10.14639/0392-100X-suppl.1-43-2023-06
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.
text/xml
1827-675X
2608
en
Giovanni Danesi
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
treatment outcome
Recurrence in cholesteatoma surgery: what have we learnt and where are we going? A narrative review
Text.Serial.Journal
https://www.actaitalica.it/
43
Annual congress report
2023-04-21
2023-04-20
2023-04-28
2023-04-28
S48-S55
1
Giovanni Danesi
2023/04/21
10.14639/0392-100X-suppl.1-43-2023-06
S48
Department of Neurosciences, Section of Otorhinolaryngology and Skull Base Microsurgery, Papa Giovanni XXIII Hospital, Bergamo, Italy
1827-675X
treatment outcome
S55
Recurrence in cholesteatoma surgery: what have we learnt and where are we going? A narrative review
https://www.actaitalica.it/article/download/2608/943
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43(SUPPL.1):S48-S55; doi: 10.14639/0392-100X-suppl.1-43-2023-06




Otology section


Recurrence in cholesteatoma surgery:
what have we learnt and where are we going?
A narrative review
Il colesteatoma ricorrente nella chirurgia dell’orecchio medio:
lezioni imparate e prospettive future. Una narrative review
Chiara Bovi1, Alberto Luchena2, Rachele Bivona3, Daniele Borsetto4, Nathan Creber5, Giovanni Danesi3
1
 Otolaryngology Department, Azienda Ospedaliera Universitaria Senese, Siena, Italy; 2 Department of Otorhinolaryngology,
University of Pavia, Foundation IRCCS Policlinico “San Matteo”, Pavia, Italy; 3 Department of Neurosciences, Section
of Otorhinolaryngology and Skull Base Microsurgery, Papa Giovanni XXIII Hospital, Bergamo, Italy; 4 Department of ENT Surgery,
Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 5 Otolaryngology, Department
of Surgery, The Royal Prince Alfred Hospital, Sydney, Australia


SUMMARY
Treatment of cholesteatoma is surgical and has historically encompassed two main tech-
niques: 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     Received: January 9, 2023
                                                                                                Accepted: January 17, 2023
cholesteatoma recurrence, with better functional outcomes. A synthetic sulphur compound
(MESNA) may have an interesting role in the overall improvement in recurrence and resid-
                                                                                                Correspondence
ual cholesteatoma disease. This narrative review critically appraises the factors associated
                                                                                                Rachele Bivona
with the risk of recurrent cholesteatoma.                                                       Department of Neurosciences, Section
KEY WORDS: cholesteatoma, recurrence, residual disease, diffusion weighted imaging,             of Otorhinolaryngology and Skull Base
treatment outcome                                                                               Microsurgery, Papa Giovanni XXIII Hospital,
                                                                                                piazza OMS 1, Bergamo, Italy
                                                                                                Tel.+ 39 0352674398
RIASSUNTO                                                                                       E-mail: rachelebivona@hotmail.it
Il trattamento del colesteatoma è chirurgico e si basa su due tecniche principali: la timpa-
noplastica aperta e la timpanoplastica chiusa. Il follow up del colesteatoma può essere ra-       How to cite this article: Bovi C, Luchena A,
diologico oppure mediante un secondo tempo chirurgico. La RM a diffusione nella diagnosi          Bivona R, et al. Recurrence in cholesteatoma sur-
di colesteatoma ricorrente e residuo ha una sensibilità e specificità maggiore della TC. In       gery: what have we learnt and where are we go-
particolare, la non-echo planar imaging DWI (non-EPI DWI) si è dimostrata superiore,              ing? A narrative review. Acta Otorhinolaryngol
consentendo in alcuni casi di non effettuare il secondo tempo chirurgico. In molti studi          Ital 2023;43(SUPPL.1):S48-S55. https://doi.
presenti in letteratura è stato osservato come il tasso di recidiva sia maggiore nella timpa-     org/10.14639/0392-100X-suppl.1-43-2023-06
noplastica chiusa rispetto a quella aperta. Inoltre, è stato dimostrato come l’obliterazione
mastoidea e l’utilizzo del potassium titanyl phosphate (KTP) laser possano ridurre la reci-     © Società Italiana di Otorinolaringoiatria
                                                                                                e Chirurgia Cervico-Facciale
diva di colesteatoma, con migliori outcomes funzionali. L’endoscopio può essere utilizzato
in aggiunta al microscopio o in maniera esclusiva, in ottica di ridurre la ricorrenza del
                                                                                                               OPEN ACCESS
colesteatoma grazie alla capacità di “guardare dietro gli angoli”. Un composto sintetico
solforico (MESNA) sembra aver dimostrato un ruolo interessante nel migliorare i tassi di        This is an open access article distributed in accordance with
                                                                                                the CC-BY-NC-ND (Creative Commons Attribution-Non-
recidiva. Questa narrative review analizza in modo critico i fattori associati al rischio di    Commercial-NoDerivatives 4.0 International) license. The
colesteatoma ricorrente.                                                                        article can be used by giving appropriate credit and mentio-
                                                                                                ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: colesteatoma, ricorrenza, residuo, RM in diffusione, trattamento e               only in the original version. For further information: https://
risultati                                                                                       creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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Introduction                                                            Cholesteatoma recidivism
Cholesteatoma is a chronic otitis of the middle ear cleft, which        A distinction must be made between recurrence and residual.
derives from an abnormal proliferation of a keratinising squa-          Recurrence occurs when a new retraction pocket is formed
mous epithelium 1. It consists of two elements: acellular kera-         from the tympanic membrane or the pars flaccida area. Risk
tin debris, which forms the content of the sac, and the matrix,         factors involved in the formation of a new retraction pocket in-
which forms the sac itself. The matrix is biologically active,          clude age 14, mucosal preservation 15 and Eustachian tube (ET)
producing proteolytic enzymes that are responsible for bone             function 16. This process appears to be related to the re-aera-
erosion 1. Cholesteatoma can be congenital or acquired. The             tion of the tympanic and mastoid cavity in the post-operative
former is due to epidermal debris that remains intruded into            period 17. It has been observed that poor aeration creates nega-
the middle ear during embryogenesis 2. The latter can be pri-           tive pressure in the middle ear cavity, thus predisposing to the
mary (if it arises from a retraction pocket) or secondary (if           formation of a retraction pocket. Other factors to consider are
it develops as a result of an epithelial migration from a tym-          the integration of the reconstructed cartilage with the residual
panic perforation, a trauma or otologic surgery) 2. Diagnosis is        tympanic membrane and the healing process. Indeed, a study
based on clinical symptoms, otoscopic findings and imaging.             by Yazama et al. identified that the major sites of recurrence
Surgery is currently the only treatment that can achieve com-           were the perimeter of the cartilage reconstruction and regions
plete removal of the disease, with conservative management              where the cartilage overlapped. In addition, persistent ET dys-
reserved for those patients with a contraindication to a general        function may contribute to deformation of the reconstructed
anaesthesia. The goals of surgery are widely accepted: primar-          cartilage 18. Residual cholesteatoma, on the other hand, occurs
ily to obtain a safe and dry ear and secondarily to preserve, and       when the surgeon unintentionally leaves disease in the tym-
potentially, restore hearing. Historically, the two main surgi-         panic or mastoid cavity, either because of the poor exposure
cal techniques are canal wall down (CWD) and canal wall up              and visualisation of the surgical field or the anatomical loca-
(CWU). CWD is a technique in which the postero-superior                 tion (e.g., tympanic sinus and facial recess 19 or because of
bony canal wall is lowered, depending on the extent of the              excessive bleeding during the surgical procedure 20). Tomlin
disease, in order to create an open mastoid cavity. An exten-           et al. 6 carried out a meta-analysis on the risk of recurrence
sion of this technique is the ‘‘radical’’ CWD mastoidectomy,            of cholesteatoma, reporting lower percentages of residual and
which involves complete removal of the middle ear, includ-              recurrent disease after CWD (range 5% to 17%) compared to
ing the sound transmission system, excluding the stapes,                CWU surgery (range 9% to 70%). The relative risk of recur-
when present, and eradication of tubal function 3. On the other         rent or residual disease was 2.87 (95% Confidence Interval:
hand, the CWU procedure implies the removal of all mastoid              2.45 to 3.37) after CWU compared to CWD.
air cells along the tegmen and sigmoid sinus, with preserva-            In addition to the elected surgical technique and the patho-
tion of the posterior ear canal wall 4,5. The main advantage of         physiological factors described above, the risk for cholestea-
CWU is the preservation of natural anatomy of the external              toma recidivism can be influenced by other factors, such as
auditory canal (EAC), facilitating healing and avoiding cavity          the extent of the disease, cholesteatoma location and presen-
problems such as accumulation of debris and caloric vertigo 3.          tation of pre-operative ear discharge 21. In several studies, a
CWU also facilitates fitting of hearing aids post-operatively,          higher risk of recidivism has been shown in pars tensa cho-
as reported in several articles in the literature 4-8. Given the        lesteatomas than in pars flaccida cholesteatomas 22. The Eu-
preservation of anatomical structures and the resulting con-            ropean Academy of Otology and Neurotology (EANO) and
servation of middle ear resonance, it appears to be associated          Japanese Otological Society (JOS) working group developed
with better hearing outcomes 9,10, although several studies             a staging system (EANO/JOS cholesteatoma classification
have failed to demonstrate a significant difference between the         system) that applies to 4 different categories of middle ear
two approaches 4,11,12. However, the CWU technique does not             cholesteatoma: pars flaccida cholesteatoma, pars tensa cho-
facilitate broad intra-operative visualisation of areas such as         lesteatoma, congenital cholesteatoma and cholesteatoma
sinus tympani, supratubal recess, the attic, the posterior crus         secondary to a tensa perforation (Tab. I) 23.
of stapes and facial recess. The implication is that residual dis-      Angeli et al. 24 attempted to evaluate the utility and prog-
ease is less easily detected compared to the CWD approach,              nostic capabilities of this staging system in predicting
increasing the rate of recurrence. The CWD procedure has the            cholesteatoma recurrence. Although this staging allows a
advantage of being able to visualise the cholesteatoma exten-           better description of the type and extent of pathology, also
sively, with complete en-bloc removal, thus ensuring surgical           permitting a clearer and more standardised description of
clearance 13. The aim of this paper is to critically review the         surgical outcomes, its prognostic value for cholesteatoma
factors affecting the risk of recurrent cholesteatoma.                  recurrence remains unproven.



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Table I. EANOS/JOS classification and staging system 23.
 Stage I         Localised cholesteatoma
                 The site of cholesteatoma origin, i.e., the attic for pars flaccida cholesteatoma, the tympanic cavity for pars tensa cholesteatoma,
                 congenital cholesteatoma, and cholesteatoma secondary to a tensa perforation
 Stage II        Cholesteatoma involving two or more sites
 Stage III           Cholesteatoma with extracranial complications or pathologic conditions includes: facial palsy, labyrinthine fistula: with conditions at risk
                     of membranous labyrinth, labyrinthitis, postauricular abscess or fistula, zygomatic abscess, neck abscess, canal wall destruction more
                     than half the length of the bony ear canal, destruction of the tegmen: with a defect that requires surgical repair, and adhesive otitis: total
                     adhesion of the pars tensa
 Stage IV            Cholesteatoma with intracranial complications Includes: purulent meningitis, epidural abscess, subdural abscess, brain abscess, sinus
                     thrombosis, and brain herniation into the mastoid cavity



Revision surgery presents some major challenges, most                                main limitation of the technique is the inability to explore
notably being the distortion of normal anatomy and loss                              the mastoid cavity during follow-up with the risk of devel-
of anatomical landmarks. This leads to increased risks and                           oping a “silent cholesteatoma”, making radiological follow-
complications during surgery and reliance upon highly ex-                            up essential. This technique has become popular in the last
perienced surgeons.                                                                  two decades with the development of non-EPI DW-MRI,
Key steps for successful surgery are confident identification of                     which facilitates detection of cholesteatoma in obliterated
the facial nerve, labyrinth and the oval window. Granulation                         or reconstructed cavities 30. Surgical techniques and materi-
tissue must be removed completely, because it is a source of                         als used for obliteration and reconstruction vary widely. The
otorrhoea and because it may underly a cholesteatoma. The                            materials used can be autologous, allogenic, or synthetic.
correct size of the meatoplasty is another key point: an inad-                       Among autologous materials, the most widely used is bone,
equate meatoplasty may, in fact, not allow complete mastoid                          harvested as pate or chips. It has the advantage of retaining
dominance and promote retention of keratin debris. It is im-                         its volume compared to soft tissue. Other materials used are
portant to emphasise that there is no single, correct procedure                      cartilage from concha or tragus and soft tissue flaps, which
to follow; the choice must always be tailored to the patient 25.                     may include fascia, periosteum and/or muscle. The most
                                                                                     widely used flap is the middle temporal artery flap, which is
CWD vs CWU: recurrence rate                                                          very versatile and resists atrophy, which is the major weak-
and quality of life                                                                  ness of muscle flaps. It is very important to be cautious when
                                                                                     harvesting any graft material, especially with bone pate, to
A debated issue between these two techniques is the post-                            not inoculate microscopic epithelial cells, which could lead
operative quality of life (QoL). Historically, CWD has al-                           to a recurrence of cholesteatoma in the future. As far as
ways been associated with worse quality of life due to the
                                                                                     synthetic materials are concerned, the most widely used is
limitations of the neo-mastoid cavity 26. However, recent
                                                                                     bioactive glass (BAG), followed by hydroxyapatite and tita-
studies show that there is no significant difference in QoL
                                                                                     nium. The major complication of synthetic materials is ex-
between CWU and CWD procedures 27,28. In particular, a
                                                                                     trusion. Choong et al. 31 in their review cited an extrusion rate
recent study by Lucidi et al. 29 compared the early and one
                                                                                     of 3.6%, which is much higher in the case of hydroxyapatite.
year-post-operative results in CWD versus CWU without
                                                                                     The latter material also makes revision surgery very com-
obliteration of the surgical cavity, demonstrating the absence
                                                                                     plicated and increases the rate of infection. However, there
of a significant difference in self-perceived quality of life. A
                                                                                     is still no consensus around the technique, type of material
significant limitation of this study is the short follow-up of
                                                                                     to be used, or the ideal timing for surgery (simultaneous or
only one year.
                                                                                     during revision surgery) 32. A systematic review and meta-
                                                                                     analysis by Illes et al. 30 collected data from 2077 operations
Mastoid obliteration                                                                 from 11 articles to evaluate the effectiveness of mastoid
Mastoid obliteration entails the surgical elimination or reduc-                      obliteration compared to the CWU technique. The results
tion of the size of a mastoid cavity. It is usually performed                        demonstrated that mastoid obliteration significantly reduced
during or following a CWD, but it can also be performed                              cholesteatoma recidivism (Odds Ratio = 0.45, Confidence
after CWU. It is a surgical technique that attempts to com-                          Interval = 0.26-0.8, p = 0.014). Furthermore, no difference
bine the advantages of CWU and CWD with the goal of re-                              in outcome was demonstrated using different materials for
ducing the incidence of residual disease and recurrence. The                         mastoid obliteration and posterior wall reconstruction.



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Endoscopic ear surgery (EES): an adjunct                              of ossicular chain preservation, ranging from 24 to 33,3%
or an alternative to microscopic surgery                              due to a better visualisation of ossicles, preventing their un-
                                                                      necessary removal.
Since the 1950s, microsurgery has been considered the tradi-          A review by Verma et al. 38 of 13 studies demonstrated that in
tional surgical technique for chronic cholesteatomatous otitis        15.82% cases residual cholesteatoma was identified by using
media. However, in recent decades, the application of the en-         an endoscope after microscopic surgery. In three (Tarabichi 40
doscope to otological surgery, with the advantage of “look-           Migirov 41 and Barakate 42), exclusive EES was performed
ing around corners”, has become popular. The microscope               with a rate of recidivism ranging from 0% to 20.6%. A limi-
offers a magnified and illuminated surgical field, allowing           tation of these studies is the short mean follow-up (43, 12
two handed surgery, binocular vision and depth perception.            and 16 months, respectively). Marchioni et al. 43,44 presented
However, the limitation of a straight line vision creates blind       a study that started in 2005 and finished in 2015 in which 244
spots, or hidden areas that are difficult to reach during sur-        ears in 234 patients were treated with exclusive endoscopic
gery 33. Endoscopic ear surgery (EES), on the other hand,             approach (n = 144) or a combined approach with mastoidec-
using angled endoscopes (30 and 45°) offers a clear visuali-          tomy (n = 100) for middle ear cholesteatoma, with at least 3
sation of hidden areas of retrotympanum, anterior epitypa-            years of follow-up. In all, 30% of patients had an exclusively
num, facial recess, and sinus tympani. It is also considered a        attic cholesteatoma, 17% an extension to mesotympanum,
minimally invasive technique, using the transcanal approach,          15% an exclusively mesotympanic disease, 30% an antrum
avoiding retroauricular incision 34. In middle ear surgery, the       extension and 7% had mastoid involvement. Residuals were
use of endoscopes can be classified in: A) assisted, in which         defined CT usually performed after 1 year of follow-up or
the endoscope is used exclusively to search for residual cho-         during a planned surgical second-look. Recidivism rate was
lesteatoma after the microsurgical approach; B) mixed, in             32%, with recurrence and residual rates, respectively, of
which microscope and endoscope are both used for surgi-               12% and 20%. Studies that compared EES to a microscopic
cal cholesteatoma eradication; C) exclusive endoscopic or             control group for cholesteatoma showed equivalent residual
TEES (Transcanal Endoscopic Ear Surgery).                             and recurrent rates, with no significant differences in hear-
Endoscopes are frequently used in cholesteatoma surgery               ing outcomes 45. The microscope and endoscope are both
only as an adjunct to the microscope for diagnostic pur-              useful tools in otological surgery, and are not in opposition
poses. Exclusive endoscopic surgery has not gained wide-              but complementary. There is no ideal surgical technique; the
spread acceptance for several reasons: only one hand can              most correct surgical technique should consider the extent of
be used for surgical manoeuvres, lack of depth perception,            the disease, the patient’s age and desire.
difficulty to perform ossicular reconstruction, frequent fog-
ging and smearing of endoscopic tip and the risk of ther-
                                                                      Laser in the treatment of cholesteatoma:
mal injury to the facial nerve, chorda tympani and cochlear
promontory with transmitted heat of the endoscope tip 35.             a way to reduce residual disease?
The indications for EES in cholesteatoma treatment are                The use of lasers in the treatment of cholesteatoma has be-
limited to the tympanic space and its subsites (epitympa-             come widespread in the last 2 decades, especially in the U.S.
num, mesotympanum, retrotympanum, protympanum and                     The most widely used laser in the treatment of cholesteato-
hypotympanum). When the cholesteatoma involves the                    ma is the potassium titanyl phosphate (KTP) laser at 532 nm
mastoid, the use of EES is controversial: some suggest                wavelength. Its strengths are the possibility of being transmit-
switching to a traditional technique with microscope or a             ted via a hand-held semi-flexible fibre-optic cable, which can
combined endoscopic and microscopic approach 36. Others               reach relatively inaccessible recesses of the middle ear, and its
believe that the exclusive use of the endoscope is still pos-         wavelength is absorbed by red pigments such as haemoglobin.
sible in a small number of cases 37.                                  At this wavelength, blood-containing structures are preferen-
Various studies have shown that the EES has significantly             tially denatured, vaporised or heated by the laser, whereas non-
reduced the residual and recurrence rate of cholesteatoma             blood containing structures, such as perilymph, have relatively
compared to microscope use alone, especially for CWU                  little penetration. The use of the KTP laser allows atraumatic
procedures. The commonest site of residual disease is the             removal of cholesteatoma from the middle ear and ossicular
sinus tympani, even in second-look procedures 38. A review            chain, and precise haemostatic removal of diseased tissue such
by Hu et al. 39 demonstrated a recurrence rate in the EES             as polyps, granulations and adhesions. Retrospective studies
approach between 0% and 10.5%, significantly lower than               have shown that the risk of residual cholesteatoma is reduced
CWU approach, but similar to the CWD approach in an                   by half 46. An important prospective study was conducted by
adult population. In addition, EES has shown a high rate              Hamilton et al. 47 in two different hospitals, in which the same



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surgeon operated using the KTP laser at one location and in           Paediatric cholesteatoma
the other without. All patients included in the study were re-
quired to undergo a second surgical procedure with full expo-         Paediatric cholesteatoma is much debated in the literature as
sure of the middle ear and mastoid, including the entire bed          there are different interpretations on its behaviour and surgi-
of the previous cholesteatoma. This study showed that 1 of 36         cal treatment. Some authors believe that cholesteatoma in
patients with procedures utilising the KTP laser had residual         children has a more aggressive growth pattern compared to
disease, compared to 10 of 33 patients without KTP laser 47.          adults, which leads to a higher incidence of both residual and
The primary risk of laser use is thermal collateral damage to         recurrent disease. This behaviour would appear to be related
exposed structures including the cochlea and the facial nerve.        to several factors: well-pneumatised mastoids in children al-
However, recent data observe that the rate of facial nerve pa-        low for more extensive disease compared with more sclerotic
ralysis is 0.6%, demonstrating that laser use appears safe if ap-     mastoid bones in adults 9; Eustachian tube anatomy and dys-
propriate safety guidelines are followed 48. Lasers seem to play      function predispose children to more frequent infections and
an increasing role in EES thanks to the better bleeding control       retraction pockets 9; a higher rate of keratinocyte proliferation
that can be challenging with one hand, and the atraumatic dis-        and a pronounced inflammatory response of the peri-matrix
section of cholesteatoma, especially on the ossicular chain.          and matrix in the paediatric population 56-59. Despite all these
Laser-assisted endoscopic cholesteatoma surgery showeda               theories, there are still many controversies, both on cholestea-
recurrence and residual rate between 0% and 19%, and not              toma behaviour and management. Indeed, there are currently
inferior to standard middle ear surgery 49. Sharma et al. 50 pre-     no studies in the literature expressing a clear consensus on the
sented a study based on a large paediatric population treated         surgical treatment of paediatric cholesteatoma. Both CWD
with purely endoscopic KTP laser resection for cholesteatoma          and CWU procedures are used: some authors are in favour
over an eight-year period. Of the 83 patients included in this        of CWU technique 60,61, others prefer CWD approach 62,63. A
study with cholesteatoma confined to the middle ear and attic,        third group is in favour of both procedures, recommending
70 were treated with KTP laser. Residual disease was detected         individualised treatment 64-66. The main purposes of surgery
in 4 patients (6%). In 3 residual disease was found close to the      in paediatric patients remain the eradication of cholesteatoma
facial nerve area that was spared from KTP laser application          and restoration of hearing function: the balance between these
in order to avoid thermal injury. In conclusion, KTP laser has        two goals is related to the incidence of recidivism and degree
been shown to reduce the risk of residual cholesteatoma and           of ossicular damage 67. A recent analysis of the literature 68
is suggested to be beneficial to preserve ossicular function and      showed that CWU is characterised by an average residual dis-
safe hearing outcomes.                                                ease of approximately 15% (range 3.8%-21%), while CWD
                                                                      is associated with an average residual and recurrent chole-
                                                                      steatoma rates of 6.5% (range 0%-11.4%) and 5.1% (range
Imaging and recurrence                                                0%-18.4%), respectively 10,11,66,69-72. These data showed that a
The most widely used radiological examination in the primary          staged approach to cholesteatoma is not necessarily more ef-
diagnosis of cholesteatoma is CT, demonstrating high sensi-           fective in reducing the rate of recidivism. In particular, CWD
tivity but low specificity 51. In the case of residual or recurrent   still represents the most efficient approach in eradication of
cholesteatomas, the sensitivity and specificity of CT drops dra-      tympano-mastoid cholesteatoma, with residual and recurrence
matically given the difficulty in distinguishing changes due to       rates close to 5%. In the light of the above-mentioned data,
previous surgery against bone erosion due to cholesteatoma 52.        surgical treatment should be individualised, considering the
In this scenario, the specificity of CT is 48%, while the sensi-      extent of the disease and the conditions of the mucosal and os-
tivity is 43% 53. These difficulties are overcome in part by us-      sicular chain 69. The management of paediatric cholesteatoma
ing diffusion weighted magnetic resonance imagining (DWI-             is difficult for multiple reasons and children can sometimes be
MRI). Cholesteatoma appears to have a high signal intensity,          difficult to monitor clinically. If we consider the longevity of
mainly attributable to its water content and restricted water         this part of population, it is mandatory to optimise the surgical
diffusion. In particular non-echo planar imaging DWI tech-            management and monitoring of these patients.
niques allow less image distortion, lower artifacts than other
DWI techniques and better identification of small lesions, re-        The prognostic role of cell proliferation
ducing the false-positive rate (the sensitivity and specificity of
Non EPI DWI-MRI are 89.79% and 94.57%, respectively) 54.
                                                                      markers in recurrent cholesteatoma
The use of DWI MRI in the diagnosis of residual or recurrent          Many studies have investigated the pathogenesis of choleste-
cholesteatomas may therefore be a viable alternative to routine       atoma and the factors leading to cell proliferation and bone
second-look surgery in some cases 55.                                 resorption. These include specific cytokeratins, inflamma-



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tion, enzymes and local pressure. In particular, an altered re-          a surgical disease, with a surgical skillset being a critical
ceptor activator of nuclear factor-kappa B ligand (RANKL)/               determinant in rates of recidivism. The emergence of EES
Osteoprotegerin (OPG) protein ratio suggests the main role               and the use of laser have opened up new surgical methods
of RANKL/OPG pathway in the inflammation related to the                  to improve surgical outcomes and prognosis, with strengths
growth of cholesteatoma, and osseous destruction due to mid-             and limitations. However, there is currently no gold stand-
dle ear cholesteatoma. Given the high proliferative rate of              ard surgical technique, as treatment must be tailored based
cholesteatoma and the tendency for recurrence, many studies              on the extent of disease and middle ear condition.
have been conducted to find specific markers involved in the             Mastoid obliteration combines the advantages of CWU and
pathophysiology of this disease. Araz et al. 73 investigated the         CWD, reducing the recidivism rate compared to CWU. The
possible correlation between the cell proliferation markers Ki-          use of lasers in cholesteatoma surgery is becoming popular
67 and proliferating cell nuclear antigen (PCNA) with chole-             due to the greater preservation of the ossicular chain and a
steatoma recurrence. Ki-67 is a factor involved in proliferative         safe hearing outcome, with promising studies demonstrat-
cells, as it is essential in the G1, S, M and G2 phases (it is           ing an improved recidivism rate.
absent in G0) 74,75. PCNA is a co-factor of DNA polymerase               The use of non-EPI DWI MRI has proved to have high
delta that participates in cell- proliferation 76. The rate of Ki-67     sensitivity and specificity in detecting recurrent or residual
and PCNA has been analysed in two groups of patients under-              disease, and is emerging as an alternative to routine second-
going CWD surgery: with recurrent cholesteatoma and non-                 look surgery.
recurrent cases after at least 2 years of follow-up. The results         Even if the near future will probably still see surgery hav-
did not demonstrate a significant difference between the two             ing a crucial role in the management of this pathology,
groups examined. Therefore, it appears that these two mark-              new technological tools (intra-operative imaging guidance,
ers do not have a predictive role in cholesteatoma recurrence.           robot) and medical therapies will hopefully improve out-
However, given the high level of Ki-67 found in cholestea-               comes in the treatment of cholesteatoma in order to win
toma cases with malleus erosion, it could be considered as an            this “eternal ear fight”.
indicator of a destructive pattern of disease.
                                                                         Conflict of interest statement
The promising role of MESNA                                              The authors declare no conflict of interest.
(sodium 2-mercaptoethanesulphonate)                                      Funding
Sodium 2-mercaptoethanesulphonate, also known as                         This research did not receive any specific grant from funding
MESNA, deserves brief mention. It is a synthetic sulphur                 agencies in the public, commercial, or not-for-profit sectors.
compound that belongs to a class of thiols that produce
mucolysis by disrupting disulphide bonds of the mucous                   Author contributions
polypeptide chains. It has been used in several diseases as a            CB, AL, RB: conception and design of the work, research
cytoprotective agent. Many studies in vivo and in vitro sug-             on PubMed, literature review, drafting of the article; GD,
gest that MESNA plays an important role as an antioxidant                DB, NC: contribution to the concept and design of the arti-
drug. Only in recent years has MESNA gained attention for                cle, critically revision.
its potential application in facilitating surgical dissection,
leading to the concept of “chemically assisted dissection”.              Ethical consideration
The fundamental principle of chemically-assisted dissection              Not applicable.
lies in the rich disulphide bonds of the adhesions between the
different tissue layers. In ENT surgery, topical MESNA has               References
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