A new development in senescence.

Cellular senescence is implicated in several pathological responses in the adult, with important repercussions in tumor suppression, wound healing, and aging. Two studies by Muñoz-Espín et al. and Storer et al. now reveal that senescence contributes to embryonic development, suggesting a primordial role in normal physiology.

Programmed cell senescence during mammalian embryonic development.

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-ß/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.

Occlusion of the Lateral Semicircular Canal, Endolymphatic Sac Surgery, and Cochlear Implantation: A Low Destructive Treatment for Unilateral Ménière's Disease and Deafness.

INTRODUCTION: Surgical treatment of Ménière's disease (MD) and deafness aims to treat vertigo and hearing disabilities. Current treatment options like labyrinthectomy and cochlear implantation (CI) have shown acceptable results but are destructive. Less destructive procedures, like the occlusion of the lateral semicircular canal and endolymphatic sac surgery, have been shown to be successful in vertigo control. The combination of both procedures with CI has not been investigated; therefore the objective of this study was to investigate the outcome of this combination in patients with single-sided MD and moderately severe to complete sensorineural hearing loss. METHODS: In this retrospective study, 10 patients with single-sided MD and moderately severe to complete sensorineural hearing loss were included. In all of them, a single-staged surgery, which consisted of CI, endolymphatic sac surgery, and occlusion of the lateral semicircular canal, was performed. The surgery was performed after a failed conservative therapy trial. The clinical outcome was evaluated by the Dizziness Handicap Inventory (DHI) and audiological tests. These were assessed preoperatively, 3 and 6 months after surgery. An MRI with a hydrops sequence was performed to support the clinical diagnosis. RESULTS: After the combined surgery, the mean DHI testing improved significantly from 71 to 30. Mean audiological monosyllabic speech testing outcome with the cochlea implant was 65% at 65 dB. The residual hearing of 2 patients could be preserved after the surgical procedure. CONCLUSION: The combination of occlusion of the lateral semicircular canal, endolymphatic sac surgery, and CI is an efficient low traumatic treatment for patients with a single-sided MD and moderately severe to complete sensorineural hearing loss.

Endolymphatic sac tumor misdiagnosed as metastatic renal cell carcinoma: Pitfalls in morphology and immunohistochemistry.

Endolymphatic sac tumor (ELST) is a rare disease that originates from the endolymphatic sac system of the inner ear. Being a low-grade malignant tumor, ELST has a mild morphology and is characterized by a slow but aggressive growth. Most clinicians and pathologists are unfamiliar with this disease. ELST can be misdiagnosed as metastatic renal cancer because of the similarity in morphology and expression of nephrogenic markers such as PAX8. The presented case of a 27-year-old man revealed that observing the characteristic location and confirming the absence of renal neoplasm to rule out the possibility of metastasis are critical for obtaining an accurate final diagnosis.

Functional outcomes and caloric response changes after endolymphatic sac decompression.

OBJECTIVE: To evaluate caloric response changes after endolymphatic sac decompression (ESD), together with hearing outcomes and the functional benefit of the operation. METHODS: A retrospective chart review of subjects who underwent endolymphatic sac decompression at a tertiary referral centre was performed. Data on audiological results, caloric testing, and functional level scale of the patients were analysed. RESULTS: Twenty-eight patients who met our criteria were eligible for enrolment in the study. The average follow-up after surgery was 25 months (range, 13-41). Postoperative pure-tone threshold averages and reduced vestibular response values (RVR) were not significantly altered by ESD; whereas, functional level scores improved significantly. CONCLUSION: Endolymphatic sac decompression is a surgical procedure that preserves hearing and vestibular function, and improves the daily functional level of patients with Ménière's disease. ESD can be preferred both in bilateral and unilateral disease because it does not alter vestibular function and preserves hearing.

Development and validation of prediction model to estimate vertigo risk after endolymphatic sac decompression in Meniere's disease: a retrospective cohort study.

PURPOSE: To study the efficacy predictors of endolymphatic sac decompression (ESD) in Meniere's disease (MD), and to establish and verify the prediction model of vertigo after ESD in patients with MD. METHODS: The retrospective cohort data of 56 patients with unilateral MD who underwent ESD surgery were recorded. A stepwise regression method was used to select optimal modeling variables, and we established a logistic regression model with the outcome of vertigo after ESD. The bootstrap method was used for internal validation. RESULTS: Potential predictors included sex, age, follow-up duration, disease course, attack duration, frequency of attack, pure-tone threshold average (PTA) of the patient's speech frequency, audiogram type, glycerin test results, MD subtype, and 10-year atherosclerotic cardiovascular disease risk classification. Using the stepwise regression method, we found that the optimal modeling variables were the audiogram type and PTA of the patient's speech frequency. The prediction model based on these two variables exhibited good discrimination [area under the receiver operating characteristic curve: 0.72 (95% confidence interval: 0.57-0.86)] and acceptable calibration (Brier score 0.21). CONCLUSION: The present model based on the audiogram type and PTA of the patient's speech frequency was found to be useful in guidance of ESD efficacy prediction and surgery selection.

Significance of endolymphatic sac surgery with and/or without simultaneous cochlea implant surgery in respect of vertigo control and speech perception in patients with Menière's disease.

PURPOSE: The focus on treating patients with Menière's Disease (MD) lies on the reduction of vertigo attacks and the preservation of sensory function. Endolympathic hydrops is considered as an epiphenomenon in MD, which can potentially be altered by endolymphatic sac surgery (ESS). Purpose of the study was to investigate the influences on vertigo control through manipulation of the perilymphatic system with or without ESS. METHODS: Retrospective data analysis of 86 consecutive patients with MD according to current diagnostic criteria after endolymphatic sac surgery alone (ESSalone; n = 45), cochlear implantation (CI) alone (CIalone; n = 12), and ESS with CI (ESS + CI; n = 29), treated at a tertiary referral center. MAIN OUTCOME MEASURES: vertigo control, speech perception pre- and postoperatively. RESULTS: Gender, side, and preoperative treatment were similar in all groups. Age was younger in the ESSalone-group with 56.2 ± 13.0 years (CIalone = 64.2 ± 11.4 years; ESS + CI = 63.1 ± 9.7 years). Definitive MD was present in all the CIalone, in 79.3% of the ESS + CI and in 59.6% of the ESSalone-patients. Likewise, vertigo control rate was 100% in the CIalone, 89.7% in the ESS + CI and 66.0% in the ESSalone-group. CONCLUSIONS: Vertigo control was improved in all three groups, however, superior in groups treated with CI, potentially contributed by the manipulation of both the endo- and perilymphatic systems. A more systematic characterization of the patients with larger case numbers and documentation of follow up data would be needed to evaluate a clinical effect more properly.

Endolymphatic sac decompression effect on secondary symptoms of Meniere's disease.

OBJECTIVE: To evaluate if endolymphatic sac decompression (ESD) significantly improves secondary symptoms of Meniere's disease including tinnitus and aural fullness. STUDY DESIGN: Survey study with retrospective chart review. SETTING: Tertiary care center. METHODS: Survey of adult patients with Meniere's disease that underwent primary ESD surgery from 2015 to 2020. Subjective reporting of pre- and postoperative aural fullness and tinnitus based on postoperative survey. Survey results and audiologic data of the patients that reported were compared pre- and postoperatively. RESULTS: Statistical analysis was performed using weighted kappa statistics to examine the level of agreement. There was a value of 0.12 for pre- and postoperative aural fullness, indicating a difference in the two groups with 77 % having improvement and only 4 % having worsening. There was a value of 0.21 for pre- and postoperative tinnitus, demonstrating a lack of agreement with 58 % having improvement and 4 % having worsening. Overall, there was significant improvement in both tinnitus and aural fullness postoperatively. There was no significant difference in word recognition score, speech reception threshold, or pure tone average between the pre- and postoperative group based on paired t-test. CONCLUSIONS: There is a significant improvement in both aural fullness and tinnitus for patients undergoing ESD with no negative effect on audiologic status. ESD is a viable option for treatment of Meniere's disease with vertigo, aural fullness, and tinnitus relief. Future prospective studies are needed to further improve the evidence of ESD's effect on secondary symptoms of Meniere's disease.

Is endolymphatic sac surgery an efficient treatment of Menière's disease patients? A systematic literature search and meta-analysis.

PURPOSE: The purpose of this work is to assess the treatment efficiency of endolymphatic sac surgery in patients with Menière's disease. METHODS: This study provides a systematic literature review and meta-analysis based on the guidelines of the Cochrane Collaboration and the Preferred Reporting Items for Systematic reviews and Meta-Analyses protocol. The main inclusion criteria of the literature review were the classification categories according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines of 1985 and 1995. RESULTS: An effect of 9.25 dB postoperative weighted average hearing loss in surgically treated individuals is classified as "clinically not significant" according to American Academy of Otolaryngology-Head and Neck Surgery 85/95. In contrast, the deterioration by 26.23% in speech comprehension is considered as "clinically significant." An improvement of functional level scale assessment by two categories and vertigo control by assessment in category B can be observed. CONCLUSION: The findings of this meta-analysis indicate that endolymphatic sac surgery may be beneficial as a treatment for Menière's disease in terms of a positive impact on functional level scale and vertigo control while yielding a negative impact on pure tone average hearing loss and on speech comprehension.

Surgical management of endolymphatic sac tumor: classification, outcomes and strategy. A single institution's experience.

PURPOSE: To review the resections of endolymphatic sac tumor (ELST) and describe our experience in the surgical management of ELST. METHODS: Retrospective investigation of consecutive patients who underwent resection of ELSTs at our hospital between 1999 and 2019. The symptoms, diagnosis, surgical findings, and outcomes were analyzed to develop a tumor staging system and corresponding surgical strategy. RESULTS: Retrospective review revealed the surgical treatment of 22 ELSTs. Based on intraoperative findings of tumor extent and size, ELSTs were classified into two types. Type-I (n = 6) referred to the small tumors that were locally confined with limited invasion of semicircular canals and dura; type-II (n = 16) referred to the large tumors that presented extensive erosion of at least one anatomic structure apart from the semicircular canals and the dura around endolymphatic sac. In this case series, Type-I ELST is amenable to resection through a transmastoidal approach, and subtotal petrosectomy is appropriate for the resection of type-II ELST. Sensorineural hearing loss (SNHL) is the most commonly preoperative symptom in both two types of cases. Five type-II ELSTs experienced recurrence and underwent reoperation, whereas all type-I ELSTs did not. CONCLUSION: ELST usually results in SNHL (95%) at the time of diagnosis. The surgical strategy and prognosis of ELST resections are different between type-I and type-II: type-I ELST is amenable to transmastoidal approach with the preservation of facial nerve, whereas type-II ELST increase the surgical difficulty and the risk of recurrence, and subtotal petrosectomy is the basic requirement for the resection of type-II ELST.

Delayed yet effective response of an endolymphatic sac tumor to radiosurgery: case report focusing on its radio-biological behavior.

Endolymphatic sac tumors (ELST), though benign are locally invasive lesions. Owing to its vascularity, complete surgical resection is often not possible and adjuvant gamma knife radiosurgery (GKRS) is advocated to control tumor growth. These lesions do not uniformly respond to radiation therapy in the initial phase and their early radiobiological course after GKRS is less understood. We discuss a case of residual ELST where a mild increase was noted at 36 months following GKRS and then regressed completely after a decade. This report possibly has the longest follow-up revealing the true efficacy of GKRS in these tumors. ELST shows a variable response in the early years after GKRS. They may remain static, regress or increase in size. One should be aware of these patterns of early radiological responses and a long term follow up is warranted as some lesions may show radiosurgical effectiveness after a long latent period.

The Diagnosis and Management of Advanced Endolymphatic Sac Tumor.

Endolymphatic sac tumor (ELST) is a group of low-grade malignant tumors originating from the endolymphatic sac of the inner ear. It is rare in the clinic and has the biological characteristics of slow growth and local aggression. Due to the lack of specificity in the clinical manifestations of patients with ELST, many cases have entered the advanced stage at the time of diagnosis. However, there are still great challenges in the treatment of advanced ELSTs. Here, the authors describe a case of advanced ELST, which relapsed after 2 operations. This time, the authors chose the transotic approach for tumor resection, which achieved the goal of complete resection of the tumor, and the patient recovered smoothly after surgery. There were no surgical complications and no tumor recurrence after the follow-up. Through literature review and our own experience, the authors suggest that complete surgical resection is the first choice for both primary and recurrent advanced ELSTs. The choice of a reasonable surgical approach is the key to ensuring complete resection of the tumor, while preoperative angiography and embolization, fine treatment of important structures during surgery, and postoperative long-term follow-up are equally important for patients with advanced ELST to obtain a good prognosis.

Endolymphatic sac tumour - a rare complication associated with von Hippel-Lindau disease.

We report the case of a 42-year - old female with familiar form von Hippel-Lindau disease (VHL) and recurrent endolymphatic sac tumour (ELST), which was presented like non-homogenous, solid and cystic expansion of the left petrous temporal bone. Histologically, there was found lamellae of bone with adjacent ligament and with papillary projections with fibrovascular core. The papillae were lined by a single layer of cuboidal epithelium with hyperchromatic and lightly pleomorphic nuclei. Sporadically, small cystic formations with eosinophilic, PAS positive secretion were noted. Imunohistochemically, the cuboidal cells showed diffuse positivity for vimentin, epithelial membrane antigen (EMA), cytokeratin AE1/AE3 and S100 protein (weakly). Other markers examined, including TTF1, PAX8 and CD10, were negative. Endolymphatic sac tumour is rare low-grade malignant epithelial tumour arising from the endolymphatic sac in the temporal bone, which occurs in 1 out of 30 000 births, with just fewer than 300 cases reported in the literature. About one third of cases are associated with von Hippel- Lindau disease, an autosomal dominant familial cancer syndrome.

Low-salt diet increases mRNA expression of aldosterone-regulated transporters in the intermediate portion of the endolymphatic sac.

The endolymphatic sac is a small sac-shaped organ at the end of the membranous labyrinth of the inner ear. The endolymphatic sac absorbs the endolymph, in which the ion balance is crucial for inner ear homeostasis. Of the three sections of the endolymphatic sac, the intermediate portion is the center of endolymph absorption, particularly sodium transport, and is thought to be regulated by aldosterone. Disorders of the endolymphatic sac may cause an excess of endolymph (endolymphatic hydrops), a histological observation in Meniere's disease. A low-salt diet is an effective treatment for Meniere's disease, and is based on the assumption that the absorption of endolymph in the endolymphatic sac abates endolymphatic hydrops through a physiological increase in aldosterone level. However, the molecular basis of endolymph absorption in each portion of the endolymphatic sac is largely unknown because of difficulties in gene expression analysis, resulting from its small size and intricate structure. The present study combined reverse transcription-quantitative polymerase chain reaction and laser capture microdissection techniques to analyze the difference of gene expression of the aldosterone-controlled epithelial Na+ channel, thiazide-sensitive Na+-Cl- cotransporter, and Na+, K+-ATPase genes in the three individual portions of the endolymphatic sac in a rat model. A low-salt diet increased the expression of aldosterone-controlled ion transporters, particularly in the intermediate portion of the endolymphatic sac. Our findings will contribute to the understanding of the physiological function of the endolymphatic sac and the pathophysiology of Meniere's disease.

Endolymphatic sac tumour: exploring the role of CT and MRI features in the diagnosis of 22 cases.

AIM: To explore the role of imaging features in the diagnosis of endolymphatic sac tumour (ELST). MATERIALS AND METHODS: Twenty-two patients with ELST confirmed at histopathology were included in this retrospective study. All patients underwent computed tomography (CT) and magnetic resonance imaging (MRI) examinations, including diffusion-weighted imaging (DWI; n=18) and dynamic contrast-enhanced (DCE) MRI (n=3). The imaging features of this series were analysed. RESULTS: All lesions appeared as irregular soft-tissue mass lesions located in the middle and posterior margin of the petrous bone. At CT, the normal vestibular aqueduct structure disappeared. Multiple osteoid tissues were present inside the tumour, and destructive bone changes had a "honeycomb" pattern. Twenty cases were accompanied by the incomplete thin bony peripheral rim along the medial margin. On both T1-weighted imaging (WI) and T2WI, all lesions showed hyperintense, hypointense, and isointense mixed signal intensity. Scattered peripheral hyperintensities were found in all cases on T1WI. The mean apparent diffusion coefficient (ADC) value of 18 lesions was (1.35 ± 0.13) × 10-3 mm2/s, which was similar to that of masseter muscles. On enhanced T1WI, all lesions had significant heterogeneous enhancement, and the vascular flowing-void effect was seen in larger lesions (≥1.5 cm). The time-signal intensity curve (TIC) showed a plateau type in all three cases. CONCLUSIONS: The imaging features of ELST, including its location, bone destruction form, MRI signal intensity, and enhancement pattern, are helpful to improve the diagnostic accuracy of this rare tumour.

Evaluation of vestibular function following endolymphatic sac surgery.

PURPOSE: To evaluate objective vestibular function after endolymphatic sac surgery (ELSS) for Menière's disease (MD), using comparative vestibular function tests: videonystagmography (VNG), vestibular evoked myogenic potentials (VEMP) and video head-impulse test (VHIT) METHODS: Patients with definite MD using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) of 1995 criteria modified in 2015 and treated with ELSS (sac decompression or sac opening) were included. The primary outcome was the preservation of vestibular function, comparing pre- and postoperative vestibular function tests: VNG, VEMP, VHIT. Secondary outcomes were control of episodes of vertigo, hearing outcome using AAO-HNS criteria, and QoL using the Menière's disease outcome questionnaire. RESULTS: 73 patients were included in the study. We found a significant preservation of vestibular function as measured by VNG and VHIT. There was no statistical difference in the presence or absence of cervical and ocular (P13/N23 and N1/P1) waves on VEMP pre- and postoperatively. 67% of patients had good control of episodes of vertigo post-operatively, with significantly better results in the sac opening group (75%). There was no significant change in hearing postoperatively, and QoL scores were significantly improved after surgery (p < 0.0001). CONCLUSION: Endolymphatic sac surgery (ELSS) is a conservative surgical treatment, which does not negatively impact vestibular function. It was associated with improved control of episodes of vertigo, preservation of hearing, and a clear improvement in QoL scores. Despite its pathophysiology not being fully understood, it remains a first-line procedure preserving vestibular function, for MD refractory to medical management.

Endolymphatic sac tumor: single-institution series of seven cases with updated review of literature.

BACKGROUND: Endolymphatic sac tumour (ELST) is a rare low-grade locally aggressive neoplasm arising from the endolymphatic duct or sac. It presents mostly with vestibulo-cochlear symptoms either sporadically or as part of von Hippel-Lindau (VHL) syndrome. Micro-neurosurgical excision remains the cornerstone of therapy with the role of radiotherapy (RT) being controversial. This is a clinico-pathological analysis of consecutive ELST patients presenting to a single-institution in India. METHODS: Neuropathology database of a tertiary-care comprehensive cancer centre was searched electronically to identify consecutive patients with histopathological diagnosis of ELST registered at the institute over last one decade. Data regarding demographic profile, clinical presentation, histopathological features, treatment details and outcomes were retrieved from electronic medical records for this retrospective analysis. RESULTS: Electronic search identified seven unique patients with biopsy-proven ELST registered at the institute between 2009 and 2020. Median age of the study cohort was 39 years (range 24-65 years) with strong male predilection (5:2 ratio) and left-sided preponderance (71%). Most common presenting symptoms were hearing loss (86%) and earache (71%) on affected side followed by headache (43%). All patients underwent maximal safe resection at initial diagnosis and were followed-up closely with periodic surveillance imaging. Two patients underwent salvage RT using high-precision conformal techniques at recurrence/progression. CONCLUSION: ELST is a rare low-grade locally aggressive neoplasm that arises generally as part of VHL syndrome or sometimes sporadically. Gross total resection provides the best chance of cure with RT being reserved for unresectable disease, large residue, medical inoperability, or as salvage therapy for recurrent/progressive tumor.

Symptoms and clinical features in patients affected by endolymphatic sac tumor: a systematic review and meta-analysis.

PURPOSE: Most ELST data in the literature are case studies or limited to small cohorts (< 16 patients). We evaluated the main clinical signs observed at endolymphatic sac tumor (ELST) diagnosis in patients with or without Von Hippel-Lindau disease. METHODS: We conducted a comprehensive literature search in PubMed, Scopus, and Web of Science. We included studies with at least 1 patient, of any age, affected by sporadic or VHL-related ELSTs reporting levels of hearing loss and facial nerve function and a comprehensive description of presenting symptoms at ELST diagnosis. We combined data for proportional meta-analysis. p values of 0.05 were considered statistically significant. Methodological quality was evaluated. Analyses were performed with MedCalc 14.8.1 software. RESULTS: A total of 26 studies, including 113 patients and 118 cases of ELSTs were included. Pooled proportion rates (95% CI) of overall hearing loss was 88.7%, (82.4-93.4), severe hearing loss was 21.6% (12.8-32.1) profound hearing loss was 39.8% (28.7-51.5), vertigo/imbalance was 42.0% (33.8-50.5), tinnitus was 61.8% (53.4-69.8) and facial nerve palsy was 30.6% (23.2-38.9). Generally, symptoms were homogeneous or moderately heterogeneous among included studies. CONCLUSION: This is the first systematic review of clinical presentations at ELST diagnosis. The most serious clinical events include profound hearing loss and facial impairment. Fluctuating hearing loss, tinnitus and vertigo are frequently reported and may confound correct and prompt ELST diagnosis.

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours.

AIMS: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours. METHODS: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis. RESULTS: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test). CONCLUSION: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.

Papillary-cystic neoplasms of the middle ear are distinct from endolymphatic sac tumours.

AIMS: Papillary neoplasms of the middle and inner ear are rare and poorly characterised. The current World Health Organization classification divides them into two major subtypes: aggressive papillary tumours (APTs) and endolymphatic sac tumours (ELSTs). The aim of this article is to present two papillary neoplasms of the middle ear that do not fit into either the classic APT category or the classic ELST category, and compare them with three ELSTs. METHODS AND RESULTS: The patients were a 48-year-old female and a 59-year-old male without a history of other neoplasms. Histology showed papillary-cystic growth of predominantly oncocytic (Case 1) or mucinous (Case 2) cells surrounded by a p63-positive basal layer. The overall histology was reminiscent of oncocytic sinonasal papilloma (Case 1) and pancreatobiliary or salivary intraductal papillary mucinous neoplasms (Case 2). Ovarian-type stroma, invasion and malignant features were absent. Immunohistochemistry revealed expression of cytokeratin (CK) 7, but not carbonic anhydrase IX (CAIX) or paired box gene 8 (PAX8) (except for very focal PAX8 expression in Case 1). The TST15 gene panel and HRAS sequencing revealed no pathogenic mutations in BRAF, KRAS, EGFR, AKT1, or HRAS. The TruSight RNA fusion panel revealed an MKRN1-BRAF fusion in Case 1. No fusion was detected in Case 2. The three ELSTs showed classic features of the entity, expressed CK7, epithelial membrane antigen, PAX8, and CAIX, and lacked a basal cell layer. CONCLUSION: These novel cases suggest that papillary tumours of the ear represent a heterogeneous spectrum of distinct neoplasms unified by a prominent papillary-cystic pattern rather than a single entity. Future studies should clarify whether the MKRN1-BRAF fusion is a defining recurrent driver event, especially in those cases reported as sinonasal-type middle ear papillomas.