Acquired middle-ear cholesteatoma is a locally destructive lesion of the tympanic cavity, composed of keratinizing squamous epithelium. Clinically, it presents with progressive conductive hearing loss, ossicular erosion, and, in severe cases, labyrinthine fistula, facial nerve palsy, or intracranial complications [1, 2]. Despite its histologically benign nature, cholesteatoma is notorious for aggressive local destruction and high recurrence rates after incomplete excision [3], making it a condition of significant surgical and clinical concern.

The term cholesteatoma, derived from the Greek “chole” (cholesterol), “steat” (fat), and “oma” (tumor), is historically misleading. When Johannes Müller first described the lesion, he interpreted it as a fatty tumor, a characterization later proven inaccurate, as these lesions contain neither cholesterol nor adipose tissue [1]. Cholesteatomas are broadly classified into congenital and acquired forms. Congenital lesions arise behind an intact tympanic membrane, typically diagnosed in early childhood. Acquired cholesteatomas develop secondary to chronic otitis media or Eustachian tube dysfunction and are further subclassified as primary—arising from retraction pockets without prior trauma—or secondary, resulting from tympanic membrane perforation or prior surgery. Anatomical origin also influences behavior: pars flaccida (attic) and pars tensa (posterior quadrant) lesions exhibit distinct growth patterns and differential risks for ossicular erosion [4]. Epidemiologically, cholesteatoma affects approximately 3 per 100,000 children and 9 per 100,000 adults annually, with a slight male predominance, peaking in the second to fourth decades for acquired forms [5].

At the molecular level, cholesteatoma pathogenesis is increasingly understood as microenvironment-dependent, with persistent inflammation serving as a central driver. Chronic cytokine activity—including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-1β, and IL-8—and stress-response proteins such as heat shock protein 27 (HSP27) promote keratinocyte proliferation, immune cell recruitment, and tissue remodeling [6]. Concurrently, matrix degradation mediated by matrix metalloproteinase (MMP)-2 and MMP-9, along with osteoclast activation, underlies the characteristic bone erosion observed clinically [7]. These processes are further amplified by oxidative stress and dysregulation of miRNAs and epigenetic modifications, which modulate apoptosis, proliferation, and inflammatory signaling. Partial epithelial-to-mesenchymal transition (EMT) contributes to keratinocyte motility and stromal remodeling, recapitulating certain hallmarks of neoplastic invasion without conferring metastatic potential [8].

Surgical excision—ranging from canal-wall-up to canal-wall-down tympanomastoidectomy—remains the cornerstone of management, aiming to eradicate disease and prevent recurrence [9]. However, these mechanistic insights provide opportunities to identify prognostic biomarkers, guide surveillance, and develop adjunctive therapies targeting inflammation, matrix remodeling, or oxidative stress.

The mini-review synthesizes emerging molecular and cellular knowledge into acquired middle-ear cholesteatoma with a translational lens, highlighting the microenvironmental drivers of local tissue destruction, recurrence, and osteolysis. By connecting mechanistic understanding to precision, locally delivered adjunctive strategies and biomarker-guided approaches, it provides a novel framework to complement surgical management. This perspective positions cholesteatoma as a model for benign yet locally aggressive, microenvironment-driven disease and offers actionable directions for future translational and clinical research.

Chronic cytokine-driven inflammation activates nuclear factor kappa B (NF‑κB), mitogen-activated protein kinase (MAPK), and janus kinase/signal transducer and activator of transcription (JAK–STAT) signaling, which together with oxidative stress and miRNA/epigenetic dysregulation drives keratinocyte proliferation and partial EMT. These epithelial changes, in concert with proteolytic matrix remodeling, osteoclast activation and fibroblast–immune cross-talk, result in bone erosion, while persistent microbial biofilms amplify local inflammation, creating a self-sustaining microenvironment that underpins cholesteatoma growth and recurrence (Figure 1, Table 1) [6, 8].

Cholesteatoma recapitulates several molecular and microenvironmental features commonly observed in neoplasia: focal hyperproliferation, chronic activation of pro-survival and inflammatory pathways (NF-κB, MAPK, JAK–STAT), protease-driven local tissue invasion (MMP family, cathepsins), recruitment of osteoclastogenic signals, and acquisition of a partial EMT phenotype that facilitates local expansion [6]. Concurrent epigenetic and small-RNA dysregulation, oxidative stress, and a tumor-like stromal–immune network further enhance cellular plasticity and matrix remodeling [8], producing a histomorphologic and functional phenotype that can appear “quasi-oncologic”. This “quasi-oncologic” pattern, characterized by invasive growth, stromal activation, and recurrence without metastatic potential, parallels other benign yet locally aggressive conditions such as desmoid-type fibromatosis (aggressive fibromatosis), endometriosis, keloids, and pigmented villonodular synovitis.

Very recent work has provided additional molecular evidence supporting cholesteatoma’s quasi-oncologic behavior. Somatic proto-oncogene mutations in MYC (2 of 22 patients) and NOTCH1 (5 of 22 patients) have been identified in a subset of middle-ear cholesteatomas, correlating with local bone destruction [28]. These findings offer key mechanistic insight, demonstrating that cholesteatoma’s aggressive local expansion is not purely inflammatory but may also involve oncogenic signaling pathways. The mutations are not universal, indicating that only a fraction of lesions—approximately 32% in this cohort—may be genetically predisposed to pronounced bone erosion (selective aggression). While this represents the first molecular evidence linking proto-oncogene alterations to cholesteatoma behavior, the small sample size underscores the need for larger studies to validate and extend these observations.

Importantly, cholesteatoma continues to lack hallmark features of malignant neoplasia, including metastatic potential, widespread chromosomal instability, and autonomous growth independent of local microenvironmental cues [29]. Apoptotic and cell-cycle checkpoints remain largely intact, and proliferation is spatially constrained to the lesion microenvironment. Conceptually, these findings reinforce the view of cholesteatoma as a benign pathology in which oncogenic programs are co-opted by a chronic inflammatory ecosystem, producing aggressive local behavior without true neoplastic transformation. This distinction has practical implications: therapeutic strategies should focus on the lesion’s microenvironmental dependencies—such as inflammation, proteolysis, osteoclast recruitment, biofilm persistence, redox imbalance, and epigenetic/RNA dysregulation [10]—rather than relying on systemic cytotoxic regimens designed for malignant disease.

Cholesteatoma’s locally aggressive, microenvironment-dependent behavior makes it particularly suited for precision, locally delivered adjuncts that complement surgical excision. Intervention may be approached across three temporal windows [30, 31]:

1) Preoperative stabilization: Short courses of topical or local agents aimed at suppressing inflammation, reducing protease activity, and limiting osteoclast-mediated bone loss before surgery.

2) Intraoperative margin therapy: Targeted depots applied to surgical margins containing anti-protease, antioxidant, anti-biofilm, or immune-modulatory agents to neutralize residual microscopic disease and reduce epithelial seeding.

3) Postoperative sustained-release therapy: Depot formulations in the mastoid or epitympanum designed to provide continuous pharmacologic action during the early wound-healing period, potentially lowering recurrence risk.

Preclinical validation could utilize organotypic cholesteatoma–bone co-cultures, ex vivo human explants, and selective in vivo otic models to replicate epithelial–stromal–osteoclast interactions, biofilm persistence, and microenvironmental regulation, while evaluating local pharmacokinetics, ototoxicity, vestibular safety, and delivery efficiency [32–34]. Current research has largely emphasized surgical technique or imaging, with molecularly targeted adjuncts remaining uncommon. Topical 5‑fluorouracil has been applied in only limited external-canal cases [35], and systematic trials addressing mechanistic pathways are lacking, highlighting an opportunity for biomarker-guided, mechanism-driven early-phase studies.

Cholesteatoma is a benign but locally aggressive disease with substantial risk for hearing loss, bone destruction, and recurrent surgery. Surgical excision remains the primary management strategy; however, high recurrence rates and variable outcomes underscore the need for adjunctive, mechanism-driven therapies. Advances in understanding the lesion’s inflammatory milieu, osteoclast activation, biofilm persistence, and molecular regulatory networks provide opportunities for precision interventions delivered directly to the middle ear, with the goals of stabilizing disease, limiting tissue damage, and preserving auditory function.

Future management may integrate surgical excision with locally targeted therapies, informed by molecular and imaging biomarkers to identify high-risk patients and monitor treatment response. Translational studies and early-phase trials focusing on axis-specific interventions, safe and effective local delivery platforms, and robust functional endpoints could help transition cholesteatoma care from reactive surgery to predictive, proactive, and personalized strategies. By aligning mechanistic insights with patient-centered clinical implementation, such approaches have the potential to reduce recurrence, minimize complications, and improve long-term hearing and quality of life for affected individuals.