical therapy
From the Department of Otolaryngology–Head and Neck Surgery,
Taipei Veterans General Hospital; the Department of Otolaryngology,
National Yang-Ming University School of Medicine; Institute of Brain
Science, National Yang-Ming University; the Department of Otolaryngology, National Defense Medical Center, Taipei, Taiwan, R.O.C.; the
Department of Otolaryngology, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, R.O.C.
Editor’s Note: This Manuscript was accepted for publication July
24, 2014.
The author has no funding, financial relationships, or conflicts of
interest to disclose.
Send correspondence to Chin-Lung Kuo, MD, No. 201, Section 2,
Shih-Pai Road, Taipei 112, Taiwan, R.O.C.
E-mail: [email protected]
DOI: 10.1002/lary.24890
Laryngoscope 125: January 2015
234
has been developed thus far, a comprehensive understanding of previous progress and recent advances in
biomolecular research on acquired cholesteatoma could
aid in the development of an effective management
strategy. This article reviews prominent theories behind
acquired cholesteatoma, presents the current state of
research on its etiopathogenesis, and highlights potential avenues for research in the future.
CURRENT THEORIES OF
ETIOPATHOGENESIS
Despite numerous clinical studies, animal experiments, and modern technologies, the mechanisms underlying the etiopathogenesis of acquired cholesteatoma
remain a subject of competing hypotheses. Four theories
dominate the debate (Fig. 1).
Invagination Theory (Retraction Pocket Theory)
The most widely accepted theory was proposed by
Wittmaack in 1933 and involves invagination or a
retraction pocket of the eardrum (Fig. 1A).3 This theory
claims that the precursors to cholesteatoma are retraction pockets of the pars flaccida, which compared to the
pars tensa, is less fibrous and less resistant to displacement. The retraction pocket is caused by negative pressure in the middle ear, which in-turn results from
Kuo: Etiopathogenesis of Acquired Cholesteatoma
Fig. 1. Four prominent theories for the etiopathogenesis of acquired cholesteatoma. (A) Invagination theory (retraction pocket theory). (B) Epithelial
invasion or migration theory (immigration theory).
(C) Squamous metaplasia theory. (D) Basal cell
hyperplasia theory (papillary ingrowth theory).
eustachian tube dysfunction (hydrops ex vacuo theory),
repeated inflammation, habitual sniffing, or a mastoid of
small volume.4–8 A deepening of the retraction pocket
with accumulation of desquamated keratin can lead to
cholesteatoma formation, which obstructs the opening of
the pocket and thereby induces ingrowth expansion into
the middle ear cleft.
Based on this theory, Tos divided cholesteatomas
into three types: 1) attic cholesteatoma, which develops
from Shrapnell’s membrane; 2) tensa retraction cholesteatoma, which involves the entire pars tensa; and 3)
sinus cholesteatomas, which originates from a posterosuperior retraction of the pars tensa that extends to the
sinus tympani.9
Theory of Epithelial Invasion or Migration
(Immigration Theory)
Another potential mechanism behind the etiopathogenesis of acquired cholesteatoma is epithelial invasion
or migration (Fig. 1B). This theory was independently
proposed by Habermann in 188810 and Bezold in 1890,11
based on their observations obtained during surgery.
Immigration theory assumes that the keratinizing squamous epithelium of the eardrum invades or migrates
into the middle ear through a traumatic or iatrogenic
defect in the eardrum. The concept of eardrum perforation as a precursor to cholesteatoma has been strengthened by recent findings from Karmody and Northrop.12
By examining histologic sections of temporal bones from
60 children, those researchers found evidence that squamous epithelium actively migrated from the eardrum
toward the middle ear. Immigration theory contradicts
the assertion that a retraction pocket acts as the precursor of acquired cholesteatoma, and was further corroborated in an animal study by Jackson and Lim,13 who
observed migration of keratinizing epithelium into cat
bulla by contact guidance.
Laryngoscope 125: January 2015
Theory of Squamous Metaplasia
The squamous metaplasia theory was first proposed
by Wendt in 1873, who theorized that metaplastic transformation of middle ear mucosa into keratinizing epithelium led to the formation of cholesteatomas (Fig. 1C).14
This theory contradicted the simplified and arbitrary
definition of acquired cholesteatoma (which described
the condition as "skin in the wrong place"), and was
widely accepted among otologists in the 19th century.15
In brief, squamous metaplasia theory stated that an
enlargement of cholesteatoma intercurrent with infection and inflammation would lead to lysis and perforation of the eardrum, resulting in the typical appearance
of acquired cholesteatoma. Sade et al. extended Wendt’s
theory by suggesting that chronic irritation can cause
pluripotent mucosal epithelial cells to become keratinizing.16 A recent animal study by Yamamoto-Fukuda et al.
also strongly supported the metaplasia theory; however,
those authors proposed that the epithelial cells in cholesteatoma originated in the eardrum, as cells from the
middle ear mucosa and the skin of the external ear
canal were not found to form cholesteatomas in response
to persistent pathological stimuli.17
Basal Cell Hyperplasia Theory (Papillary
Ingrowth Theory)
In 1925, the squamous metaplasia theory was challenged by Lange, who proposed the theory of basal cell
hyperplasia (Fig. 1D).18 Lange theorized that the subepithelial tissue of Prussak’s space could be invaded by cholesteatoma microcysts within Shrapnell’s membrane
(pars flaccida). Prussak’s space is a recess bound medially by the neck of malleus, laterally by the pars flaccida, superiorly by the lateral malleolar fold, and
inferiorly by the lateral process of malleus. According to
basal cell hyperplasia theory, keratin-filled microcysts,
Kuo: Etiopathogenesis of Acquired Cholesteatoma
235
buds, or pseudopods are formed in the basal layer of the
epithelium,19 and retraction pockets or eardrum perforations are not necessarily a prerequisite to the formation
of cholesteatoma. This theory has been substantiated by
several clinical, experimental, and animal studies, and
may explain the occurrence of acquired cholesteatomas
behind an intact eardrum.19,20
A number of otologists believe that the pathogenesis
of cholesteatoma is a complex hybrid process involving
these four seemingly discrete mechanisms.8,21 In 2000,
Sudhoff and Tos combined the theories of invagination
and basal cell hyperplasia to explain the formation of
retraction pocket cholesteatoma.8
RECENT BIOMOLECULAR ADVANCES IN THE
UNDERSTANDING OF ETIOPATHOGENESIS
Cholesteatoma has been recognized for more than 3
centuries; however, the nature of the disorder has yet to
be determined. Several plausible mechanisms have been
proposed for acquired cholesteatoma; however, no single
theory has been able to explain the clinical characteristics of all cholesteatoma types: uncoordinated hyperproliferation, invasion, migration, altered differentiation,
aggressiveness, and recidivism.21 Modern technologies
have thus prompted a number of researchers to seek
explanations at the molecular level.
POTENTIAL GENOMIC ALTERATIONS
IN CHOLESTEATOMAS
Researchers have demonstrated the high proliferative activity of cholesteatoma epithelium using a variety
of proliferation markers such as cytokeratins 13/16, Ki67, proliferating cell nuclear antigen, thrombomodulin,
argyrophilic nuclear organizer regions, and thymidine.21–24 Compared to normal skin, the cholesteatoma
epithelium exhibits a significantly higher percentage of
marker-labeled cells. The most direct hypothesis explaining this high proliferation activity is the assertion that
cholesteatomas are premalignant or low-grade well-differentiated squamous cell neoplasias.25 However, obtaining evidence to confirm this hypothesis may require
further DNA analysis of cholesteatomatous masses.26
Recent studies using microarray analysis techniques
have demonstrated that cholesteatoma tissue expresses
many tumor-relevant genes that could play a role in
pathogenesis.27 For example, epidermal growth factor
receptor (EGFR) has been shown to be related to proliferation and differentiation in normal cells in vivo.28 The
upregulation and activation of the EGFR, observed in several tumor types, plays an important role in both tumor
initiation and progression.29,30 Overexpression of EGFR
has also been identified in cholesteatomas, suggesting
that variations in EGFR gene regulation could be associated with the proliferation of cholesteatomas.28 Another
example of defective gene regulation in cholesteatomas is
the overexpression of transforming growth factor a (TGFa), which is a potent stimulator of cell growth and a specific ligand involved in the activation of EGFR.31
Additionally, the proto-oncogenes c-myc and c-jun
have been strongly linked to keratinocyte differentiation
Laryngoscope 125: January 2015
236
and proliferation in cholesteatomas.32–35 The c-myc gene
is located on chromosome 8q24. Previous studies have
shown that the aneuploidy of chromosome 8 and copynumber alterations of the c-myc gene are associated
with the proliferative and aggressive nature of cholesteatomas.34–36 Aneusomy of chromosomes 7 and 17 has
also been suggested to play a crucial role in cholesteatoma growth and bone destruction.36
INSUFFICIENT EVIDENCE FOR GENOMIC
INSTABILITY IN CHOLESTEATOMA
Connexins, or gap junction proteins, are a family of
structurally related transmembrane proteins that
assemble to form intercellular channels allowing the
rapid transport of selected ions and small molecules.37
Twenty-one connexins have been identified in humans.
Connexin 26, also known as gap junction beta-2 (GJB2),
is a transmembrane protein encoded by the GJB2 gene,
which is expressed in the cochlea and the skin. Mutations in the GJB2 gene have been shown to cause congenital nonsyndromic sensorineural hearing loss and
hyperkeratotic skin disorders.38 Microarray analysis by
Klenke et al. revealed that the expression of GJB2 gene
is higher in cholesteatoma tissue than in the skin of the
external auditory canal.27 Choung et al. identified the
upregulation of connexin 26 in the epithelium of cholesteatoma in the human middle ear, compared to that
found in normal retroauricular skin and the skin of the
ear canal.37 Alterations in the expression of connexin 26
may contribute to the multifactorial pathogenesis of cholesteatoma by modifying the intercellular communication
between keratinocytes37; therefore, it is reasonable to
assume that mutations in the GJB2 gene could alter the
development of the cholesteatoma and/or influence the
aggressiveness of the lesion.38 However, a prospective
observational study by James et al. failed to identify a
correlation between GJB2 gene mutations and the severity of cholesteatoma (i.e., the extent of the cholesteatoma
and number of eroded ossicles) in 98 cases of pediatric
cholesteatoma.38 In addition, James et al. found that
only 14% of children with cholesteatoma present variants of the gene GJB2.38 Based on the existing
evidence, it is difficult to support a relationship
between GJB2 gene mutations and the development of
cholesteatoma.
Several tumor suppressor genes (e.g., p53, p27,
CDH18, 19 and ID4, PAX3, LAMC2, and TRAF2B) have
been shown to be down-regulated in cholesteatomas.25,27,39,40 For instance, tumor suppressor p53,
encoded by the Tp53 gene, protects the cell from genome
mutations and propagation of DNA damage.25,41,42
Mutations in the p53 gene give rise to mutant p53 proteins that are highly expressed in various types of cancer.25,42 Moreover, p53 has been shown to be more
strongly expressed in cholesteatoma than in normal skin
cells of the eardrum.25
The fact that cholesteatomas present a greater
number of p53-positive cells does not necessarily mean
that the p53 gene has "mutated." Additionally, there is a
wide variation in the percentage of p53-positive cells in
Kuo: Etiopathogenesis of Acquired Cholesteatoma
all subgroups of cholesteatomas.25 Furthermore, hyperproliferative keratinocytic lesions comprise a wide range
of nontumorigenic, pretumorigenic, and tumorigenic conditions.43 As with cholesteatomas, these lesions rarely
progress to become apparent neoplasms.
In contrast, several cytogenetic and histopathological studies have revealed that cellular dysplasia, an
early neoplastic process, is not a critical event in the
genesis of cholesteatoma.24,25,44,45 Specifically, in previous research, inherent genomic instability (in the form
of abnormal or aneuploid quantities of DNA) was not
consistently found to be a critical feature of
cholesteatoma.25,46–49
In summary, observations at the biomolecular level
have not yet provided sufficient genomic evidence to support premalignant or malignant processes in cholesteatoma. Revealing the actual underlying association
between cholesteatoma and neoplasms will require further investigation.
EPIGENETIC REGULATION IN
CHOLESTEATOMA: THE ROLE OF
MICRORNAS
MicroRNAs are noncoding small RNA molecules
(containing 22–24 nucleotides) that regulate the expression of post-transcriptional messenger RNA (mRNA) via
the initiation of mRNA degradation or the inhibition of
translation.50–54 Dysregulation of microRNA expression
has been implicated in neoplastic and hyperproliferative
diseases.51,54 Although microRNAs were identified as
early as 1989,55 it was not until the early 2000s that
microRNAs were recognized as a particular category of
biological regulator with conserved functions.56–58 In
2009, Friedland et al. first described the potential role of
microRNA in regulating growth and proliferation in
adult acquired cholesteatoma.54 This study identified
increased levels of microRNA-21 (hsa-mir-21) concurrent
with decreased levels of phosphatase and tensin homolog
(PTEN) and programmed cell death 4 (PDCD4) in cholesteatoma, compared to the levels found in normal postauricular skin. PTEN and PDCD4 have been recognized
as potent tumor suppressors controlling various aspects
of apoptosis, proliferation, invasion, and migration.
Friedland et al. postulated that the upregulation of
microRNA-21 could lead to the suppression of PTEN and
PDCD4, resulting in keratinocyte proliferation, migration, growth, and invasion in cholesteatoma.
In another study examining the role of microRNAs
in the pathogenesis of cholesteatomas, Chen and Qin
found higher levels of microRNA-21 and a more pronounced reduction in PTEN and PDCD4 protein levels
in cholesteatoma tissue, compared to that of normal
skin, particularly in pediatric patients. Differences
between pediatric and adult cholesteatomas with regard
to microRNA-21 and its targets (PTEN and PDCD4)
were consistent with clinical observations, in which the
keratinocyte proliferation levels were higher in children
than in adults.38,51,59 Chen and Qin further compared
cholesteatomas and normal skin tissue with regard to
microRNA-let-7a and its target protein, the high
Laryngoscope 125: January 2015
mobility group AT-hook 2 (HMGA2). HMGA2 has been
identified as an oncogene, the overexpression of which is
a common characteristic of neoplastic cells in experimental as well as human models.60 Chen and Qin identified
the upregulation of microRNA-let-7a concurrent with
the downregulation of HMGA2 in cholesteatomas, compared with those observed in normal skin. They postulated that microRNA-let-7a may inhibit the expression
of HMGA2, leading to a reduction in the proliferation of
cholesteatoma cells and increased keratinocyte apoptosis. The stimulatory effect of microRNA-21 on cell proliferation and the antiproliferative effect of microRNA-let7a suggest that a dynamic balance may be involved in
the invasive behavior and benign non-neoplastic nature
of cholesteatoma.
OVER-REACTION OF HOST IMMUNE
RESPONSE TO INFLAMMATION
Researchers have attempted to identify the precise
molecular and cellular dysfunction involved in the cholesteatoma pathogenesis. In contrast to neoplastic transformation, several studies have revealed an association
between the progression of cholesteatoma and host
immune response to inflammation, such as that observed
in the process of wound healing.25,61–63 In particular,
Fig. 2. Molecular pathogenesis and mechanisms of cholesteatoma. The interactions between matrix keratinocytes and perimatrix fibroblasts play an important role in the process of tissue
homeostasis within cholesteatoma. Differentiation, proliferation
and migration of the matrix keratinocytes require both paracrine
and autocrine signaling. EGF 5 epidermal growth factor;
GM-CSF 5 granulocyte-macrophage colony stimulating factor;
IL 5 interleukin; KGF 5 keratinocytes growth factor; PDGF 5
platelet-derived growth factor; PTHrP 5 parathyroid hormonerelated protein; TGF 5 transforming growth factor; TNF-a 5 tumor
necrosis factor-alpha.
Kuo: Etiopathogenesis of Acquired Cholesteatoma
237
paracrine and autocrine interactions between matrix
keratinocytes and perimatrix fibroblasts play an important role in homeostasis and tissue regeneration within
cholesteatomas.64,65
As shown in Fig. 2, matrix keratinocytes release
proinflammatory cytokines, such as interleukin (IL)21a,
IL-1b, IL-6, and IL-8. The keratinocytes also secrete
parathyroid-hormone–related protein (PTHrP), which
has been listed as a member of the cytokine network
and a factor contributing to bone destruction.66
These keratinocyte-derived cytokines subsequently
induce perimatrix fibroblasts to secrete several other
cytokines, such as keratinocyte growth factor, granulocyte
macrophage-colony stimulating factor, epidermal growth
factor (EGF), tumor necrosis factor-alpha, platelet-derived
growth factor (PDGF), and TGF-a.67–69 These fibroblastderived cytokines in turn induce the differentiation, proliferation, and migration of matrix keratinocytes.21,39,62,64
In addition to paracrine regulatory mechanisms,
autocrine loops also play a role in maintaining tissue
homeostasis. For example, TGF-a and TGF-b are constitutively expressed in hyperproliferative epithelium, regulating keratinocyte proliferation and differentiation in
a process similar to that of the autocrine system (Fig.
2).65,70,71 Additionally, infiltrating inflammatory cells
also secrete cytokines to stimulate the induction of
hyperproliferative cells in all layers of the cholesteatoma
epidermis.20,21,25
Host innate immune response is thus a doubleedged sword. The immune system protects the host
against infectious threats; however, over-reactive
immune responses also seriously threaten the host by
contributing to the aggressiveness of cholesteatoma.
REGULATION OF ANGIOGENESIS AND
ANGIOGENIC GROWTH FACTORS
During inflammation, various cell populations (e.g.,
monocytes, macrophages, and infiltrating leukocytes) in
the matrix and perimatrix release a variety of angiogenic factors, such as vascular endothelial growth factor,
EGF, TGF-a, PDGF, IL-8, and cyclooxygenase 2, which
subsequently initiate angiogenesis.72,73 Angiogenesis
within the perimatrix enables the sustained migration of
keratinocytes into the middle ear cavity.72 It has thus
been concluded that angiogenesis is pivotal to the proliferation and aggressiveness of cholesteatoma.
BONE RESORPTION
Bone resorption can be triggered by the effects of
local pressure; however, in the 1950s, a link between the
chemical lysis of cholesteatoma and bone destruction was
proposed.74 The first step in bone resorption is the
recruitment of bone marrow mononuclear cells, followed
by multinucleation of those cells to form osteoclasts.21
Osteoclastogenesis can be promoted by the upregulated
cytokines in cholesteatoma, which can have direct or indirect effects on osteoclasts. These cytokines include IL-1,
IL-6, IL-17, interferon-beta, and PTHrP.21,75,76 Recently,
immunohistochemical analysis has revealed that receptor
activator of nuclear factor kappa-B ligand (RANKL) plays
Laryngoscope 125: January 2015
238
a pivotal role in inflammatory bone resorption.77 Activated T and B cells have been found to be important cellular sources of RANKL for osteoclastogenesis.77
Matrix-metalloproteinases (MMPs) are a family of
proteolytic enzymes synthesized by various types of cells
such as fibroblasts, keratinocytes, macrophages, and
endothelial cells. Recent studies have shown that MMPs
can promote aggressiveness in cholesteatoma with regard
to the destruction of bony tissue.21,39 Pediatric cholesteatomas present particularly severe inflammation with a
greater number of metalloproteinases, such that the pediatric disease is characterized as being more aggressive
than its counterpart in adults.78 Furthermore, an upregulation of MMP expression (e.g., MMP1, MMP9, MMP10,
and MMP12) and a decrease in associated enzyme inhibitors (tissue inhibitor of metalloproteinases) constitute
degradation of the extracellular matrix.27
THE ROLE OF INFECTION
Recent breakthroughs have suggested that infections in the middle ear may stimulate the aggressiveness
of cholesteatoma.62 Squamous epithelium can be rendered destructive in an environment of chronic infection,54 such that the osteolytic effects of cholesteatoma
are enhanced. Furthermore, biofilm-forming bacteria
within the cholesteatoma matrix could explain
antibiotic-resistant middle ear infections and have been
shown to play a crucial role in cholesteatoma pathogenesis.79,80 For example, the biofilm-forming Pseudomonas
aeruginosa lipopolysaccharide has been shown to activate keratinocyte hyperproliferation.62
Aerobic organisms such as P aeruginosa require
oxygen to survive. The process of aerobic metabolism
induces the production of reactive oxygen species (ROS),
which are highly toxic and deleterious to biological macromolecules. Aerobic cells have developed systems in
which antioxidants are used to control the flux of ROS.81
Increases in oxidative stress and decreases in the level
of antioxidants have recently been identified in cholesteatoma patients. An imbalance between oxidative processes and antioxidants increases biofilm production and
has been shown to be involved in cholesteatoma
pathogenesis.82,83
The presence of bacteria may also prevent the cholesteatoma epithelium from activating terminal differentiation and returning to a quiescent state, thereby
leading to ongoing proliferative, migratory, and invasive
behaviors.25 In addition, the pH of the keratin debris of
cholesteatoma has been found to be acidic, and the acidity of keratin debris escaped from the cholesteatoma sac
has been proposed to be a critical factor in bone destruction.84,85 Researchers have proven that these acids are
derived from aerobic (e.g., Staphylococcus aureus and
Proteus species) as well as anaerobic (e.g., Peptococcus
and Bacteroides species) microorganisms.86
THE TRUE NATURE OF CHOLESTEATOMA
HAS YET TO BE DETERMINED
A few cases of cholesteatoma-related carcinoma
have been reported87–89; however, a causal association
Kuo: Etiopathogenesis of Acquired Cholesteatoma
between cholesteatoma and carcinoma remains to be
identified. Is cholesteatoma a premalignant or malignant
neoplasm? Existing evidence remains insufficient to
make a definitive conclusion.
Nonetheless, cholesteatomas clearly exhibit clinical
features similar to those observed in neoplasms. Based
on the current evidence thus far, cholesteatomas can be
considered an example of uncontrolled cell growth, capable of altering the balance toward cellular hyperproliferation and enhancing the capacity for invasion and
osteolysis. The dysregulation of cell growth control
involves internal genomic or epigenetic alterations and
external stimuli, which induce excessive host immune
response to inflammatory and infectious processes. This
comprises several complex and dynamic pathophysiologic
changes that involve extracellular and intracellular signal transduction cascades.
CONCLUSIONS
Recent advances in biomolecular research have
enhanced our understanding of the etiopathogenesis of
acquired cholesteatoma. Nonetheless, management of
this condition has not progressed substantially, and
treatments remain predominantly surgical. Exploring
alternative avenues through biomolecular research could
expand the spectrum of therapeutic choices and lead to
the development of nonsurgical options for the treatment
of acquired cholesteatoma.
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