Cholesteatoma is a locally destructive keratinizing squamous epithelial lesion of the middle ear and mastoid. It is associated with chronic otorrhea, hearing loss, progressive local bone erosion, and clinically important postoperative recurrence risk.
Conditions with similar clinical presentations that must be differentiated from Cholesteatoma:
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Cholesteatoma. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Definition. Middle ear cholesteatoma is defined by the ectopic presence and expansion of keratinizing stratified squamous epithelium in normally non-keratinizing middle-ear/mastoid spaces. Popescu et al. (2024) define it as “the presence of keratinized stratified squamous epithelium within the cavity,” highlighting its destructive biology and propensity for bone erosion (published Nov 2024; https://doi.org/10.3390/jcm13226791) (popescu2024comprehensivemanagementof pages 1-2).
Core histopathologic compartments (matrix/perimatrix model). Contemporary mechanistic models distinguish: - Matrix: hyperproliferative keratinizing epithelium. - Peri-matrix (perimatrix): inflamed subepithelial granulation/connective tissue rich in fibroblasts, vessels, and immune cells. Rolesi et al. (2023) describe cholesteatoma as having keratin lamellae content, a hyperproliferative keratinizing matrix, and an inflamed peri-matrix with stromal/inflammatory elements (published Jul 2023; https://doi.org/10.3390/jpm13081189) (rolesi2023studyofangiogenic pages 2-4, rolesi2023studyofangiogenic pages 1-2).
Etiologic classes. Rolesi et al. (2023) summarize two principal clinical categories: congenital (often presenting as a pearly white mass behind an intact tympanic membrane and theorized to arise from ectodermal rests) versus acquired (commonly arising from retraction pockets due to chronic inflammation/dysventilation or via epithelial ingrowth through tympanic membrane defects) (rolesi2023studyofangiogenic pages 1-2).
Bone erosion: enzymatic and inflammatory mechanisms dominate. In a large contemporary clinical synthesis, Popescu et al. (2024) state: “Enzymatic lysis is considered the primary explanation” for bone erosion, citing collagenase detection in cholesteatoma tissue/adjacent skin and hypotheses locating erosive activity in the matrix or subepithelial granulation tissue (popescu2024comprehensivemanagementof pages 1-2). Additional mechanisms (pressure effects, osteoclast activation by inflammatory mediators, chronic osteomyelitis-like changes) are also discussed (popescu2024comprehensivemanagementof pages 24-26).
Cholesteatoma matrix keratinocytes display hyperproliferation and altered differentiation programs. In adult acquired cholesteatoma, Dambergs et al. (2023) report increased Ki-67 (MKI67) and NF-κB immunostaining in cholesteatoma compared with control skin, supporting increased proliferative signaling and survival (Feb 2023; https://doi.org/10.3390/medicina59020306) (dambergs2023morphopathogenesisofadult pages 1-2, dambergs2023morphopathogenesisofadult pages 13-14). NF-κB correlated with Ki-67 (r=0.538, p=0.017), consistent with a coordinated pro-proliferative axis (dambergs2023morphopathogenesisofadult pages 13-14).
GO/Process mapping (examples): epithelial cell proliferation (GO:0050673), regulation of apoptotic process (GO:0042981), NF-kappaB signaling (GO:0043123) (dambergs2023morphopathogenesisofadult pages 1-2, dambergs2023morphopathogenesisofadult pages 13-14).
Rolesi et al. (2023) and Popescu et al. (2024) emphasize that cholesteatoma aggressiveness emerges from bidirectional signaling between matrix keratinocytes and peri-matrix stromal/immune cells, functioning like a chronic wound-healing microenvironment (rolesi2023studyofangiogenic pages 10-12, rolesi2023studyofangiogenic pages 2-4, popescu2024comprehensivemanagementof pages 24-26).
Rolesi et al. outline a cytokine/growth-factor loop in which keratinocyte-derived cytokines (e.g., IL-1 family, IL-6/IL-8) activate fibroblasts and other peri-matrix cells, driving additional mediators (EGF, TNF, PDGF, TGF-α, KGF, GM-CSF) that reinforce epithelial proliferation, angiogenesis, and remodeling (rolesi2023studyofangiogenic pages 10-12, rolesi2023studyofangiogenic pages 2-4).
Quantitative biomarker evidence (2023): Rolesi et al. measured optical density (OD) signals for key pathways and found markedly increased inflammatory/proliferative markers in pediatric acquired cholesteatoma (rolesi2023studyofangiogenic pages 8-10, rolesi2023studyofangiogenic pages 5-8): - pSTAT3 highest in pediatric acquired (mean OD 125.54±4.88) vs congenital (88.51±5.97) vs adult acquired (75.49±2.72). (rolesi2023studyofangiogenic pages 8-10) - IL-1β peri-matrix OD: pediatric acquired 148.68±4.07 vs adult acquired 108.44±9.47 vs congenital peri-matrix 39.12±0.93 (many comparisons p<0.001). (rolesi2023studyofangiogenic pages 8-10, rolesi2023studyofangiogenic pages 5-8)
GO/Process mapping (examples): cytokine-mediated signaling pathway (GO:0019221), STAT cascade (GO:0097696), chronic inflammatory response (GO:0002544) (rolesi2023studyofangiogenic pages 8-10, rolesi2023studyofangiogenic pages 5-8).
A recurring mechanistic theme is dysregulation of matrix metalloproteinases (MMPs) and inhibitors (TIMPs) in the perimatrix, enabling extracellular matrix turnover, granulation tissue expansion, and coupling to bone resorption.
Popescu et al. (2024) also emphasize perimatrix collagenases/metalloproteinases as major contributors to osteolysis (popescu2024comprehensivemanagementof pages 24-26).
GO/Process mapping (examples): extracellular matrix disassembly (GO:0022617), collagen catabolic process (GO:0030574) (dambergs2024comparisonoftissue pages 14-15, popescu2024comprehensivemanagementof pages 24-26).
Bone destruction in cholesteatoma reflects both enzymatic matrix degradation and activation of osteoclast biology.
GO/Process mapping (examples): osteoclast differentiation (GO:0030316), bone resorption (GO:0045453) (bologa2025biologyofrecurrent pages 4-5).
The perimatrix is frequently described as a vascularized, reactive compartment that supports growth and tissue destruction.
Quantitative biomarker evidence: Rolesi et al. (2023) report strong increases in angiogenic signaling in pediatric acquired disease (rolesi2023studyofangiogenic pages 5-8): - VEGF-C (VEGFC) peri-matrix OD: pediatric acquired 190.98±11.91 vs adult acquired 105.93±4.11 vs congenital 38.16±1.88. - PDGFr (PDGFRA/PDGFRB; reported as PDGFr) peri-matrix OD: pediatric acquired 227.51±9.10 vs adult acquired 94.97±4.87 vs congenital 37.34±1.64. Rolesi et al. further state VEGF/PDGFr signals were significantly higher in acquired versus congenital cases (p<0.001), greatest at the peri-matrix level, with higher values in pediatric cohorts (rolesi2023studyofangiogenic pages 10-12).
Dambergs et al. (2023) reported VEGF correlations with TIMP-2 and NF-κB (e.g., VEGF vs TIMP-2 r=0.581, p=0.009; VEGF vs NF-κB r=0.512, p=0.025), supporting coordinated remodeling/angiogenic signaling (dambergs2023morphopathogenesisofadult pages 13-14).
GO/Process mapping: angiogenesis (GO:0001525), VEGF signaling pathway (GO:0048010) (rolesi2023studyofangiogenic pages 5-8, dambergs2023morphopathogenesisofadult pages 13-14).
Dambergs et al. (2023) report significant overexpression of human β-defensin-2 (DEFB4A; HβD-2) (p=0.004) in cholesteatoma and strong positive correlations with IL-1 (r=0.822, p=0.000) and NF-κB (r=0.692, p=0.001), consistent with inflammatory induction of epithelial antimicrobial responses (dambergs2023morphopathogenesisofadult pages 14-15).
GO/Process mapping: antimicrobial humoral response (GO:0019730), innate immune response (GO:0045087) (dambergs2023morphopathogenesisofadult pages 14-15).
A notable recent development is the mechanistic framing of cholesteatoma as exhibiting a partial EMT phenotype linked to invasion and recurrence potential.
Zeng et al. (Mar 2024; Cell Cycle; https://doi.org/10.1080/15384101.2024.2345481) report that osteopontin (SPP1/OPN) is elevated in cholesteatoma and drives a partial EMT pattern: reduced epithelial features and increased mesenchymal markers (e.g., vimentin, fibronectin) without induction of canonical full-EMT markers such as N-cadherin/α-SMA, consistent with p-EMT (zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2).
Mechanistically, the study identifies an AKT–ZEB2 axis as mediating OPN-driven p-EMT and pro-migratory/pro-survival keratinocyte behavior, supported by functional rescue with ZEB2 knockdown and pathway readouts (zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41).
Key molecules repeatedly implicated across 2023–2024 studies include: - Inflammation / signaling: IL1B, IL1A, STAT3 (pSTAT3), TGFB1, NFKB1 (rolesi2023studyofangiogenic pages 5-8, dambergs2023morphopathogenesisofadult pages 13-14, dambergs2024comparisonoftissue pages 14-15) - Angiogenesis: VEGFC, PDGFR (reported as PDGFr), VEGF signaling (rolesi2023studyofangiogenic pages 5-8, rolesi2023studyofangiogenic pages 10-12) - ECM remodeling: MMP2, MMP9, TIMP2, TIMP4 (dambergs2024comparisonoftissue pages 14-15, dambergs2023morphopathogenesisofadult pages 10-12) - Epithelial proliferation: MKI67, PCNA (dambergs2023morphopathogenesisofadult pages 1-2, dambergs2023morphopathogenesisofadult pages 13-14) - Innate immunity: DEFB4A (HβD-2), DEFB104A (HβD-4) (dambergs2023morphopathogenesisofadult pages 14-15) - p-EMT/invasion: SPP1 (OPN), AKT, ZEB2 (zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2, zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41) - Developmental signaling: SHH (dambergs2023morphopathogenesisofadult pages 14-15, dambergs2024comparisonoftissue pages 14-15)
GO biological processes (suggested for annotation; mechanistically supported): - Epithelial cell proliferation (GO:0050673) (dambergs2023morphopathogenesisofadult pages 1-2) - Cytokine-mediated signaling pathway (GO:0019221) (rolesi2023studyofangiogenic pages 10-12) - NF-κB signaling (GO:0043123) (dambergs2023morphopathogenesisofadult pages 13-14) - Angiogenesis (GO:0001525) (rolesi2023studyofangiogenic pages 5-8) - Extracellular matrix disassembly (GO:0022617) (dambergs2024comparisonoftissue pages 14-15) - Osteoclast differentiation (GO:0030316) and bone resorption (GO:0045453) (bologa2025biologyofrecurrent pages 4-5) - Epithelial to mesenchymal transition (GO:0001837) (zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2) - Biofilm formation (GO:0042710) (kanodia2024metagenomeanalysisof pages 6-9)
Cellular components (where processes occur; suggested): - Extracellular space / extracellular matrix (MMP/TIMP activity; collagenases) (popescu2024comprehensivemanagementof pages 24-26, dambergs2024comparisonoftissue pages 14-15) - Plasma membrane/cytosol/nucleus (NF-κB and STAT3 activation; ZEB2 transcriptional reprogramming) (rolesi2023studyofangiogenic pages 8-10, zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41)
A coherent, evidence-aligned sequence (acquired cholesteatoma) is: 1. Trigger/initiators: chronic middle-ear inflammation and dysventilation (retraction pockets), recurrent infection, and/or epithelial ingress through tympanic membrane defects (rolesi2023studyofangiogenic pages 1-2). 2. Matrix establishment: keratinizing epithelium accumulates keratin debris; DWI MRI is sensitive to characteristic keratinous content (popescu2024comprehensivemanagementof pages 2-3). 3. Perimatrix activation: inflammatory cytokines and fibroblast/immune activation create a chronic wound-like, angiogenic stroma (rolesi2023studyofangiogenic pages 10-12). 4. Expansion and invasion: hyperproliferation (MKI67/NF-κB), remodeling (MMP/TIMP), and angiogenesis (VEGF/PDGFr) support growth; partial EMT programs (OPN–AKT–ZEB2) may further enhance migration and persistence (dambergs2023morphopathogenesisofadult pages 13-14, dambergs2024comparisonoftissue pages 14-15, zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41). 5. Bone erosion: enzymatic lysis/collagenases, inflammatory osteoclast activation, and microenvironmental factors drive osteolysis and ossicular destruction (popescu2024comprehensivemanagementof pages 1-2, popescu2024comprehensivemanagementof pages 24-26, bologa2025biologyofrecurrent pages 4-5). 6. Clinical sequelae and recurrence: persistent/recurrent inflammation and biofilm-associated microbiota contribute to chronicity and recidivism; residual disease after surgery is a key driver of recurrence (popescu2024comprehensivemanagementof pages 15-18, popescu2024comprehensivemanagementof pages 24-26).
Key clinical phenotypes (suggested Human Phenotype Ontology [HP] mapping; examples): - Conductive hearing loss (HP:0000405) due to ossicular erosion and middle-ear mass effects (ossicular destruction ≈80%) (popescu2024comprehensivemanagementof pages 1-2). - Otorrhea (HP:0001738) and chronic infection-related symptoms, often influenced by persistent microbiota/biofilm (popescu2024comprehensivemanagementof pages 24-26). - Temporal bone osteolysis / ossicular chain destruction (phenotype framing supported by imaging and intraoperative descriptions) (popescu2024comprehensivemanagementof pages 7-10). - Facial nerve palsy risk / labyrinthine fistulae / intracranial complications (recognized complications in clinical series) (popescu2024comprehensivemanagementof pages 15-18).
(i) Partial EMT as a mechanistic driver and therapeutic target (2024). Zeng et al. provide evidence that OPN/SPP1 promotes keratinocyte proliferation, survival, migration, and p-EMT via AKT–ZEB2, and that blockade of OPN signaling improves cholesteatoma-like symptoms in a rat model (zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2, zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41).
(ii) Pediatric acquired cholesteatoma biomarker intensification (2023). Rolesi et al. quantitatively show that pediatric acquired disease has substantially higher peri-matrix IL-1β and angiogenic signaling (VEGF-C/PDGFr) and stronger STAT3 activation than adult acquired or congenital forms (rolesi2023studyofangiogenic pages 5-8, rolesi2023studyofangiogenic pages 10-12).
(iii) Microbiome/metagenome profiling (2024). Kanodia et al. (Apr 2024; https://doi.org/10.1007/s12070-024-04678-9) report metagenomic compositions from 15 cholesteatoma samples, commonly dominated by Proteobacteria (up to ~95% reads in 9/15) with frequent Pseudomonas/Klebsiella/Escherichia, and Firmicutes-dominant profiles in a subset (kanodia2024metagenomeanalysisof pages 1-2, kanodia2024metagenomeanalysisof pages 6-9). These studies support a move from culture-based microbiology to sequencing-informed pathogen ecology in chronic ear disease.
(iv) miRNA profiling as a regulatory layer (2024). Xie et al. (Jun 2024; https://doi.org/10.1186/s12920-024-01932-5) report 121 differentially expressed miRNAs in cholesteatoma vs matched skin (56 up, 65 down), with top changes including miR-21-5p/miR-142-5p (up) and miR-508-3p/miR-509-3p/miR-211-5p (down), and predicted key targets (TGFBR2, MBNL1, NFAT5) (xie2024identificationofmirna pages 1-2). (Note: enriched GO/KEGG categories were not extractable from the available excerpt.)
Surgery remains central. Bovi et al. describe cholesteatoma as “a surgical disease,” emphasizing operative technique and follow-up strategy as key determinants of recidivism (Apr 2023; https://doi.org/10.14639/0392-100x-suppl.1-43-2023-06) (bovi2023recurrenceincholesteatoma pages 4-6).
Technique selection impacts residual/recurrence risk. In Bovi et al. (2023), CWU approaches show higher residual disease (average ~15%, range 3.8–21%) than CWD (average residual 6.5%; recurrence 5.1%), and CWU has ~2.87 relative risk of recurrent/residual disease compared to CWD in a meta-analysis (bovi2023recurrenceincholesteatoma pages 4-6, bovi2023recurrenceincholesteatoma pages 2-3).
Imaging for postoperative detection (implementation). Non–echo planar imaging diffusion-weighted MRI is highlighted as a high-performance tool to detect residual/recurrent disease; Bovi et al. report: “the sensitivity and specificity of Non EPI DWI-MRI are 89.79% and 94.57%, respectively” and it may allow avoidance of routine second-look surgery in some cases (bovi2023recurrenceincholesteatoma pages 4-6).
Adjuncts to reduce recidivism. Endoscopic ear surgery (EES), mastoid obliteration, and KTP lasers are noted as practical strategies; mastoid obliteration is associated with reduced recidivism (OR 0.45, 95% CI 0.26–0.8) (bovi2023recurrenceincholesteatoma pages 3-4). MESNA is noted as an adjunct with potential benefit across retrospective studies (bovi2023recurrenceincholesteatoma pages 6-7).
Disease entity: Cholesteatoma (middle ear; acquired and congenital forms). MONDO ID was not retrievable from the available literature excerpts in this run.
Anatomy (UBERON): middle ear cavity/epithelium (UBERON:0001756); temporal bone/mastoid/ossicles (contextual; referenced clinically) (popescu2024comprehensivemanagementof pages 24-26, popescu2024comprehensivemanagementof pages 1-2).
Cell types (CL): keratinocyte (CL:0000312); fibroblast (CL:0000057); T cell (CL:0000084); macrophage (CL:0000235); endothelial cell (CL:0000115); osteoclast (CL:0000092) (popescu2024comprehensivemanagementof pages 24-26, bologa2025biologyofrecurrent pages 4-5, rolesi2023studyofangiogenic pages 5-8).
Genes/proteins (HGNC examples): SPP1, ZEB2, AKT1, STAT3, IL1B, TGFB1, NFKB1, MKI67, MMP2, MMP9, TIMP2, TIMP4, DEFB4A, SHH (zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41, rolesi2023studyofangiogenic pages 5-8, dambergs2023morphopathogenesisofadult pages 10-12, dambergs2023morphopathogenesisofadult pages 14-15).
Chemicals (CHEBI example): MESNA (sodium 2-mercaptoethanesulfonate) (bovi2023recurrenceincholesteatoma pages 6-7).
GO processes (examples): epithelial proliferation (GO:0050673); angiogenesis (GO:0001525); ECM disassembly (GO:0022617); osteoclast differentiation (GO:0030316); EMT (GO:0001837); biofilm formation (GO:0042710) (dambergs2023morphopathogenesisofadult pages 13-14, rolesi2023studyofangiogenic pages 5-8, dambergs2024comparisonoftissue pages 14-15, zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2, kanodia2024metagenomeanalysisof pages 6-9).
| Mechanistic Module | Key Molecules (HGNC) | Cell Types (CL) | Anatomy (UBERON) | Dysregulated Pathways / GO Terms | Key Evidence (Study, Year, DOI) | Quantitative / Statistical Highlights | Citation IDs |
|---|---|---|---|---|---|---|---|
| Keratinocyte Hyperproliferation & Survival | MKI67 (Ki-67), NFKB1 (NF-κB), PCNA, ID1 | Keratinocyte (CL:0000312) | Middle ear epithelium (UBERON:0001756) | Epithelial cell proliferation (GO:0050673); NF-kappaB signaling (GO:0043123); Anti-apoptosis | Dambergs et al. (2023) [doi:10.3390/medicina59020306]; Dambergs et al. (2024) [doi:10.3390/diagnostics14060662] | Ki-67 matrix vs skin epithelium: p=0.000. NF-κB matrix vs epithelium: p=0.001. NF-κB correlates with Ki-67 (r=0.538, p=0.017) suggesting proliferative role. | (dambergs2023morphopathogenesisofadult pages 1-2, dambergs2023morphopathogenesisofadult pages 13-14, dambergs2023morphopathogenesisofadult pages 14-15) |
| Inflammation & Proliferative Signaling | IL1A, IL1B, IL6, TGFB1 (TGF-β), STAT3 | T cell (CL:0000084), Fibroblast (CL:0000057) | Peri-matrix (Granulation tissue) | Cytokine-mediated signaling (GO:0019221); STAT cascade (GO:0097696); Wound healing | Rolesi et al. (2023) [doi:10.3390/jpm13081189]; Dambergs et al. (2023) [doi:10.3390/medicina59020306] | pSTAT3 nuclear OD highest in pediatric acquired (125.54) vs adult (75.49). IL-1β peri-matrix OD: pediatric (148.68) vs adult (108.44) (p<0.001). IL-1 correlates with IL-10 (r=0.820). | (rolesi2023studyofangiogenic pages 8-10, rolesi2023studyofangiogenic pages 10-12, dambergs2023morphopathogenesisofadult pages 13-14) |
| Partial EMT (p-EMT) | SPP1 (Osteopontin), ZEB2, AKT1 | Keratinocyte (CL:0000312) | Middle ear epithelium | Epithelial to mesenchymal transition (GO:0001837); Cell migration (GO:0016477) | Zeng et al. (2024) [doi:10.1080/15384101.2024.2345481] | OPN treatment upregulates Vimentin/Fibronectin (mesenchymal) and downregulates epithelial markers; siZEB2 abolishes these effects (in vitro). | (zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2, zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41) |
| Matrix Remodeling & Bone Erosion | MMP2, MMP9, TIMP2, TIMP4 | Fibroblast, Macrophage | Temporal bone / Ossicles | Extracellular matrix disassembly (GO:0022617); Collagen catabolism | Dambergs et al. (2024) [doi:10.3390/diagnostics14060662]; Popescu et al. (2024) [doi:10.3390/jcm13226791] | MMP-9 reduced in matrix vs skin (p=0.008). Strong correlation: MMP-2 matrix vs perimatrix (r=0.803, p=0.000 in children). Enzymatic lysis confirmed as primary erosion driver. | (dambergs2023morphopathogenesisofadult pages 1-2, popescu2024comprehensivemanagementof pages 1-2, dambergs2024comparisonoftissue pages 14-15) |
| Osteoclastogenesis | TNFSF11 (RANKL), TNFRSF11B (OPG), TNF (TNF-α) | Osteoclast (CL:0000092), T/B Lymphocytes | Mastoid bone / Ossicles | Osteoclast differentiation (GO:0030316); Bone resorption (GO:0045453) | Bologa et al. (2025) [doi:10.47162/rjme.65.4.24]; Popescu et al. (2024) [doi:10.3390/jcm13226791] | T- and B-cells identified as sources of RANKL driving osteolysis. Bone destruction observed in ~90% of cases on imaging. | (bologa2025biologyofrecurrent pages 4-5, popescu2024comprehensivemanagementof pages 24-26, popescu2024comprehensivemanagementof pages 7-10) |
| Angiogenesis | VEGFC, PDGFRA, VEGFA | Endothelial cell (CL:0000115) | Peri-matrix (vascular stroma) | Angiogenesis (GO:0001525); VEGF signaling (GO:0048010) | Rolesi et al. (2023) [doi:10.3390/jpm13081189] | VEGF-C peri-matrix OD: pediatric (190.98) vs congenital (38.16) (p<0.001). PDGFr levels significantly higher in acquired vs congenital (p<0.001). | (rolesi2023studyofangiogenic pages 10-12, rolesi2023studyofangiogenic pages 5-8) |
| Innate Immunity | DEFB4A (HβD-2), DEFB104A (HβD-4) | Epithelial cell | Middle ear mucosa | Antimicrobial humoral response (GO:0019730); Innate immune response | Dambergs et al. (2023) [doi:10.3390/medicina59020306] | HβD-2 significantly overexpressed in cholesteatoma vs control (p=0.004); correlates strongly with IL-1 (r=0.822, p=0.000). | (dambergs2023morphopathogenesisofadult pages 1-2, dambergs2023morphopathogenesisofadult pages 14-15) |
| Developmental Signaling | SHH (Sonic Hedgehog) | Fibroblast / Stromal cell | Peri-matrix | Tissue morphogenesis (GO:0048729); Cell differentiation | Dambergs et al. (2023) [doi:10.3390/medicina59020306] | SHH overexpressed in perimatrix vs control connective tissue (p=0.000); correlates with MMP-2 (r=0.786) and NF-κB (r=0.753). | (dambergs2023morphopathogenesisofadult pages 1-2, dambergs2024comparisonoftissue pages 14-15, dambergs2023morphopathogenesisofadult pages 14-15) |
| Microbiome & Biofilm | Pseudomonas, Staphylococcus, Proteobacteria | Bacteria (NCBI:txid2) | Middle ear cavity | Biofilm formation (GO:0042710) | Kanodia et al. (2024) [doi:10.1007/s12070-024-04678-9]; Popescu et al. (2024) [doi:10.3390/jcm13226791] | Proteobacteria dominated 9/15 samples (up to 95% reads). Biofilms (S. aureus/P. aeruginosa) linked to persistence/recurrence. | (popescu2024comprehensivemanagementof pages 24-26, kanodia2024metagenomeanalysisof pages 1-2, kanodia2024metagenomeanalysisof pages 6-9) |
Table: Summary of key pathophysiological modules in cholesteatoma, including hyperproliferation, inflammation, bone erosion, and angiogenesis, with quantitative evidence from 2023–2025 studies.
References
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(rolesi2023studyofangiogenic pages 10-12): Rolando Rolesi, Fabiola Paciello, Gaetano Paludetti, Eugenio De Corso, Bruno Sergi, and Anna Fetoni. Study of angiogenic, pro-apoptotic, and pro-inflammatory factors in congenital and acquired cholesteatomas. Journal of Personalized Medicine, 13:1189, Jul 2023. URL: https://doi.org/10.3390/jpm13081189, doi:10.3390/jpm13081189. This article has 4 citations.
(rolesi2023studyofangiogenic pages 8-10): Rolando Rolesi, Fabiola Paciello, Gaetano Paludetti, Eugenio De Corso, Bruno Sergi, and Anna Fetoni. Study of angiogenic, pro-apoptotic, and pro-inflammatory factors in congenital and acquired cholesteatomas. Journal of Personalized Medicine, 13:1189, Jul 2023. URL: https://doi.org/10.3390/jpm13081189, doi:10.3390/jpm13081189. This article has 4 citations.
(rolesi2023studyofangiogenic pages 5-8): Rolando Rolesi, Fabiola Paciello, Gaetano Paludetti, Eugenio De Corso, Bruno Sergi, and Anna Fetoni. Study of angiogenic, pro-apoptotic, and pro-inflammatory factors in congenital and acquired cholesteatomas. Journal of Personalized Medicine, 13:1189, Jul 2023. URL: https://doi.org/10.3390/jpm13081189, doi:10.3390/jpm13081189. This article has 4 citations.
(dambergs2023morphopathogenesisofadult pages 10-12): Kristaps Dambergs, Gunta Sumeraga, and Māra Pilmane. Morphopathogenesis of adult acquired cholesteatoma. Medicina, 59:306, Feb 2023. URL: https://doi.org/10.3390/medicina59020306, doi:10.3390/medicina59020306. This article has 13 citations.
(dambergs2024comparisonoftissue pages 14-15): Kristaps Dambergs, Gunta Sumeraga, and Māra Pilmane. Comparison of tissue factors in the ontogenetic aspects of human cholesteatoma. Diagnostics, 14:662, Mar 2024. URL: https://doi.org/10.3390/diagnostics14060662, doi:10.3390/diagnostics14060662. This article has 4 citations.
(bologa2025biologyofrecurrent pages 4-5): Ramona Andreea Bologa, Florin Anghelina, Mihaela Roxana Mitroi, Mircea Sorin Ciolofan, Carmen Aurelia Mogoantă, Alina Nicoleta Căpitănescu, Alexandru Florian Grecu, Liliana Anghelina, and Mihai-Marius Botezat. Biology of recurrent cholesteatoma in a romanian young patient – a case report. Romanian Journal of Morphology and Embryology, 65:775-780, Feb 2025. URL: https://doi.org/10.47162/rjme.65.4.24, doi:10.47162/rjme.65.4.24. This article has 1 citations and is from a peer-reviewed journal.
(dambergs2023morphopathogenesisofadult pages 14-15): Kristaps Dambergs, Gunta Sumeraga, and Māra Pilmane. Morphopathogenesis of adult acquired cholesteatoma. Medicina, 59:306, Feb 2023. URL: https://doi.org/10.3390/medicina59020306, doi:10.3390/medicina59020306. This article has 13 citations.
(zeng2024osteopontindrivenpartialepithelialmesenchymal pages 1-2): Lingling Zeng, Li Xie, Jin Hu, Chao He, Aiguo Liu, Xiang Lu, and Wen Zhou. Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma. Cell Cycle, 23:537-554, Mar 2024. URL: https://doi.org/10.1080/15384101.2024.2345481, doi:10.1080/15384101.2024.2345481. This article has 5 citations and is from a peer-reviewed journal.
(zeng2024osteopontindrivenpartialepithelialmesenchymal media 37734d41): Lingling Zeng, Li Xie, Jin Hu, Chao He, Aiguo Liu, Xiang Lu, and Wen Zhou. Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma. Cell Cycle, 23:537-554, Mar 2024. URL: https://doi.org/10.1080/15384101.2024.2345481, doi:10.1080/15384101.2024.2345481. This article has 5 citations and is from a peer-reviewed journal.
(bovi2023recurrenceincholesteatoma pages 6-7): Chiara Bovi, Alberto Luchena, Rachele Bivona, Daniele Borsetto, Nathan Creber, and Giovanni Danesi. Recurrence in cholesteatoma surgery: what have we learnt and where are we going? a narrative review. Acta Otorhinolaryngologica Italica, 43:S48-S55, Apr 2023. URL: https://doi.org/10.14639/0392-100x-suppl.1-43-2023-06, doi:10.14639/0392-100x-suppl.1-43-2023-06. This article has 44 citations and is from a peer-reviewed journal.
(kanodia2024metagenomeanalysisof pages 6-9): Anupam Kanodia, Rabia Monga, Mohd Ilyas, Yash Verma, Sarita Mohapatra, Narayana Sudha Rao, Meenal Vyas, Kapil Sikka, and Krishnamohan Atmakuri. Metagenome analysis of cholesteatoma-associated bacteria: a pilot study. Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India, 76 4:3307-3318, Apr 2024. URL: https://doi.org/10.1007/s12070-024-04678-9, doi:10.1007/s12070-024-04678-9. This article has 0 citations.
(popescu2024comprehensivemanagementof pages 2-3): Cristina Popescu, Renata Maria Văruț, Monica Puticiu, Vlad Ionut Belghiru, Mihai Banicioiu, Luciana Teodora Rotaru, Mihaela Popescu, Arsenie Cristian Cosmin, and Alin Iulian Silviu Popescu. Comprehensive management of cholesteatoma in otitis media: diagnostic challenges, imaging advances, and surgical outcome. Journal of Clinical Medicine, 13:6791, Nov 2024. URL: https://doi.org/10.3390/jcm13226791, doi:10.3390/jcm13226791. This article has 12 citations.
(popescu2024comprehensivemanagementof pages 15-18): Cristina Popescu, Renata Maria Văruț, Monica Puticiu, Vlad Ionut Belghiru, Mihai Banicioiu, Luciana Teodora Rotaru, Mihaela Popescu, Arsenie Cristian Cosmin, and Alin Iulian Silviu Popescu. Comprehensive management of cholesteatoma in otitis media: diagnostic challenges, imaging advances, and surgical outcome. Journal of Clinical Medicine, 13:6791, Nov 2024. URL: https://doi.org/10.3390/jcm13226791, doi:10.3390/jcm13226791. This article has 12 citations.
(popescu2024comprehensivemanagementof pages 7-10): Cristina Popescu, Renata Maria Văruț, Monica Puticiu, Vlad Ionut Belghiru, Mihai Banicioiu, Luciana Teodora Rotaru, Mihaela Popescu, Arsenie Cristian Cosmin, and Alin Iulian Silviu Popescu. Comprehensive management of cholesteatoma in otitis media: diagnostic challenges, imaging advances, and surgical outcome. Journal of Clinical Medicine, 13:6791, Nov 2024. URL: https://doi.org/10.3390/jcm13226791, doi:10.3390/jcm13226791. This article has 12 citations.
(kanodia2024metagenomeanalysisof pages 1-2): Anupam Kanodia, Rabia Monga, Mohd Ilyas, Yash Verma, Sarita Mohapatra, Narayana Sudha Rao, Meenal Vyas, Kapil Sikka, and Krishnamohan Atmakuri. Metagenome analysis of cholesteatoma-associated bacteria: a pilot study. Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India, 76 4:3307-3318, Apr 2024. URL: https://doi.org/10.1007/s12070-024-04678-9, doi:10.1007/s12070-024-04678-9. This article has 0 citations.
(xie2024identificationofmirna pages 1-2): Mengyao Xie, Qi Tang, Shu Wang, Xiaowu Huang, Zhiyuan Wu, Zhijin Han, Chen Li, Bin Wang, Yingying Shang, and Hua Yang. Identification of mirna expression profile in middle ear cholesteatoma using small rna-sequencing. BMC Medical Genomics, Jun 2024. URL: https://doi.org/10.1186/s12920-024-01932-5, doi:10.1186/s12920-024-01932-5. This article has 3 citations and is from a peer-reviewed journal.
(bovi2023recurrenceincholesteatoma pages 4-6): Chiara Bovi, Alberto Luchena, Rachele Bivona, Daniele Borsetto, Nathan Creber, and Giovanni Danesi. Recurrence in cholesteatoma surgery: what have we learnt and where are we going? a narrative review. Acta Otorhinolaryngologica Italica, 43:S48-S55, Apr 2023. URL: https://doi.org/10.14639/0392-100x-suppl.1-43-2023-06, doi:10.14639/0392-100x-suppl.1-43-2023-06. This article has 44 citations and is from a peer-reviewed journal.
(bovi2023recurrenceincholesteatoma pages 2-3): Chiara Bovi, Alberto Luchena, Rachele Bivona, Daniele Borsetto, Nathan Creber, and Giovanni Danesi. Recurrence in cholesteatoma surgery: what have we learnt and where are we going? a narrative review. Acta Otorhinolaryngologica Italica, 43:S48-S55, Apr 2023. URL: https://doi.org/10.14639/0392-100x-suppl.1-43-2023-06, doi:10.14639/0392-100x-suppl.1-43-2023-06. This article has 44 citations and is from a peer-reviewed journal.
(bovi2023recurrenceincholesteatoma pages 3-4): Chiara Bovi, Alberto Luchena, Rachele Bivona, Daniele Borsetto, Nathan Creber, and Giovanni Danesi. Recurrence in cholesteatoma surgery: what have we learnt and where are we going? a narrative review. Acta Otorhinolaryngologica Italica, 43:S48-S55, Apr 2023. URL: https://doi.org/10.14639/0392-100x-suppl.1-43-2023-06, doi:10.14639/0392-100x-suppl.1-43-2023-06. This article has 44 citations and is from a peer-reviewed journal.
(bonnard2023theriskof pages 1-2): Åsa Bonnard, Cecilia Engmér Berglin, Josephine Wincent, Per Olof Eriksson, Eva Westman, Maria Feychting, and Hanna Mogensen. The risk of cholesteatoma in individuals with first-degree relatives surgically treated for the disease. JAMA Otolaryngology–Head & Neck Surgery, 149:390, May 2023. URL: https://doi.org/10.1001/jamaoto.2023.0048, doi:10.1001/jamaoto.2023.0048. This article has 19 citations.
(borgstrom2024occurrenceofmucosaaffecting pages 1-2): Agnes Modée Borgström, Hanna Mogensen, Cecilia Engmér Berglin, Johan Knutsson, and Åsa Bonnard. Occurrence of mucosa-affecting diseases of the upper airways in middle ear cholesteatoma patients: a nationwide case–control study. European Archives of Oto-Rhino-Laryngology, 281:4081-4087, Mar 2024. URL: https://doi.org/10.1007/s00405-024-08567-3, doi:10.1007/s00405-024-08567-3. This article has 1 citations and is from a peer-reviewed journal.
(borgstrom2024occurrenceofmucosaaffecting pages 4-5): Agnes Modée Borgström, Hanna Mogensen, Cecilia Engmér Berglin, Johan Knutsson, and Åsa Bonnard. Occurrence of mucosa-affecting diseases of the upper airways in middle ear cholesteatoma patients: a nationwide case–control study. European Archives of Oto-Rhino-Laryngology, 281:4081-4087, Mar 2024. URL: https://doi.org/10.1007/s00405-024-08567-3, doi:10.1007/s00405-024-08567-3. This article has 1 citations and is from a peer-reviewed journal.
name: Cholesteatoma
creation_date: "2026-03-06T19:58:09Z"
updated_date: "2026-03-06T22:39:02Z"
category: Structural
description: >
Cholesteatoma is a locally destructive keratinizing squamous epithelial lesion
of the middle ear and mastoid. It is associated with chronic otorrhea, hearing
loss, progressive local bone erosion, and clinically important postoperative
recurrence risk.
disease_term:
preferred_term: cholesteatoma
term:
id: MONDO:0006530
label: cholesteatoma
synonyms:
- middle ear cholesteatoma
classifications:
harrisons_chapter:
- classification_value: disorder of ear
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior, often resulting in ossicular erosion, hearing loss, labyrinthine fistula, and, rarely, intracranial complications."
explanation: Cholesteatoma is a middle-ear lesion causing ossicular erosion and hearing loss, fitting the ear disease sub-chapter of ENT disorders.
has_subtypes:
- name: Acquired cholesteatoma
description: >
The more common form develops in the setting of chronic middle-ear disease
and retraction-pocket biology.
evidence:
- reference: PMID:38337530
reference_title: "Cholesteatoma Severity Determines the Risk of Recurrent Paediatric Cholesteatoma More Than the Surgical Approach."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Review of children with primary acquired or congenital cholesteatoma."
explanation: Supports acquired cholesteatoma as a recognized major subtype in pediatric cohorts.
- name: Congenital cholesteatoma
description: >
Congenital cholesteatoma presents without prior surgery and is analyzed
separately from acquired disease in clinical recurrence studies.
evidence:
- reference: PMID:38337530
reference_title: "Cholesteatoma Severity Determines the Risk of Recurrent Paediatric Cholesteatoma More Than the Surgical Approach."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Review of children with primary acquired or congenital cholesteatoma."
explanation: Supports congenital cholesteatoma as a distinct clinical subtype.
prevalence:
- population: Chronic otitis media patients at a Brazilian referral hospital
percentage: 24.5
notes: >
In this untreated chronic otitis media cohort, 419 of 1710 patients had
cholesteatoma.
evidence:
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the patients with chronic otitis media, 419 (24.5%) had cholesteatoma"
explanation: Provides a cohort-level prevalence estimate within chronic otitis media.
epidemiology:
- name: Annual incidence
description: >
A population-based Danish study estimated incidence at 6.8 cases per 100,000
persons per year.
unit: cases per 100000 person-years
evidence:
- reference: PMID:28244845
reference_title: "Incidence, 10-year recidivism rate and prognostic factors for cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Incidence rate was 6.8 per 100 000 per year."
explanation: Supports the population incidence estimate for cholesteatoma.
- name: Long-term recidivism after surgery
description: >
Postoperative recurrence or residual disease remains common over long-term
follow-up.
unit: cumulative recidivism proportion at 10 years
evidence:
- reference: PMID:28244845
reference_title: "Incidence, 10-year recidivism rate and prognostic factors for cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 10-year cumulative recidivism rate was 0.44 (95 per cent confidence interval, 0.37-0.53)."
explanation: Quantifies the substantial long-term recurrence burden after surgery.
- name: Familial aggregation
description: >
Individuals with a first-degree relative surgically treated for cholesteatoma
have a substantially increased disease risk, supporting a familial
predisposition in a subset of cases.
notes: Family history was uncommon overall, so it likely explains only a minority of all cases.
evidence:
- reference: PMID:36929420
reference_title: "The Risk of Cholesteatoma in Individuals With First-degree Relatives Surgically Treated for the Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The risk of having a cholesteatoma surgery was almost 4 times higher in individuals having a first-degree relative surgically treated for the disease (OR, 3.9; 95% CI, 3.1-4.8)"
explanation: Nationwide case-control data support a meaningful familial risk signal in cholesteatoma.
histopathology:
- name: Keratinizing squamous epithelial lesion
description: >
Histologically, acquired middle-ear cholesteatoma is a benign keratinizing
squamous epithelial lesion despite its locally invasive and erosive clinical
behavior.
diagnostic: true
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion"
explanation: Review-level evidence captures the core histopathologic identity of cholesteatoma.
pathophysiology:
- name: Wnt/beta-catenin pathway activation in cholesteatoma epithelium
description: >
Cholesteatoma epithelial cells show increased beta-catenin signaling, which
promotes proliferative gene-expression programs and lesion growth.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:31933930
reference_title: "Wnt/β-catenin signaling regulates pathogenesis of human middle ear cholesteatoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "β-Catenin expression evidently increased in middle ear cholesteatoma cells when compared with normal epithelial cells."
explanation: In vitro analysis directly shows increased beta-catenin expression in cholesteatoma epithelium.
downstream:
- target: Keratinizing squamous epithelium overgrowth in the middle ear
description: Increased beta-catenin signaling drives cholesteatoma epithelial proliferation and expansion.
causal_link_type: DIRECT
evidence:
- reference: PMID:31933930
reference_title: "Wnt/β-catenin signaling regulates pathogenesis of human middle ear cholesteatoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Wnt/β-catenin signaling induced cell proliferation and up-regulated expressions of targeted genes in human middle ear cholesteatoma."
explanation: Directly supports a causal link from Wnt/beta-catenin activation to epithelial proliferation.
- name: Osteopontin/AKT/ZEB2-driven partial epithelial-mesenchymal transition
description: >
Elevated osteopontin signaling promotes a partial epithelial-mesenchymal
transition state in cholesteatoma keratinocytes, increasing proliferation,
survival, and migratory behavior without a full mesenchymal conversion.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: epithelial to mesenchymal transition
term:
id: GO:0001837
label: epithelial to mesenchymal transition
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:38662954
reference_title: "Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues."
explanation: Supports osteopontin upregulation in human cholesteatoma tissue.
- reference: PMID:38662954
reference_title: "Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells."
explanation: In vitro mechanistic data support OPN-driven partial EMT as a lesion-propagating program.
downstream:
- target: Keratinizing squamous epithelium overgrowth in the middle ear
description: Partial EMT increases keratinocyte persistence and growth within the lesion.
causal_link_type: DIRECT
evidence:
- reference: PMID:38662954
reference_title: "Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells."
explanation: Directly links OPN-driven partial EMT to the proliferative and migratory phenotype that expands cholesteatoma tissue.
- name: Keratinizing squamous epithelium overgrowth in the middle ear
description: >
The lesion consists of expanding keratinizing squamous epithelium within the
middle ear space, producing a persistent mass with destructive local behavior.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: keratinization
term:
id: GO:0031424
label: keratinization
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
- preferred_term: tympanic membrane
term:
id: UBERON:0002364
label: tympanic membrane
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior"
explanation: Review-level synthesis supports epithelial overgrowth as the defining lesion architecture.
downstream:
- target: Perimatrix inflammatory cytokine and STAT3 signaling amplification
description: Matrix-perimatrix signaling drives a chronic inflammatory and proliferative stromal response.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- keratinocyte-derived cytokine release
- fibroblast and immune-cell activation
evidence:
- reference: PMID:33627146
reference_title: "Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We propose that cholesteatoma recurrence is based on TLR4 signalling imprinted in the cholesteatoma cells. It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts."
explanation: Cholesteatoma cell co-culture data directly support matrix-perimatrix paracrine signaling that amplifies stromal inflammation and fibroblast proliferation.
- target: Activin A-mediated local osteoclastogenesis
description: The expanding lesion establishes a local stromal microenvironment that promotes osteoclast differentiation.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- stromal fibroblast activation
- chronic local inflammatory signaling
evidence:
- reference: PMID:36883320
reference_title: "Higher degree of keratinization correlated with severe bone destruction in acquired Cholesteatoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro studies showed that keratinocytes directly promoted monocytes differentiating into osteoclasts."
explanation: Directly supports a mechanistic link from the keratinizing lesion epithelium to local osteoclastogenic signaling.
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis"
explanation: Human cholesteatoma tissue data support the stromal activin A osteoclastogenic intermediate within the lesion microenvironment.
- name: Perimatrix inflammatory cytokine and STAT3 signaling amplification
description: >
The perimatrix behaves as a chronically inflamed stromal compartment with
increased IL-1beta, STAT3, TGF-beta, and related signaling, especially in
more aggressive acquired disease.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
- preferred_term: T cell
term:
id: CL:0000084
label: T cell
biological_processes:
- preferred_term: cytokine-mediated signaling pathway
term:
id: GO:0019221
label: cytokine-mediated signaling pathway
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:37623440
reference_title: "Study of Angiogenic, Pro-Apoptotic, and Pro-Inflammatory Factors in Congenital and Acquired Cholesteatomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Expression of angiogenic, inflammatory, and proliferative biomarkers is significantly increased in acquired cholesteatomas in children as compared to congenital and acquired forms in adults"
explanation: Human tissue study supports intensified inflammatory and proliferative signaling in more aggressive acquired cholesteatoma.
- reference: PMID:36837507
reference_title: "Morphopathogenesis of Adult Acquired Cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The similarity in the expression of IL-1 and IL-10 suggests the dysregulation of the local immune status in cholesteatoma."
explanation: Independent immunohistochemical study supports a dysregulated local inflammatory milieu.
downstream:
- target: Extracellular matrix remodeling in the perimatrix
description: Cytokine and NF-kappaB-linked signaling promotes stromal matrix remodeling.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- fibroblast activation
- protease induction
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Recent mechanistic studies, including single-cell transcriptomics, spatial proteomics, and epigenetic profiling, reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation"
explanation: Review synthesis supports inflammatory lesion biology as an upstream driver of proteolytic stromal remodeling.
- target: Ear pain
description: Chronic inflammatory activation in the perimatrix can produce otalgia through local tissue irritation and inflammatory mediator signaling.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- inflammatory mediator sensitization
- local tissue irritation
evidence:
- reference: PMID:33627146
reference_title: "Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts."
explanation: Supports a strongly inflammatory lesion microenvironment capable of producing local painful irritation.
- reference: PMID:41552209
reference_title: "Impact of Surgical Treatment on the Quality of Life in Patients With Chronic Otitis Media With Cholesteatoma: A Prospective Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Main symptoms included tinnitus (68%), otalgia (64%), and otorrhea (64%)."
explanation: Confirms otalgia as a common clinical manifestation in cholesteatoma.
- name: Polymicrobial bacterial persistence in cholesteatoma tissue
description: >
Cholesteatoma frequently contains persistent polymicrobial communities,
commonly dominated by Proteobacteria or Firmicutes, which can reinforce
chronicity in the diseased middle-ear environment.
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:39130256
reference_title: "Metagenome Analysis of Cholesteatoma-associated Bacteria: A Pilot Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cholesteatoma usually harbors a poly-microbial infection."
explanation: Metagenomic profiling supports persistent polymicrobial colonization in cholesteatoma tissue.
- reference: PMID:39130256
reference_title: "Metagenome Analysis of Cholesteatoma-associated Bacteria: A Pilot Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cholesteatoma is primarily associated with Proteobacteria and Firmicutes phyla, even in complicated disease."
explanation: Defines the dominant microbial groups identified in cholesteatoma-associated tissue.
downstream:
- target: Perimatrix inflammatory cytokine and STAT3 signaling amplification
description: Persistent microbial communities can sustain chronic inflammatory activation in the lesion microenvironment.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- innate immune activation
- chronic epithelial and stromal cytokine signaling
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Emerging evidence further implicates oxidative stress, RNA and epigenetic modifications, miRNA dysregulation, and immune cell infiltration as central modulators of lesion chronicity and bone resorption."
explanation: Review synthesis supports persistent microbial/inflammatory lesion ecology as a driver of chronic inflammatory amplification.
- target: Chronic Otorrhea
description: Persistent polymicrobial infection can sustain chronic ear discharge in cholesteatoma.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- chronic suppurative middle-ear inflammation
- infected keratin debris accumulation
evidence:
- reference: PMID:39130256
reference_title: "Metagenome Analysis of Cholesteatoma-associated Bacteria: A Pilot Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cholesteatoma usually harbors a poly-microbial infection."
explanation: Supports persistent infection within cholesteatoma tissue as an upstream driver of suppurative symptoms.
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Typically, it presents with hypoacusis and continuous otorrhea as symptoms."
explanation: Confirms chronic otorrhea as a common clinical manifestation of acquired middle-ear cholesteatoma.
- name: Extracellular matrix remodeling in the perimatrix
description: >
Remodeling enzymes in the perimatrix promote extracellular matrix turnover
and structural reorganization of the cholesteatoma stromal compartment.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: extracellular matrix disassembly
term:
id: GO:0022617
label: extracellular matrix disassembly
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Recent mechanistic studies, including single-cell transcriptomics, spatial proteomics, and epigenetic profiling, reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation"
explanation: Review-level evidence supports proteolytic extracellular-matrix remodeling as a distinct pathophysiologic event.
- reference: PMID:36837507
reference_title: "Morphopathogenesis of Adult Acquired Cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the MMP-9 in the matrix and the MMP-9 in the epithelium (p = 0.008)"
explanation: Human cholesteatoma tissue study supports abnormal matrix-remodeling factor expression in the lesion.
downstream:
- target: Neoangiogenesis in the perimatrix
description: Remodeling-associated stromal factor networks promote new vessel formation in the perimatrix.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- VEGF signaling
- TIMP-2-associated stromal crosstalk
evidence:
- reference: PMID:36837507
reference_title: "Morphopathogenesis of Adult Acquired Cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intercorrelations between VEGF, NF-κβ and TIMP-2 induce neo-angiogenesis in adult cholesteatoma."
explanation: Supports a link from stromal remodeling-associated factor networks to neoangiogenesis.
- name: Neoangiogenesis in the perimatrix
description: >
Angiogenic signaling in the perimatrix promotes new vessel formation and a
vascularized stromal niche that supports lesion persistence.
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: angiogenesis
term:
id: GO:0001525
label: angiogenesis
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:36837507
reference_title: "Morphopathogenesis of Adult Acquired Cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intercorrelations between VEGF, NF-κβ and TIMP-2 induce neo-angiogenesis in adult cholesteatoma."
explanation: Human cholesteatoma tissue study directly supports neoangiogenesis as a distinct perimatrix event.
- reference: PMID:37623440
reference_title: "Study of Angiogenic, Pro-Apoptotic, and Pro-Inflammatory Factors in Congenital and Acquired Cholesteatomas."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Expression of angiogenic, inflammatory, and proliferative biomarkers is significantly increased in acquired cholesteatomas in children as compared to congenital and acquired forms in adults"
explanation: Supports angiogenic upregulation as a distinct feature of more aggressive acquired cholesteatoma.
downstream:
- target: Local temporal bone erosion
description: The vascularized perimatrix supports continuing osteolysis and structural damage.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- vascular support for inflammatory stroma
- osteoclast activation
evidence:
- reference: PMID:41767763
reference_title: "Benign, persistent, and invasive: mechanistic and translational approaches to middle-ear cholesteatoma."
supports: SUPPORT
evidence_source: OTHER
snippet: "Collectively, these processes establish a self-sustaining pro-osteolytic microenvironment that drives bone erosion and postoperative recurrence."
explanation: Review synthesis supports the transition from remodeled inflammatory stroma to ongoing bone erosion.
- name: Activin A-mediated local osteoclastogenesis
description: >
A pathogenic fibroblast subset within cholesteatoma tissue produces inhibin
beta A/activin A, which promotes local osteoclast differentiation and creates
a pro-osteolytic microenvironment.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
- preferred_term: osteoclast
term:
id: CL:0000092
label: osteoclast
biological_processes:
- preferred_term: bone remodeling
term:
id: GO:0046849
label: bone remodeling
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA."
explanation: Human single-cell data identify the fibroblast program linked to osteoclastogenic signaling.
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation."
explanation: Establishes activin A as the local mediator connecting cholesteatoma stroma to osteoclastogenesis.
downstream:
- target: Local temporal bone erosion
description: Osteoclastogenic signaling promotes erosion of adjacent ossicles and temporal bone.
causal_link_type: DIRECT
evidence:
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis"
explanation: Directly supports the osteoclastogenesis-to-bone-destruction causal edge.
- name: Local temporal bone erosion
description: >
Cholesteatoma progressively erodes surrounding temporal-bone structures,
creating the substrate for more specific destructive complications.
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
- preferred_term: mastoid process of temporal bone
term:
id: UBERON:0011220
label: mastoid process of temporal bone
evidence:
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation."
explanation: Human cholesteatoma study directly supports persistent local bone erosion as a core disease mechanism.
downstream:
- target: Ossicular chain erosion
description: Continued osteolysis frequently extends into the malleus, incus, and stapes.
causal_link_type: DIRECT
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intraoperative findings of LFs include stapes erosion (78.6%), malleus erosion (78.6%), incus erosion (92.9%)"
explanation: Surgical series directly documents frequent ossicular erosion as a downstream consequence of destructive cholesteatoma.
- target: Semicircular canal dehiscence
description: Progressive erosive cholesteatoma can breach the otic capsule and expose the semicircular canal.
causal_link_type: DIRECT
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Compared to the non-LF group, the LF group showed significantly higher incidence of stapes erosion ( P < 0.001), tegmen tympani dehiscence ( P = 0.016) and semicircular canal dehiscence ( P < 0.001)."
explanation: Surgical series directly supports semicircular canal dehiscence as a downstream erosive complication of advanced cholesteatoma.
- target: Tympanic facial canal dehiscence
description: Advanced erosive disease can extend into the tympanic facial canal.
causal_link_type: DIRECT
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intraoperative findings of LFs include stapes erosion (78.6%), malleus erosion (78.6%), incus erosion (92.9%), dehiscence of tegmen tympani (28.6%) and tympanic facial canal (64.3%)."
explanation: Surgical series directly supports facial-canal dehiscence as a destructive complication of advanced cholesteatoma.
- name: Ossicular chain erosion
description: >
Cholesteatoma commonly erodes the malleus, incus, and stapes, disrupting the
ossicular transmission pathway.
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intraoperative findings of LFs include stapes erosion (78.6%), malleus erosion (78.6%), incus erosion (92.9%)"
explanation: Surgical series directly supports ossicular chain destruction as a frequent erosive event in advanced cholesteatoma.
downstream:
- target: Conductive Hearing Loss
description: Ossicular discontinuity and erosion impair mechanical sound conduction across the middle ear.
causal_link_type: DIRECT
evidence:
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mean air-bone gap was 29.84dB"
explanation: Air-bone gap measurements support conductive hearing loss as the clinical consequence of impaired ossicular transmission.
- name: Tympanic facial canal dehiscence
description: >
Destructive cholesteatoma can extend into the tympanic facial canal,
exposing the facial nerve to local erosive and inflammatory injury.
locations:
- preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Intraoperative findings of LFs include stapes erosion (78.6%), malleus erosion (78.6%), incus erosion (92.9%), dehiscence of tegmen tympani (28.6%) and tympanic facial canal (64.3%)."
explanation: Directly supports tympanic facial canal involvement as a destructive complication of advanced cholesteatoma.
downstream:
- target: Facial palsy
description: Facial canal exposure and injury can lead to facial nerve dysfunction.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- local inflammatory facial nerve injury
- direct erosive compromise of the facial nerve canal
evidence:
- reference: PMID:40096720
reference_title: "Labyrinthine Fistulas in cholesteatoma : Surgical outcome on auditory function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Facial nerve paralysis was observed in 5 patients (10.9%)."
explanation: Clinical series documents facial nerve palsy as a downstream complication in cholesteatoma cases with labyrinthine fistula and advanced local destruction.
- name: Semicircular canal dehiscence
description: >
Advanced cholesteatoma can erode into the semicircular canal, creating a
bony dehiscence that predisposes to labyrinthine fistula and vestibular symptoms.
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Compared to the non-LF group, the LF group showed significantly higher incidence of stapes erosion ( P < 0.001), tegmen tympani dehiscence ( P = 0.016) and semicircular canal dehiscence ( P < 0.001)."
explanation: Directly supports semicircular canal dehiscence as a specific destructive event in cholesteatoma complicated by labyrinthine fistula.
downstream:
- target: Labyrinthine fistula
description: Semicircular canal breach can progress to a clinically evident labyrinthine fistula.
causal_link_type: DIRECT
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the middle ear cholesteatomas, 15.6% ( n = 14) of ears were complicated by LF."
explanation: Clinical series documents labyrinthine fistula as the complication associated with canal dehiscence in advanced cholesteatoma.
- target: Vertigo
description: Labyrinthine involvement from semicircular canal dehiscence can trigger vestibular symptoms.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- labyrinthine fistula
- abnormal vestibular stimulation
evidence:
- reference: PMID:40096720
reference_title: "Labyrinthine Fistulas in cholesteatoma : Surgical outcome on auditory function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Vertigo was present in 43.5% of patients."
explanation: Clinical cohort of cholesteatomatous labyrinthine fistula supports vertigo as a downstream vestibular consequence of canal breach.
phenotypes:
- name: Conductive Hearing Loss
category: EAR_NOSE_THROAT
frequency: FREQUENT
description: >
Conductive hearing impairment is common because cholesteatoma disrupts
normal sound transmission across the middle ear and ossicular chain.
phenotype_term:
preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mean air-bone gap was 29.84dB"
explanation: Audiometric air-bone gap supports a conductive hearing-loss phenotype in acquired middle ear cholesteatoma.
- name: Chronic Otorrhea
category: EAR_NOSE_THROAT
frequency: FREQUENT
description: >
Persistent or recurrent ear discharge is a typical presenting manifestation
of acquired middle-ear cholesteatoma.
notes: No precise HPO term for otorrhea was verified locally in this pass, so this phenotype remains intentionally unannotated.
evidence:
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Typically, it presents with hypoacusis and continuous otorrhea as symptoms."
explanation: Clinical cohort abstract explicitly identifies continuous otorrhea as a typical presenting symptom.
- name: Ear pain
category: EAR_NOSE_THROAT
frequency: FREQUENT
description: >
Otalgia is a common presenting symptom in cholesteatoma and reflects local
inflammatory irritation within the middle ear and adjacent structures.
phenotype_term:
preferred_term: Ear pain
term:
id: HP:0030766
label: Ear pain
evidence:
- reference: PMID:41552209
reference_title: "Impact of Surgical Treatment on the Quality of Life in Patients With Chronic Otitis Media With Cholesteatoma: A Prospective Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Main symptoms included tinnitus (68%), otalgia (64%), and otorrhea (64%)."
explanation: Prospective cohort data directly support otalgia as a common cholesteatoma symptom.
- name: Progressive Sensorineural Hearing Loss
category: EAR_NOSE_THROAT
frequency: OCCASIONAL
context: Particularly documented in pediatric longitudinal follow-up cohorts.
description: >
Some children with cholesteatoma develop progressive sensorineural hearing
loss over time and require ongoing audiologic monitoring even after an
initially normal bone-conduction baseline.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:34860720
reference_title: "Cholesteatoma Is Associated With Pediatric Progressive Sensorineural Hearing Loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The statistical analyses demonstrated an association between cholesteatoma and pediatric progressive sensorineural hearing loss."
explanation: Large longitudinal pediatric dataset supports progressive SNHL as a clinically relevant phenotype subset.
- name: Tinnitus
category: EAR_NOSE_THROAT
description: >
Tinnitus can accompany middle-ear cholesteatoma as part of the associated
hearing symptom complex.
phenotype_term:
preferred_term: Tinnitus
term:
id: HP:0000360
label: Tinnitus
evidence:
- reference: PMID:41552209
reference_title: "Impact of Surgical Treatment on the Quality of Life in Patients With Chronic Otitis Media With Cholesteatoma: A Prospective Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Main symptoms included tinnitus (68%), otalgia (64%), and otorrhea (64%)."
explanation: Prospective cohort study directly supports tinnitus as a common symptom in chronic otitis media with cholesteatoma.
- name: Vertigo
category: NEUROLOGICAL
frequency: OCCASIONAL
context: Particularly associated with labyrinthine fistula complicating erosive cholesteatoma.
description: >
Vertigo can occur when cholesteatoma erodes the labyrinth, most often the
lateral semicircular canal, producing vestibular symptoms.
phenotype_term:
preferred_term: Vertigo
term:
id: HP:0002321
label: Vertigo
evidence:
- reference: PMID:40096720
reference_title: "Labyrinthine Fistulas in cholesteatoma : Surgical outcome on auditory function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Vertigo was present in 43.5% of patients."
explanation: Clinical cohort of cholesteatomatous labyrinthine fistula directly supports vertigo as an important vestibular complication phenotype.
- name: Facial palsy
category: NEUROLOGICAL
frequency: RARE
context: Typically seen in more advanced cholesteatoma complicated by labyrinthine fistula or facial canal involvement.
description: >
Facial nerve palsy is an uncommon but clinically important complication of
advanced erosive cholesteatoma.
phenotype_term:
preferred_term: Facial palsy
term:
id: HP:0010628
label: Facial palsy
evidence:
- reference: PMID:40096720
reference_title: "Labyrinthine Fistulas in cholesteatoma : Surgical outcome on auditory function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Facial nerve paralysis was observed in 5 patients (10.9%)."
explanation: Clinical series of cholesteatomatous labyrinthine fistula documents facial nerve palsy as a recognized complication phenotype.
- name: Labyrinthine fistula
category: EAR_NOSE_THROAT
frequency: OCCASIONAL
context: Represents an advanced erosive complication of middle-ear cholesteatoma.
description: >
Advanced cholesteatoma can erode the labyrinth, producing a labyrinthine
fistula that is usually identified radiologically or intraoperatively.
notes: No precise HPO term for labyrinthine fistula was verified locally in this pass, so this complication remains intentionally unannotated.
evidence:
- reference: PMID:37675676
reference_title: "Managing cholesteatomas with labyrinthine fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the middle ear cholesteatomas, 15.6% ( n = 14) of ears were complicated by LF."
explanation: Surgical cohort directly documents labyrinthine fistula as a recurring complication phenotype in middle-ear cholesteatoma.
environmental:
- name: Obstructive Eustachian tube dysfunction
presence: Predisposing
description: >
Chronic obstructive Eustachian tube dysfunction promotes middle-ear pressure
abnormalities and retraction biology that increase cholesteatoma risk.
effect: Can predispose to middle-ear atelectatic change and cholesteatoma formation.
evidence:
- reference: PMID:40805865
reference_title: "Balloon Eustachian Tuboplasty: A Systematic Review of Technique, Safety, and Clinical Outcomes in Chronic Obstructive Eustachian Tube Dysfunction."
supports: SUPPORT
evidence_source: OTHER
snippet: "Obstructive Eustachian tube dysfunction (OETD) is common in adults and may lead to middle-ear conditions such as atelectasis and cholesteatoma."
explanation: Systematic review directly supports obstructive Eustachian tube dysfunction as a predisposing context.
- name: Upper airway mucosal inflammatory disease
presence: Associated
description: >
Chronic rhinitis, chronic sinusitis, nasal polyposis, and adenoid disease are
associated with cholesteatoma, supporting a shared mucosal inflammatory or
ventilation-related predisposition.
effect: Associated upper-airway mucosal disease may increase cholesteatoma risk.
evidence:
- reference: PMID:38517544
reference_title: "Occurrence of mucosa-affecting diseases of the upper airways in middle ear cholesteatoma patients: a nationwide case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Chronic rhinitis, chronic sinusitis and nasal polyposis were more common in cholesteatoma patients than in controls (OR 1.5 to 2.5) as were both adenoid and tonsil surgery (OR > 4)"
explanation: Nationwide case-control data support upper-airway mucosal disease as a disease-associated predisposing context.
diagnosis:
- name: Otoscopy
description: >
Clinical otoscopy is a first-line diagnostic examination used to identify
retraction pockets, keratin debris, and other suspicious middle-ear findings.
diagnosis_term:
preferred_term: otoscopy
term:
id: MAXO:0001198
label: otoscopy
evidence:
- reference: PMID:40411260
reference_title: "Clinicoradiological Evaluation of Cholesteatoma: Integrating Clinical, CT, and MRI Diagnostics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients underwent clinical evaluation (history, otoscopy, and audiometry) followed by HRCT and EPI-DWI imaging."
explanation: Prospective diagnostic study supports otoscopy as a core component of initial cholesteatoma evaluation.
- name: Pure-tone audiometry
description: >
Audiometry characterizes conductive hearing loss, tracks air-bone gaps, and
supports longitudinal monitoring for progressive sensorineural involvement.
diagnosis_term:
preferred_term: diagnostic procedure
term:
id: MAXO:0000003
label: diagnostic procedure
results: Often shows a conductive deficit with measurable air-bone gap.
evidence:
- reference: PMID:40411260
reference_title: "Clinicoradiological Evaluation of Cholesteatoma: Integrating Clinical, CT, and MRI Diagnostics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients underwent clinical evaluation (history, otoscopy, and audiometry) followed by HRCT and EPI-DWI imaging."
explanation: Confirms audiometry as part of the standard diagnostic workup.
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The mean air-bone gap was 29.84dB"
explanation: Provides the characteristic audiometric abnormality seen in acquired cholesteatoma.
- name: High-resolution computed tomography of the temporal bone
description: >
HRCT provides anatomic detail on middle-ear extension, mastoid involvement,
and bone erosion, but is less specific than diffusion-weighted MRI for
lesion confirmation.
diagnosis_term:
preferred_term: computed tomography procedure
term:
id: MAXO:0000571
label: computed tomography procedure
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:40411260
reference_title: "Clinicoradiological Evaluation of Cholesteatoma: Integrating Clinical, CT, and MRI Diagnostics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "EPI-DWI remains the preferred imaging modality for cholesteatoma diagnosis, while HRCT provides complementary information on middle ear anatomy and bone erosion."
explanation: Supports HRCT as the structural imaging modality for anatomy and bony destruction.
- name: Diffusion-weighted magnetic resonance imaging
description: >
Echo-planar diffusion-weighted MRI is the preferred imaging modality for
cholesteatoma confirmation because it outperforms HRCT for lesion detection.
diagnosis_term:
preferred_term: magnetic resonance imaging procedure
term:
id: MAXO:0000424
label: magnetic resonance imaging procedure
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
evidence:
- reference: PMID:40411260
reference_title: "Clinicoradiological Evaluation of Cholesteatoma: Integrating Clinical, CT, and MRI Diagnostics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Diffusion-weighted magnetic resonance imaging (DW-MRI) demonstrated superior sensitivity (92.7%) and specificity (89.4%) compared with HRCT (sensitivity: 75.5%; specificity: 70.2%)."
explanation: Directly supports DWI MRI as the more accurate imaging test for cholesteatoma diagnosis.
treatments:
- name: Tympanomastoidectomy-based surgical excision
description: >
Definitive management usually requires operative removal of cholesteatoma
with tympanoplasty- and/or mastoidectomy-based approaches chosen according to
disease extent and surgeon goals.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: mastoid process of temporal bone
term:
id: UBERON:0011220
label: mastoid process of temporal bone
target_phenotypes:
- preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
target_mechanisms:
- target: Keratinizing squamous epithelium overgrowth in the middle ear
treatment_effect: INHIBITS
description: Surgical excision removes the expanding keratinizing lesion bulk.
evidence:
- reference: PMID:39327289
reference_title: "Exclusive endoscopic tympanoplasty efficacy in the treatment of cholesteatoma without mastoid involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exclusive endoscopic tympanoplasty has been shown to be effective in removing cholesteatoma in patients without evidence of mastoid involvement"
explanation: Supports surgical lesion removal as direct interruption of cholesteatoma epithelial burden.
- target: Local bone erosion and ossicular destruction
treatment_effect: MODULATES
description: Removal of disease aims to stop ongoing local erosive damage.
evidence:
- reference: PMID:36774407
reference_title: "Radiological and audiological predictors of stapes destruction in adherent pars tensa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "High preoperative awareness of the possibility of destruction of the stapes superstructure would enable the surgeon to make a timely decision to provide surgical intervention before progression to severe stapes destruction"
explanation: Clinical cohort data directly support surgery as an intervention used to prevent progression of ossicular destruction.
evidence:
- reference: PMID:38337530
reference_title: "Cholesteatoma Severity Determines the Risk of Recurrent Paediatric Cholesteatoma More Than the Surgical Approach."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Surgery without mastoidectomy, including totally endoscopic ear surgery, had 11% 5-year recurrence. Canal wall-up tympanomastoidectomy (CWU) and canal wall-down/mastoid obliteration both had 23% 5-year recurrence."
explanation: Supports the use of multiple operative strategies in contemporary cholesteatoma care and quantifies recurrence context.
- reference: PMID:27236633
reference_title: "Characteristics of 419 patients with acquired middle ear cholesteatoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the surgical cases, 16.8% underwent closed tympanomastoidectomy and 75.2% open tympanomastoidectomy."
explanation: Cohort data confirm tympanomastoidectomy-based surgery as standard real-world management.
- name: Exclusive endoscopic tympanoplasty for selected non-mastoid disease
description: >
In carefully selected patients without mastoid involvement, exclusive
endoscopic tympanoplasty can remove cholesteatoma with recurrence rates
comparable to more traditional microscopic approaches.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
qualifiers:
- predicate:
preferred_term: has participant
term:
id: RO:0000057
label: has participant
value:
preferred_term: tympanic membrane
term:
id: UBERON:0002364
label: tympanic membrane
target_phenotypes:
- preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
target_mechanisms:
- target: Keratinizing squamous epithelium overgrowth in the middle ear
treatment_effect: INHIBITS
description: Endoscopic excision removes localized cholesteatoma when mastoid extension is absent.
evidence:
- reference: PMID:39327289
reference_title: "Exclusive endoscopic tympanoplasty efficacy in the treatment of cholesteatoma without mastoid involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exclusive endoscopic tympanoplasty has been shown to be effective in removing cholesteatoma in patients without evidence of mastoid involvement"
explanation: Directly supports endoscopic removal of localized cholesteatoma burden.
evidence:
- reference: PMID:39327289
reference_title: "Exclusive endoscopic tympanoplasty efficacy in the treatment of cholesteatoma without mastoid involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Exclusive endoscopic tympanoplasty has been shown to be effective in removing cholesteatoma in patients without evidence of mastoid involvement"
explanation: Supports this less invasive surgical option in anatomically selected patients.
- name: Longitudinal postoperative audiologic surveillance
description: >
Ongoing hearing follow-up is warranted because some patients, especially
children, develop progressive sensorineural hearing loss over time even after
initial evaluation or surgery.
treatment_term:
preferred_term: diagnostic procedure
term:
id: MAXO:0000003
label: diagnostic procedure
target_phenotypes:
- preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:34860720
reference_title: "Cholesteatoma Is Associated With Pediatric Progressive Sensorineural Hearing Loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These findings inform clinical management by suggesting that children with cholesteatoma diagnoses may be at increased risk for progressive sensorineural hearing loss and should receive continued monitoring even after a normal masked BC baseline has been established."
explanation: Directly supports longitudinal postoperative or follow-up audiologic monitoring as a management strategy.
differential_diagnoses:
- name: Chronic suppurative otitis media without cholesteatoma
description: >
Chronic otorrhea and hearing loss can overlap substantially, but
cholesteatoma requires exclusion of a destructive keratinizing lesion by
targeted imaging and histopathology.
distinguishing_features:
- Cholesteatoma shows diffusion restriction on DWI MRI and erosive middle-ear disease on imaging.
- HRCT is complementary for bone erosion, while histopathology remains the diagnostic gold standard.
evidence:
- reference: PMID:40411260
reference_title: "Clinicoradiological Evaluation of Cholesteatoma: Integrating Clinical, CT, and MRI Diagnostics."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The integration of clinical findings with EPI-DWI and HRCT significantly enhances the diagnostic accuracy for cholesteatoma"
explanation: Supports the use of multimodal imaging to distinguish cholesteatoma from non-cholesteatomatous chronic otitis media.
- name: Otomycosis
disease_term:
preferred_term: otomycosis
term:
id: MONDO:0000262
label: otomycosis
description: >
Otomycosis can mimic cholesteatoma when chronic otorrhea and debris are the
dominant presenting features.
distinguishing_features:
- Otomycosis is centered in the external auditory canal and is associated with fungal debris rather than a middle-ear keratinizing lesion.
- Cholesteatoma is more strongly associated with focal bone erosion and destructive middle-ear disease.
evidence:
- reference: PMID:38334859
reference_title: "Fungal Otitis Externa (Otomycosis) Associated with Aspergillus Flavus: A Case Image."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A head/neck CT showed completely normal mastoid, middle ear and external auditory canal regions without any evidence of opacification or bone erosion."
explanation: Case-level human evidence shows otomycosis can present with otorrhea and canal debris but lacks the middle-ear opacification and bony erosion expected in cholesteatoma.
- reference: PMID:38334859
reference_title: "Fungal Otitis Externa (Otomycosis) Associated with Aspergillus Flavus: A Case Image."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Otoscopic examination of the right ear disclosed aggregates of dried, brown, fibrillar material and debris occluding the external auditory canal and obstructing the otherwise intact tympanic membrane."
explanation: Directly supports the distinguishing feature that otomycosis is centered in the external auditory canal with fungal debris rather than a middle-ear keratinizing lesion.
- name: Semicircular Canal Dehiscence Syndrome
disease_term:
preferred_term: semicircular canal dehiscence syndrome
term:
id: MONDO:0018484
label: semicircular canal dehiscence syndrome
description: >
Semicircular canal dehiscence syndrome can overlap with cholesteatoma when
patients present with tinnitus, conductive hearing loss, dizziness, or other
otologic complaints.
distinguishing_features:
- SCDS is characterized by sound- or pressure-induced vestibular symptoms and third-window auditory findings rather than chronic otorrhea or a keratinizing middle-ear lesion.
- Temporal bone CT in SCDS shows superior semicircular canal dehiscence, whereas cholesteatoma is defined by destructive middle-ear disease and keratin debris.
evidence:
- reference: PMID:22312921
reference_title: "Histopathology of the temporal bone in a case of superior canal dehiscence syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient developed bilateral aural fullness, pulsatile tinnitus, and difficulty tolerating loud noises after minor head trauma at 53 years of age."
explanation: Human SCDS case demonstrates overlapping otologic symptoms that may enter the differential diagnosis against cholesteatoma, while the syndrome remains anatomically and mechanistically distinct.
datasets:
- accession: PMID:37537159
title: Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
description: >
Single-cell RNA-seq dataset from human cholesteatoma tissue used to define a
pathogenic fibroblast subset linked to local osteoclast differentiation and
bone destruction.
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
sample_types:
- preferred_term: cholesteatoma tissue
term:
id: UBERON:0001756
label: middle ear
tissue_term:
preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
conditions:
- human cholesteatoma tissue
publication: PMID:37537159
evidence:
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples"
explanation: Supports this publication as a reusable single-cell human cholesteatoma dataset.
findings:
- statement: Human cholesteatoma single-cell profiling identified an inhibin beta A-positive fibroblast population linked to osteoclast differentiation and bone destruction.
evidence:
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA."
explanation: Identifies the key fibroblast subset discovered by the dataset.
- reference: PMID:37537159
reference_title: "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation."
explanation: Connects the fibroblast transcriptomic program to the osteoclastogenic mechanism.
- accession: PMID:38890701
title: Identification of miRNA expression profile in middle ear cholesteatoma using small RNA-sequencing
description: >
Small RNA-seq dataset comparing cholesteatoma tissue with matched normal
retroauricular skin to define differentially expressed miRNAs and infer
regulatory pathways relevant to disease pathogenesis.
notes: Small RNA sequencing study represented with the closest available schema data_type.
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: BULK_RNA_SEQ
sample_types:
- preferred_term: cholesteatoma tissue
term:
id: UBERON:0001756
label: middle ear
tissue_term:
preferred_term: middle ear
term:
id: UBERON:0001756
label: middle ear
- preferred_term: retroauricular skin tissue
term:
id: UBERON:0001003
label: skin epidermis
tissue_term:
preferred_term: skin epidermis
term:
id: UBERON:0001003
label: skin epidermis
conditions:
- acquired middle ear cholesteatoma
- matched normal retroauricular skin
publication: PMID:38890701
evidence:
- reference: PMID:38890701
reference_title: "Identification of miRNA expression profile in middle ear cholesteatoma using small RNA-sequencing."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The miRNA expression profiling was performed using small RNA sequencing"
explanation: Supports this publication as a bulk tissue small RNA sequencing dataset for cholesteatoma.
findings:
- statement: Cholesteatoma tissue showed 121 differentially expressed miRNAs compared with matched skin, implicating TGFBR2, MBNL1, and NFAT5 as potential regulatory targets.
evidence:
- reference: PMID:38890701
reference_title: "Identification of miRNA expression profile in middle ear cholesteatoma using small RNA-sequencing."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The miRNA expression profile revealed 121 significantly differentially expressed miRNAs in cholesteatoma compared to normal skin tissues, with 56 upregulated and 65 downregulated."
explanation: Summarizes the primary differential-expression signal from the small RNA-seq dataset.
- reference: PMID:38890701
reference_title: "Identification of miRNA expression profile in middle ear cholesteatoma using small RNA-sequencing."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The interaction network of the the 2 most upregulated (hsa-miR-21-5p and hsa-miR-142-5p) and 3 most downregulated (hsa-miR-508-3p, hsa-miR-509-3p and hsa-miR-211-5p) miRNAs identified TGFBR2, MBNL1, and NFAT5 as potential key target genes in middle ear cholesteatoma."
explanation: Captures the candidate target-gene network inferred from the differentially expressed miRNAs.
clinical_trials:
- name: NCT05921643
phase: NOT_APPLICABLE
status: RECRUITING
description: >
Prospective observational study evaluating short- and medium-term outcomes
of mastoid filling with bioactive glass during primary adult cholesteatoma
surgery.
target_phenotypes:
- preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: clinicaltrials:NCT05921643
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Then a filling material is used to fill the mastoid (GlassBONE™ or Bonalive™), and above all to stabilize the cartilaginous fragment to prevent a recurrence."
explanation: Official study record supports this recruiting mastoid-filling study focused on recurrence prevention after cholesteatoma surgery.
- name: NCT04672187
phase: NOT_APPLICABLE
status: COMPLETED
description: >
Completed observational study comparing preoperative HRCT and audiologic
assessment with intraoperative endoscopic findings in middle-ear cholesteatoma.
evidence:
- reference: clinicaltrials:NCT04672187
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The aim of this study is to assess the accuracy of preoperative HRCT of the temporal bone combined with the preoperative audiologic assessment compared with the intraoperative endoscopic middle ear finding."
explanation: Official record supports this completed imaging-plus-audiology diagnostic study in cholesteatoma.
- name: NCT03954288
phase: NOT_APPLICABLE
status: UNKNOWN
description: >
Observational biomarker study measuring serum sclerostin levels in
cholesteatoma patients to explore bone-remodeling biology with potential clinical relevance.
evidence:
- reference: clinicaltrials:NCT03954288
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The aim of this study is to investigate the levels of sclerostin in patients with cholesteatoma."
explanation: Official record supports prospective evaluation of a bone-remodeling biomarker in cholesteatoma patients.