Recurrence in cholesteatoma surgery: what have we learnt and where are we going? A narrative review| ACTA Otorhinolaryngologica Italica

Abstract

Treatment of cholesteatoma is surgical and has historically encompassed two main techniques: canal wall up (CWU) and canal wall down (CWD) tympanoplasty. Follow-up for cholesteatoma is still debated and can be either radiological or with second-look surgery. MRI with diffusion weighted sequences has proved to have high sensitivity and specificity in detecting recurrent or residual disease. Specifically, non-echo planar imaging DWI (non-EPI DWI) has been shown to be superior to other imaging techniques, allowing, in some cases, to avoid second-look surgery. Both residual and recurrence rates are higher in CWU compared to CWD procedures. Endoscopic ear surgery (EES) has become popular with the advantage of “looking around corners”. The endoscope is used in addition to a microscope or exclusively to reduce cholesteatoma recurrence. In addition, it has been demonstrated that mastoid obliteration and the use of potassium titanyl phosphate laser (KTP) can reduce cholesteatoma recurrence, with better functional outcomes. A synthetic sulphur compound (MESNA) may have an interesting role in the overall improvement in recurrence and residual cholesteatoma disease. This narrative review critically appraises the factors associated with the risk of recurrent cholesteatoma.

Introduction

Cholesteatoma is a chronic otitis of the middle ear cleft, which derives from an abnormal proliferation of a keratinising squamous epithelium ¹. It consists of two elements: acellular keratin debris, which forms the content of the sac, and the matrix, which forms the sac itself. The matrix is biologically active, producing proteolytic enzymes that are responsible for bone erosion ¹. Cholesteatoma can be congenital or acquired. The former is due to epidermal debris that remains intruded into the middle ear during embryogenesis ². The latter can be primary (if it arises from a retraction pocket) or secondary (if it develops as a result of an epithelial migration from a tympanic perforation, a trauma or otologic surgery) ². Diagnosis is based on clinical symptoms, otoscopic findings and imaging. Surgery is currently the only treatment that can achieve complete removal of the disease, with conservative management reserved for those patients with a contraindication to a general anaesthesia. The goals of surgery are widely accepted: primarily to obtain a safe and dry ear and secondarily to preserve, and potentially, restore hearing. Historically, the two main surgical techniques are canal wall down (CWD) and canal wall up (CWU). CWD is a technique in which the postero-superior bony canal wall is lowered, depending on the extent of the disease, in order to create an open mastoid cavity. An extension of this technique is the ‘‘radical’’ CWD mastoidectomy, which involves complete removal of the middle ear, including the sound transmission system, excluding the stapes, when present, and eradication of tubal function ³. On the other hand, the CWU procedure implies the removal of all mastoid air cells along the tegmen and sigmoid sinus, with preservation of the posterior ear canal wall ^4,5. The main advantage of CWU is the preservation of natural anatomy of the external auditory canal (EAC), facilitating healing and avoiding cavity problems such as accumulation of debris and caloric vertigo ³. CWU also facilitates fitting of hearing aids post-operatively, as reported in several articles in the literature ^4-8. Given the preservation of anatomical structures and the resulting conservation of middle ear resonance, it appears to be associated with better hearing outcomes ^9,10, although several studies have failed to demonstrate a significant difference between the two approaches ^4,11,12. However, the CWU technique does not facilitate broad intra-operative visualisation of areas such as sinus tympani, supratubal recess, the attic, the posterior crus of stapes and facial recess. The implication is that residual disease is less easily detected compared to the CWD approach, increasing the rate of recurrence. The CWD procedure has the advantage of being able to visualise the cholesteatoma extensively, with complete en-bloc removal, thus ensuring surgical clearance ¹³. The aim of this paper is to critically review the factors affecting the risk of recurrent cholesteatoma.

Cholesteatoma recidivism

A distinction must be made between recurrence and residual. Recurrence occurs when a new retraction pocket is formed from the tympanic membrane or the pars flaccida area. Risk factors involved in the formation of a new retraction pocket include age ¹⁴, mucosal preservation ¹⁵ and Eustachian tube (ET) function ¹⁶. This process appears to be related to the re-aeration of the tympanic and mastoid cavity in the post-operative period ¹⁷. It has been observed that poor aeration creates negative pressure in the middle ear cavity, thus predisposing to the formation of a retraction pocket. Other factors to consider are the integration of the reconstructed cartilage with the residual tympanic membrane and the healing process. Indeed, a study by Yazama et al. identified that the major sites of recurrence were the perimeter of the cartilage reconstruction and regions where the cartilage overlapped. In addition, persistent ET dysfunction may contribute to deformation of the reconstructed cartilage ¹⁸. Residual cholesteatoma, on the other hand, occurs when the surgeon unintentionally leaves disease in the tympanic or mastoid cavity, either because of the poor exposure and visualisation of the surgical field or the anatomical location (e.g., tympanic sinus and facial recess ¹⁹ or because of excessive bleeding during the surgical procedure ²⁰). Tomlin et al. ⁶ carried out a meta-analysis on the risk of recurrence of cholesteatoma, reporting lower percentages of residual and recurrent disease after CWD (range 5% to 17%) compared to CWU surgery (range 9% to 70%). The relative risk of recurrent or residual disease was 2.87 (95% Confidence Interval: 2.45 to 3.37) after CWU compared to CWD.

In addition to the elected surgical technique and the pathophysiological factors described above, the risk for cholesteatoma recidivism can be influenced by other factors, such as the extent of the disease, cholesteatoma location and presentation of pre-operative ear discharge ²¹. In several studies, a higher risk of recidivism has been shown in pars tensa cholesteatomas than in pars flaccida cholesteatomas ²². The European Academy of Otology and Neurotology (EANO) and Japanese Otological Society (JOS) working group developed a staging system (EANO/JOS cholesteatoma classification system) that applies to 4 different categories of middle ear cholesteatoma: pars flaccida cholesteatoma, pars tensa cholesteatoma, congenital cholesteatoma and cholesteatoma secondary to a tensa perforation (Tab. I) ²³.

Angeli et al. ²⁴ attempted to evaluate the utility and prognostic capabilities of this staging system in predicting cholesteatoma recurrence. Although this staging allows a better description of the type and extent of pathology, also permitting a clearer and more standardised description of surgical outcomes, its prognostic value for cholesteatoma recurrence remains unproven.

Revision surgery presents some major challenges, most notably being the distortion of normal anatomy and loss of anatomical landmarks. This leads to increased risks and complications during surgery and reliance upon highly experienced surgeons.

Key steps for successful surgery are confident identification of the facial nerve, labyrinth and the oval window. Granulation tissue must be removed completely, because it is a source of otorrhoea and because it may underly a cholesteatoma. The correct size of the meatoplasty is another key point: an inadequate meatoplasty may, in fact, not allow complete mastoid dominance and promote retention of keratin debris. It is important to emphasise that there is no single, correct procedure to follow; the choice must always be tailored to the patient ²⁵.

CWD vs CWU: recurrence rate and quality of life

A debated issue between these two techniques is the post-operative quality of life (QoL). Historically, CWD has always been associated with worse quality of life due to the limitations of the neo-mastoid cavity ²⁶. However, recent studies show that there is no significant difference in QoL between CWU and CWD procedures ^27,28. In particular, a recent study by Lucidi et al. ²⁹ compared the early and one year-post-operative results in CWD versus CWU without obliteration of the surgical cavity, demonstrating the absence of a significant difference in self-perceived quality of life. A significant limitation of this study is the short follow-up of only one year.

Mastoid obliteration

Mastoid obliteration entails the surgical elimination or reduction of the size of a mastoid cavity. It is usually performed during or following a CWD, but it can also be performed after CWU. It is a surgical technique that attempts to combine the advantages of CWU and CWD with the goal of reducing the incidence of residual disease and recurrence. The main limitation of the technique is the inability to explore the mastoid cavity during follow-up with the risk of developing a “silent cholesteatoma”, making radiological follow-up essential. This technique has become popular in the last two decades with the development of non-EPI DW-MRI, which facilitates detection of cholesteatoma in obliterated or reconstructed cavities ³⁰. Surgical techniques and materials used for obliteration and reconstruction vary widely. The materials used can be autologous, allogenic, or synthetic. Among autologous materials, the most widely used is bone, harvested as pate or chips. It has the advantage of retaining its volume compared to soft tissue. Other materials used are cartilage from concha or tragus and soft tissue flaps, which may include fascia, periosteum and/or muscle. The most widely used flap is the middle temporal artery flap, which is very versatile and resists atrophy, which is the major weakness of muscle flaps. It is very important to be cautious when harvesting any graft material, especially with bone pate, to not inoculate microscopic epithelial cells, which could lead to a recurrence of cholesteatoma in the future. As far as synthetic materials are concerned, the most widely used is bioactive glass (BAG), followed by hydroxyapatite and titanium. The major complication of synthetic materials is extrusion. Choong et al. ³¹ in their review cited an extrusion rate of 3.6%, which is much higher in the case of hydroxyapatite. The latter material also makes revision surgery very complicated and increases the rate of infection. However, there is still no consensus around the technique, type of material to be used, or the ideal timing for surgery (simultaneous or during revision surgery) ³². A systematic review and meta-analysis by Illes et al. ³⁰ collected data from 2077 operations from 11 articles to evaluate the effectiveness of mastoid obliteration compared to the CWU technique. The results demonstrated that mastoid obliteration significantly reduced cholesteatoma recidivism (Odds Ratio = 0.45, Confidence Interval = 0.26-0.8, p = 0.014). Furthermore, no difference in outcome was demonstrated using different materials for mastoid obliteration and posterior wall reconstruction.

Endoscopic ear surgery (EES): an adjunct or an alternative to microscopic surgery

Since the 1950s, microsurgery has been considered the traditional surgical technique for chronic cholesteatomatous otitis media. However, in recent decades, the application of the endoscope to otological surgery, with the advantage of “looking around corners”, has become popular. The microscope offers a magnified and illuminated surgical field, allowing two handed surgery, binocular vision and depth perception. However, the limitation of a straight line vision creates blind spots, or hidden areas that are difficult to reach during surgery ³³. Endoscopic ear surgery (EES), on the other hand, using angled endoscopes (30 and 45°) offers a clear visualisation of hidden areas of retrotympanum, anterior epitypanum, facial recess, and sinus tympani. It is also considered a minimally invasive technique, using the transcanal approach, avoiding retroauricular incision ³⁴. In middle ear surgery, the use of endoscopes can be classified in: A) assisted, in which the endoscope is used exclusively to search for residual cholesteatoma after the microsurgical approach; B) mixed, in which microscope and endoscope are both used for surgical cholesteatoma eradication; C) exclusive endoscopic or TEES (Transcanal Endoscopic Ear Surgery).

Endoscopes are frequently used in cholesteatoma surgery only as an adjunct to the microscope for diagnostic purposes. Exclusive endoscopic surgery has not gained widespread acceptance for several reasons: only one hand can be used for surgical manoeuvres, lack of depth perception, difficulty to perform ossicular reconstruction, frequent fogging and smearing of endoscopic tip and the risk of thermal injury to the facial nerve, chorda tympani and cochlear promontory with transmitted heat of the endoscope tip ³⁵. The indications for EES in cholesteatoma treatment are limited to the tympanic space and its subsites (epitympanum, mesotympanum, retrotympanum, protympanum and hypotympanum). When the cholesteatoma involves the mastoid, the use of EES is controversial: some suggest switching to a traditional technique with microscope or a combined endoscopic and microscopic approach ³⁶. Others believe that the exclusive use of the endoscope is still possible in a small number of cases ³⁷.

Various studies have shown that the EES has significantly reduced the residual and recurrence rate of cholesteatoma compared to microscope use alone, especially for CWU procedures. The commonest site of residual disease is the sinus tympani, even in second-look procedures ³⁸. A review by Hu et al. ³⁹ demonstrated a recurrence rate in the EES approach between 0% and 10.5%, significantly lower than CWU approach, but similar to the CWD approach in an adult population. In addition, EES has shown a high rate of ossicular chain preservation, ranging from 24 to 33,3% due to a better visualisation of ossicles, preventing their unnecessary removal.

A review by Verma et al. ³⁸ of 13 studies demonstrated that in 15.82% cases residual cholesteatoma was identified by using an endoscope after microscopic surgery. In three (Tarabichi ⁴⁰ Migirov ⁴¹ and Barakate ⁴²), exclusive EES was performed with a rate of recidivism ranging from 0% to 20.6%. A limitation of these studies is the short mean follow-up (43, 12 and 16 months, respectively). Marchioni et al. ^43,44 presented a study that started in 2005 and finished in 2015 in which 244 ears in 234 patients were treated with exclusive endoscopic approach (n = 144) or a combined approach with mastoidectomy (n = 100) for middle ear cholesteatoma, with at least 3 years of follow-up. In all, 30% of patients had an exclusively attic cholesteatoma, 17% an extension to mesotympanum, 15% an exclusively mesotympanic disease, 30% an antrum extension and 7% had mastoid involvement. Residuals were defined CT usually performed after 1 year of follow-up or during a planned surgical second-look. Recidivism rate was 32%, with recurrence and residual rates, respectively, of 12% and 20%. Studies that compared EES to a microscopic control group for cholesteatoma showed equivalent residual and recurrent rates, with no significant differences in hearing outcomes ⁴⁵. The microscope and endoscope are both useful tools in otological surgery, and are not in opposition but complementary. There is no ideal surgical technique; the most correct surgical technique should consider the extent of the disease, the patient’s age and desire.

Laser in the treatment of cholesteatoma: a way to reduce residual disease?

The use of lasers in the treatment of cholesteatoma has become widespread in the last 2 decades, especially in the U.S. The most widely used laser in the treatment of cholesteatoma is the potassium titanyl phosphate (KTP) laser at 532 nm wavelength. Its strengths are the possibility of being transmitted via a hand-held semi-flexible fibre-optic cable, which can reach relatively inaccessible recesses of the middle ear, and its wavelength is absorbed by red pigments such as haemoglobin. At this wavelength, blood-containing structures are preferentially denatured, vaporised or heated by the laser, whereas non-blood containing structures, such as perilymph, have relatively little penetration. The use of the KTP laser allows atraumatic removal of cholesteatoma from the middle ear and ossicular chain, and precise haemostatic removal of diseased tissue such as polyps, granulations and adhesions. Retrospective studies have shown that the risk of residual cholesteatoma is reduced by half ⁴⁶. An important prospective study was conducted by Hamilton et al. ⁴⁷ in two different hospitals, in which the same surgeon operated using the KTP laser at one location and in the other without. All patients included in the study were required to undergo a second surgical procedure with full exposure of the middle ear and mastoid, including the entire bed of the previous cholesteatoma. This study showed that 1 of 36 patients with procedures utilising the KTP laser had residual disease, compared to 10 of 33 patients without KTP laser ⁴⁷. The primary risk of laser use is thermal collateral damage to exposed structures including the cochlea and the facial nerve. However, recent data observe that the rate of facial nerve paralysis is 0.6%, demonstrating that laser use appears safe if appropriate safety guidelines are followed ⁴⁸. Lasers seem to play an increasing role in EES thanks to the better bleeding control that can be challenging with one hand, and the atraumatic dissection of cholesteatoma, especially on the ossicular chain. Laser-assisted endoscopic cholesteatoma surgery showeda recurrence and residual rate between 0% and 19%, and not inferior to standard middle ear surgery ⁴⁹. Sharma et al. ⁵⁰ presented a study based on a large paediatric population treated with purely endoscopic KTP laser resection for cholesteatoma over an eight-year period. Of the 83 patients included in this study with cholesteatoma confined to the middle ear and attic, 70 were treated with KTP laser. Residual disease was detected in 4 patients (6%). In 3 residual disease was found close to the facial nerve area that was spared from KTP laser application in order to avoid thermal injury. In conclusion, KTP laser has been shown to reduce the risk of residual cholesteatoma and is suggested to be beneficial to preserve ossicular function and safe hearing outcomes.

Imaging and recurrence

The most widely used radiological examination in the primary diagnosis of cholesteatoma is CT, demonstrating high sensitivity but low specificity ⁵¹. In the case of residual or recurrent cholesteatomas, the sensitivity and specificity of CT drops dramatically given the difficulty in distinguishing changes due to previous surgery against bone erosion due to cholesteatoma ⁵². In this scenario, the specificity of CT is 48%, while the sensitivity is 43% ⁵³. These difficulties are overcome in part by using diffusion weighted magnetic resonance imagining (DWI-MRI). Cholesteatoma appears to have a high signal intensity, mainly attributable to its water content and restricted water diffusion. In particular non-echo planar imaging DWI techniques allow less image distortion, lower artifacts than other DWI techniques and better identification of small lesions, reducing the false-positive rate (the sensitivity and specificity of Non EPI DWI-MRI are 89.79% and 94.57%, respectively) ⁵⁴. The use of DWI MRI in the diagnosis of residual or recurrent cholesteatomas may therefore be a viable alternative to routine second-look surgery in some cases ⁵⁵.

Paediatric cholesteatoma

Paediatric cholesteatoma is much debated in the literature as there are different interpretations on its behaviour and surgical treatment. Some authors believe that cholesteatoma in children has a more aggressive growth pattern compared to adults, which leads to a higher incidence of both residual and recurrent disease. This behaviour would appear to be related to several factors: well-pneumatised mastoids in children allow for more extensive disease compared with more sclerotic mastoid bones in adults ⁹; Eustachian tube anatomy and dysfunction predispose children to more frequent infections and retraction pockets ⁹; a higher rate of keratinocyte proliferation and a pronounced inflammatory response of the peri-matrix and matrix in the paediatric population ^56-59. Despite all these theories, there are still many controversies, both on cholesteatoma behaviour and management. Indeed, there are currently no studies in the literature expressing a clear consensus on the surgical treatment of paediatric cholesteatoma. Both CWD and CWU procedures are used: some authors are in favour of CWU technique ^60,61, others prefer CWD approach ^62,63. A third group is in favour of both procedures, recommending individualised treatment ^64-66. The main purposes of surgery in paediatric patients remain the eradication of cholesteatoma and restoration of hearing function: the balance between these two goals is related to the incidence of recidivism and degree of ossicular damage ⁶⁷. A recent analysis of the literature ⁶⁸ showed that CWU is characterised by an average residual disease of approximately 15% (range 3.8%-21%), while CWD is associated with an average residual and recurrent cholesteatoma rates of 6.5% (range 0%-11.4%) and 5.1% (range 0%-18.4%), respectively ^{10,11,66,69-72}. These data showed that a staged approach to cholesteatoma is not necessarily more effective in reducing the rate of recidivism. In particular, CWD still represents the most efficient approach in eradication of tympano-mastoid cholesteatoma, with residual and recurrence rates close to 5%. In the light of the above-mentioned data, surgical treatment should be individualised, considering the extent of the disease and the conditions of the mucosal and ossicular chain ⁶⁹. The management of paediatric cholesteatoma is difficult for multiple reasons and children can sometimes be difficult to monitor clinically. If we consider the longevity of this part of population, it is mandatory to optimise the surgical management and monitoring of these patients.

The prognostic role of cell proliferation markers in recurrent cholesteatoma

Many studies have investigated the pathogenesis of cholesteatoma and the factors leading to cell proliferation and bone resorption. These include specific cytokeratins, inflammation, enzymes and local pressure. In particular, an altered receptor activator of nuclear factor-kappa B ligand (RANKL)/Osteoprotegerin (OPG) protein ratio suggests the main role of RANKL/OPG pathway in the inflammation related to the growth of cholesteatoma, and osseous destruction due to middle ear cholesteatoma. Given the high proliferative rate of cholesteatoma and the tendency for recurrence, many studies have been conducted to find specific markers involved in the pathophysiology of this disease. Araz et al. ⁷³ investigated the possible correlation between the cell proliferation markers Ki-67 and proliferating cell nuclear antigen (PCNA) with cholesteatoma recurrence. Ki-67 is a factor involved in proliferative cells, as it is essential in the G1, S, M and G2 phases (it is absent in G0) ^74,75. PCNA is a co-factor of DNA polymerase delta that participates in cell- proliferation ⁷⁶. The rate of Ki-67 and PCNA has been analysed in two groups of patients undergoing CWD surgery: with recurrent cholesteatoma and non-recurrent cases after at least 2 years of follow-up. The results did not demonstrate a significant difference between the two groups examined. Therefore, it appears that these two markers do not have a predictive role in cholesteatoma recurrence. However, given the high level of Ki-67 found in cholesteatoma cases with malleus erosion, it could be considered as an indicator of a destructive pattern of disease.

The promising role of MESNA (sodium 2-mercaptoethanesulphonate)

Sodium 2-mercaptoethanesulphonate, also known as MESNA, deserves brief mention. It is a synthetic sulphur compound that belongs to a class of thiols that produce mucolysis by disrupting disulphide bonds of the mucous polypeptide chains. It has been used in several diseases as a cytoprotective agent. Many studies in vivo and in vitro suggest that MESNA plays an important role as an antioxidant drug. Only in recent years has MESNA gained attention for its potential application in facilitating surgical dissection, leading to the concept of “chemically assisted dissection”. The fundamental principle of chemically-assisted dissection lies in the rich disulphide bonds of the adhesions between the different tissue layers. In ENT surgery, topical MESNA has been used from ear and skull base to head and neck diseases. A review including 5 retrospective studies showed overall improvement in recurrence and residual cholesteatoma disease after MESNA application during surgery ^77,78. Further studies are needed to confirm these interesting findings.

Conclusions

Cholesteatoma is a disease with an intrinsic tendency to recidivism and its management is challenging. It remains a surgical disease, with a surgical skillset being a critical determinant in rates of recidivism. The emergence of EES and the use of laser have opened up new surgical methods to improve surgical outcomes and prognosis, with strengths and limitations. However, there is currently no gold standard surgical technique, as treatment must be tailored based on the extent of disease and middle ear condition.

Mastoid obliteration combines the advantages of CWU and CWD, reducing the recidivism rate compared to CWU. The use of lasers in cholesteatoma surgery is becoming popular due to the greater preservation of the ossicular chain and a safe hearing outcome, with promising studies demonstrating an improved recidivism rate.

The use of non-EPI DWI MRI has proved to have high sensitivity and specificity in detecting recurrent or residual disease, and is emerging as an alternative to routine second-look surgery.

Even if the near future will probably still see surgery having a crucial role in the management of this pathology, new technological tools (intra-operative imaging guidance, robot) and medical therapies will hopefully improve outcomes in the treatment of cholesteatoma in order to win this “eternal ear fight”.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

CB, AL, RB: conception and design of the work, research on PubMed, literature review, drafting of the article; GD, DB, NC: contribution to the concept and design of the article, critically revision.

Ethical consideration

Not applicable.

Figures and tables

References

1. Smouha EE, Bojrab DI. Cholesteatoma. Thieme Medical Publishers: New York; 2011.
2. Mansour S, Magnan J, Nicolas K. Middle ear diseases. advances in diagnosis and management. Springer Cham: Berlin; 2018. DOI
3. Kuo CL, Liao WH, Shiao AS. A review of current progress in acquired cholesteatoma management. Eur Arch Otorhinolaryngol. 2015; 272:3601-3609. DOI
4. Nikolopoulos TP, Gerbesiotis P. Surgical management of cholesteatoma: the two main options and the third way - atticotomy/limited mastoidectomy. Int J Pediatr Otorhinolaryngol. 2009; 73:1222-7. DOI
5. Dornhoffer JL, Friedman AB, Gluth MB. Management of acquired cholesteatoma in the pediatric population. Curr Opin Otolaryngol Head Neck Surg. 2013; 21:440-445. DOI
6. Tomlin J, Chang D, McCutcheon B. Surgical technique and recurrence in cholesteatoma: a meta-analysis. Audiol Neurootol. 2013; 18:135-142. DOI
7. Dodson EE, Hashisaki GT, Hobgood TC. Intact canal wall mastoidectomy with tympanoplasty for cholesteatoma in children. Laryngoscope. 1998; 108:977-983. DOI
8. Naclerio R, Neely JG, Alford BR. A retrospective analysis of the intact canal wall tympanoplasty with mastoidectomy. Am J Otol. 1981; 2:315-317.
9. Schraff SA, Strasnick B. Pediatric cholesteatoma: a retrospective review. Int J Pediatr Otorhinolaryngol. 2006; 70:385-393. DOI
10. Shirazi MA, Muzaffar K, Leonetti JP. Surgical treatment of pediatric cholesteatomas. Laryngoscope. 2006; 116:1603-1607. DOI
11. Göçmen H, Kiliç R, Ozdek A. Surgical treatment of cholesteatoma in children. Int J Pediatr Otorhinolaryngol. 2003; 67:867-872. DOI
12. Kim MB, Choi J, Lee JK. Hearing outcomes according to the types of mastoidectomy: a comparison between canal wall up and canal wall down mastoidectomy. Clin Exp Otorhinolaryngol. 2010; 3:203-206. DOI
13. Vital V. Pediatric cholesteatoma: personal experience and review of the literature. Otorhinolaryngol Head Neck Surg. 2011; 45:5-14.
14. Vartiainen E. Factors associated with recurrence of cholesteatoma. J Laryngol Otol. 1995; 109:590-592. DOI
15. Tanabe M, Takahashi H, Honjo I. Factors affecting recovery of mastoid aeration after ear surgery. Eur Arch Otorhinolaryngol. 1999; 256:220-223. DOI
16. Magnuson B. Tubal closing failure in retraction type cholesteatoma and adhesive middle ear lesions. Acta Otolaryngol. 1978; 86:408-417. DOI
17. Suzuki J. Reconstructive surgery of the middle ear. Elsevier Science: Amsterdam; 1999.
18. Yazama H, Kunimoto Y, Hasegawa K. Characteristics of repeated recidivism in surgical cases of cholesteatoma requiring canal wall reconstruction. Ear Nose Throat J. 2021;1455613211048575. DOI
19. Shelton C, Sheehy JL. Tympanoplasty: review of 400 staged cases. Laryngoscope. 1990; 100:679-681. DOI
20. le Nobel GJ, Cushing SL, Papsin BC. Intra-operative bleeding and the risk of residual cholesteatoma: a multivariate analysis. Otol Neurotol. 2017; 38:529-534. DOI
21. Kerckhoffs KG, Kommer MB, van Strien TH. The disease recurrence rate after the canal wall up or canal wall down technique in adults. Laryngoscope. 2016; 126:980-987. DOI
22. Stankovic M. Follow-up of cholesteatoma surgery: open versus closed tympanoplasty. ORL J Otorhinolaryngol Relat Spec. 2007; 69:299-305. DOI
23. Yung M, Tetsua T, Olszewska E. EAONO/JOS joint consensus statements on the definitions, classification, and staging of middle ear cholesteatoma. J Int Adv Otol. 2017; 13:1-8. DOI
24. Angeli S, Shahal D, Brown CS. Predicting recidivism for acquired cholesteatoma: evaluation of a current staging system. Otol Neurotol. 2020; 41:1391-1396. DOI
25. Weiss MH, Parisier SC, Han JC. Surgery for recurrent and residual cholesteatoma. Laryngoscope. 1992; 102:145-151. DOI
26. Bhatia S, Karmarkar S, DeDonato G. Canal wall down mastoidectomy: causes of failure, pitfalls and their management. J Laryngol Otol. 1995; 109:583-589. DOI
27. Lailach S, Kemper M, Lasurashvili N. Health-related quality of life measurement after cholesteatoma surgery: comparison of three different surgical techniques. Eur Arch Otorhinolaryngol. 2015; 272:3177-3185. DOI
28. Quaranta N, Iannuzzi L, Petrone P. Quality of life after cholesteatoma surgery: intact-canal wall tympanoplasty versus canal wall-down tympanoplasty with mastoid obliteration. Ann Otol Rhinol Laryngol. 2014; 123:89-93. DOI
29. Lucidi D, De Corso E, Paludetti G. Quality of life and functional results in canal wall down vs canal wall up mastoidectomy. Acta Otorhinolaryngol Ital. 2019; 39:53-60. DOI
30. Illés K, Meznerics FA, Dembrovszky F. Mastoid obliteration decreases the recurrent and residual disease: systematic review and meta-analysis. Laryngoscope. 2022. DOI
31. Choong KWK, Kwok MMK, Shen Y. Materials used for mastoid obliteration and its complications: a systematic review. ANZ J Surg. 2022; 92:994-1006. DOI
32. Mendlovic ML, Monroy Llaguno DA, Schobert Capetillo IH. Mastoid obliteration and reconstruction techniques: a review of the literature. J Otol. 2021; 16:178-184. DOI
33. Kozin ED, Lee DJ. Basic principles of endoscopic ear surgery. Oper Tech Otolaryngol. 2017; 28:2-10.
34. Marchioni D, Villari D, Alicandri-Ciufelli M. Endoscopic open technique in patients with middle ear cholesteatoma. Eur Arch Otorhinolaryngol. 2011; 268:1557-1563. DOI
35. Nishiike S, Oshima K, Imai T. A novel endoscopic hydro-mastoidectomy technique for transcanal endoscopic ear surgery. J Laryngol Otol. 2019; 133:248-250. DOI
36. Bae MR, Kang WS, Chung JW. Comparison of the clinical results of attic cholesteatoma treatment: endoscopic versus microscopic ear surgery. Clin Exp Otorhinolaryngol. 2019; 12:156-162. DOI
37. Imai T, Nishiike S, Oshima K. The resected area of the posterior wall of the external auditory canal during transcanal endoscopic ear surgery for cholesteatoma. Auris Nasus Larynx. 2017; 44:141-146. DOI
38. Verma B, Dabholkar YG. Role of endoscopy in surgical management of cholesteatoma: a systematic review. J Otol. 2020; 15:166-170. DOI
39. Hu Y, Teh BM, Hurtado G. Can endoscopic ear surgery replace microscopic surgery in the treatment of acquired cholesteatoma? A contemporary review. Int J Pediatr Otorhinolaryngol. 2020; 131:109872. DOI
40. Tarabichi M. Endoscopic management of limited attic cholesteatoma. Laryngoscope. 2004; 114:1157-1162. DOI
41. Migirov L, Shapira Y, Horowitz Z. Exclusive endoscopic ear surgery for acquired cholesteatoma: preliminary results. Otol Neurotol. 2011; 32:433-436. DOI
42. Barakate M, Bottrill I. Combined approach tympanoplasty for cholesteatoma: impact of middle-ear endoscopy. J Laryngol Otol. 2008; 122:120-124. DOI
43. Marchioni D, Villari D, Mattioli F. Endoscopic management of attic cholesteatoma: a single-institution experience. Otolaryngol Clin North Am. 2013; 46:201-209. DOI
44. Alicandri-Ciufelli M, Marchioni D, Kakehata S. Endoscopic management of attic cholesteatoma: long-term results. Otolaryngol Clin North Am. 2016; 49:1265-1270. DOI
45. Chiao W, Chieffe D, Fina M. Endoscopic management of primary acquired cholesteatoma. Otolaryngol Clin North Am. 2021; 54:129-145. DOI
46. le Nobel GJ, James AL. Recommendations for potassium-titanyl-phosphate laser in the treatment of cholesteatoma. J Int Adv Otol. 2016; 12:332-336. DOI
47. Hamilton JW. Efficacy of the KTP laser in the treatment of middle ear cholesteatoma. Otol Neurotol. 2005; 26:135-139. DOI
48. Lau K, Stavrakas M, Yardley M. Lasers in cholesteatoma surgery: a systematic review. Ear Nose Throat J. 2021; 100:94S-99S. DOI
49. Fyrmpas G, Tsetsos N, Katotomichelakis M. Lasers in endoscopic middle ear surgery: where do we stand today?. Eur Arch Otorhinolaryngol. 2021; 278:4169-4177. DOI
50. Sharma SD, Swarup A, James AL. Use of the KTP laser in totally endoscopic cholesteatoma surgery. J Laryngol Otol. 2020; 134:362-365. DOI
51. Baráth K, Huber AM, Stämpfli P. Neuroradiology of cholesteatomas. AJNR Am J Neuroradiol. 2011; 32:221-229. DOI
52. Corrales CE, Blevins NH. Imaging for evaluation of cholesteatoma: current concepts and future directions. Curr Opin Otolaryngol Head Neck Surg. 2013; 21:461-467. DOI
53. Tierney PA, Pracy P, Blaney SP. An assessment of the value of the pre-operative computed tomography scans prior to otoendoscopic “second look” in intact canal wall mastoid surgery. Clin Otolaryngol Allied Sci. 1999; 24:274-276. DOI
54. Muzaffar J, Metcalfe C, Colley S. Diffusion-weighted magnetic resonance imaging for residual and recurrent cholesteatoma: a systematic review and meta-analysis. Clin Otolaryngol. 2017; 42:536-543. DOI
55. Keeler JA, Kaylie DM. Cholesteatoma: is a second stage necessary?. Laryngoscope. 2016; 126:1499-1500. DOI
56. Bujía J, Holly A, Antolí-Candela F. Immunobiological peculiarities of cholesteatoma in children: quantification of epithelial proliferation by MIB1. Laryngoscope. 1996; 106:865-868. DOI
57. Dornelles C, Meurer L, Selaimen da Costa S. Histologic description of acquired cholesteatomas: comparison between children and adults. Braz J Otorhinolaryngol. 2006; 72:641-648. DOI
58. Dornelles Cde C, da Costa SS, Meurer L. Comparison of acquired cholesteatoma between pediatric and adult patients. Eur Arch Otorhinolaryngol. 2009; 266:1553-1561. DOI
59. Quaranta A, Resta L, Santangelo A. Otomastoid cholesteatoma in children: histopathological findings. Int J Pediatr Otorhinolaryngol. 1986; 12:121-126. DOI
60. Sheehy JL. Cholesteatoma surgery in children. Am J Otol. 1985; 6:170-172.
61. Jansen C. Cholesteatoma in children. Clin Otolaryngol Allied Sci. 1978; 3:349-352. DOI
62. Palva A, Karma P, Kärjä J. Cholesteatoma in children. Arch Otolaryngol. 1977; 103:74-77. DOI
63. Jahnke V. Clinical, pathological and therapeutic aspects of cholesteatoma in children. Cholesteatoma and mastoid surgery. Proceedings of Second International Conference on Cholesteatoma and Mastoid Surgery. 1982;25-27.
64. Tos M. Treatment of cholesteatoma in children. A long-term study of results. Am J Otol. 1983; 4:189-197.
65. Smyth GD. Post-operative cholesteatoma in combined approach tympanoplasty. Fifteen year report on tympanoplasty. Part I. J Laryngol Otol. 1976; 90:597-621. DOI
66. Parisier SC, Hanson MB, Han JC. Pediatric cholesteatoma: an individualized, single-stage approach. Otolaryngol Head Neck Surg. 1996; 115:107-114. DOI
67. Sergi B, Galli J, Battista M. Dealing with paediatric cholesteatoma: how we changed our management. Acta Otorhinolaryngol Ital. 2014; 34:138-143.
68. Piras G, Sykopetrites V, Taibah A. Long term outcomes of canal wall up and canal wall down tympanomastoidectomies in pediatric cholesteatoma. Int J Pediatr Otorhinolaryngol. 2021; 150:110887. DOI
69. Kuo CL, Lien CF, Shiao AS. Mastoid obliteration for pediatric suppurative cholesteatoma: long-term safety and sustained effectiveness after 30 years’ experience with cartilage obliteration. Audiol Neurootol. 2014; 19:358-369. DOI
70. Yung M, Jacobsen NL, Vowler SL. A 5-year observational study of the outcome in pediatric cholesteatoma surgery. Otol Neurotol. 2007; 28:1038-1040. DOI
71. Vercruysse JP, De Foer B, Somers T. Mastoid and epitympanic bony obliteration in pediatric cholesteatoma. Otol Neurotol. 2008; 29:953-960. DOI
72. Drahy A, De Barros A, Lerosey Y. Acquired cholesteatoma in children: strategies and medium-term results. Eur Ann Otorhinolaryngol Head Neck Dis. 2012; 129:225-229. DOI
73. Araz Server E, Kalaycık Ertugay Ç, Baykal Koca S. Predictive role of Ki-67 and Proliferative-Cell Nuclear Antigen (PCNA) in recurrent cholesteatoma. J Int Adv Otol. 2019; 15:38-42. DOI
74. Mallet Y, Nouwen J, Lecomte-Houcke Aggressiveness and quantification of epithelial proliferation of middle ear cholesteatoma by MIB1. Laryngoscope. 2003; 113:328-331. DOI
75. Raynov AM, Moon SK, Choung YH. Nucleoplasm staining patterns and cell cycle-associated expression of Ki-67 in middle ear cholesteatoma. Am J Otolaryngol. 2005; 26:296-301. DOI
76. Paunesku T, Mittal S, Protić M. Proliferating cell nuclear antigen (PCNA): ringmaster of the genome. Int J Radiat Biol. 2001; 77:1007-1021. DOI
77. Orobello N, Harrington C, Reilly BK. Updates in paediatric cholesteatoma. Curr Opin Otolaryngol Head Neck Surg. 2022; 30:422-425. DOI
78. Moffa A, Fiore V, Sabatino L. A “chemical help” in middle-ear surgery? A systematic review on sodium 2-mercaptoethanesulfonate. J Laryngol Otol. 2021; 135:660-667. DOI