and Neck Surgery di Otorinolaringoiatria e Chirurgia Cervico-Faccialee Chirurgia of Otorhinolaryngology Head Volume 40 Volume October 2020 Official Journal of the Italian Society of the Italian Journal Official Organo Ufficiale della Società Italiana della Società Italiana Organo Ufficiale Otology microsurgery Transmeatal for intralabyrinthine and intrameatal schwannomas: a reappraisal Letter to the Editor Current evidence on confocal laser endomicroscopy for noninvasive head and neck cancer imaging

Laryngology Modular approach in OPHL: are there preoperative predictors? Outcomes of balloon dilation for paediatric laryngeal stenosis Rhinology Exploring the role of nasal cytology in chronic rhinosinusitis of congenital nasolacrimal Treatment duct cyst: the role of endoscopic marsupialisation OSAHS Behavioural disorders and parental stress in children suffering from obstructive sleep apnoea syndrome: a pre- and post-adenotonsillectomy a pre- and post-adenotonsillectomy confrontation

a preclinical investigation in a cadaver lab retroauricular approach (RAND-3D): VITOM-3D assisted neck dissection via a for head and neck cancer Obstructive sleep apnoea after radiotherapy Head and neck neck space infections New laboratory predictive tools in deep Review Otolaryngology Units: a nationwide study Impact of COVID-19 pandemic on Italian protection snorkelling masks for intraoperative Overview of different modified full-face COVID-19 POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv. in L. 27/02/2004 n° 46 art. 1, comma 1, DCB PISA - Iscrizione al tribunale di Pisa al n. 10 del 30-07-93 - Finito di stampare presso IGP, Pisa - Novembre 2020 - ISSN: 0392-100X (Print) - ISSN: 1827-675X (Online). ISSN: 1827-675X - (Print) 0392-100X ISSN: - 2020 Novembre - Pisa IGP, presso stampare di Finito - 30-07-93 del 10 n. al Pisa di tribunale al Iscrizione - PISA DCB 1, comma 1, art. 46 n° 27/02/2004 L. in conv. 353/2003 D.L. - Postale Abbonamento in Spedizione - SPA ITALIANE POSTE

ACTA Otorhinolaryngologica Italica, 40/5, 317-398 , 2020 Editorial Board Editor-in-Chief: M. Ansarin President of S.I.O.: G. Paludetti Former Presidents of S.I.O.: L. Coppo, A. Ottaviani, P. Puxeddu, G. Sperati, D. Passali, E. de Campora, A. Sartoris, P. Laudadio, M. De Benedetto, S. Conticello, D. Casolino, A. Rinaldi Ceroni, M. Piemonte, R. Fiorella, A. Camaioni, A. Serra, G. Spriano, R. Filipo, C.A. Leone, E. Cassandro, C. Vicini, M. Bussi

Editorial Staff Editor-in-Chief: M. Ansarin Division of Otolaryngology and Head & Neck Surgery, European Institute of Oncology IRCCS Via Ripamonti, 435 - 20141 Milan, Italy Tel. +39 02 57489490 - Fax +39 02 94379216 [email protected] Associate Editors: P. Canzi Dipartimento di Otorinolaringoiatria, Università di Pavia, Fondazione IRCCS Policlinico “San Matteo”, Pavia, Italy [email protected] E. De Corso Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy [email protected] Official Journal of the Italian Society A. Karligkiotis of Otorhinolaryngology Head and Neck Surgery Struttura Complessa di Otorinolaringoiatria, ASST Sette Laghi - Ospedale di Circolo e Fondazione Macchi, Varese, Italy Organo Ufficiale della Società Italiana [email protected] M.G. Rugiu di Otorinolaringoiatria e Chirurgia Cervico-Facciale SOC ORL, Azienda Universitaria Integrata di Udine, Italy [email protected] Former Editors-in-Chief: E. Zanoletti Otorinolaringoiatria, Ospedale-Università di Padova, Italy C. Calearo, E. de Campora, A. Staffieri, M. Piemonte, F. Chiesa, G. Paludetti [email protected] Editorial Coordinator: Italian Scientific Board International Scientific Board F. Chu Division of Otolaryngology and Head & Neck Surgery M. Alicandri-Ciufelli J. Betka European Institute of Oncology IRCCS, Milan, Italy Policlinico, Modena Charles University, Prague Czech Republik [email protected] G. Bellocchi P. Clement Scientific Secretariat: Ospedale “San Camillo”, Roma ENT Department,University Hospital, Brussels, Belgium G. Pietrobon A. Bertolin M. Pais Clemente Division of Otolaryngology and Head & Neck Surgery Presidio Ospedaliero, Vittorio Veneto Department of Otolaryngology, University of Porto, Portugal European Institute of Oncology IRCCS, Milan, Italy F. Dispenza R.W. Gilbert [email protected] Policlinico “Paolo Giaccone”, Palermo Otolaryngology H&N Surgery, University of Toronto, Canada Editorial Assistant: M. Falcioni M. Halmagyi P. Moore Azienda Ospedaliera, Parma Royal Prince Alfred Hospital, Camperdown, Australia Copy Editor: F. Fiorino L.P. Kowalski L. Andreazzi - [email protected] Ospedale “Mater Salutis”, Legnago A C Camargo Cancer Center, Sao Paulo, Brazil Treasurer: J. Galli R. Laszig F. Pagella Dipartimento di Otorinolaringoiatria, Università di Pavia, Fondazione Policlinico Gemelli, Roma Universitäts-HNO-Klinik, Freiburg, Germany IRCCS Policlinico “San Matteo”, Pavia, Italy G. Giourgos C.R. Leemans [email protected] Ospedale “Papa Giovanni XXIII”, Bergamo VU University Medical Center, Amsterdam, The Netherlands A. Greco F. Marchal Argomenti di Acta Otorhinolaryngologica Italica Policlinico “Umberto I”, Roma Hopitaux Universitaires, Geneve, Switzerland Editor-in-Chief: M. Ansarin Editorial Coordinator: M. Tagliabue - [email protected] G. Marioni G. O’Donoghue Division of Otolaryngology and Head & Neck Surgery Azienda Ospedaliera, Padova ENT Department, Queen’s Medical Centre, Nottingham, UK European Institute of Oncology IRCCS, Milan, Italy A. Murri M. Remacle Ospedale “Guglielmo Da Saliceto”, Piacenza CHL Clinique d’Eich, Luxembourg © Copyright 2020 by P. Petrone R.J. Salvi Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale Ospedale “San Giacomo”, Monopoli Center for Hearing and Deafness, Buffalo, NY, USA Via Luigi Pigorini, 6/3 - 00162 Rome, Italy C. Piazza B. Scola Yurrita Istituto Nazionale dei Tumori, Milano Hospital General Universitario G. Marañón, Madrid, Spain Managing Editor N.A.A. Quaranta J. Shah M. Ansarin Policlinico, Bari Memorial Sloan Kettering Cancer Centrer, New York, USA R. Teggi H. Stammberger Publisher Pacini Editore Srl Ospedale “San Raffaele”, Milano Medical University, Graz, Austria Via Gherardesca, 1 - 56121 Pisa, Italy D. Testa H.P. Zenner Tel. +39 050 313011 -Fax +39 050 3130300 Seconda Università, Napoli Universitäts Hals-Nasen-Ohren-Klinik, Tübingen, Germany [email protected] - www.pacinimedicina.it

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Volume 40 October 2020 COVID-19 Overview of different modified full-face snorkelling masks for intraoperative protection Panoramica delle diverse maschere snorkelling modificate per la protezione intraoperatoria C. Vicini, G. Cammaroto, G. Meccariello, G. Iannella, M. Fragale, T. Cacco, C. Sampieri, L. Guastini, E. Castello, G. Parrinello, A. De Vito, G. Gulotta, I.C. Visconti, P. Abita, S. Pelucchi, G. Bianchi, M.N. Melegatti, G. Garulli, F. Bosco, A. Gennaiotti, S. Berrettini, M. Magnani, M. Troncossi, G. Peretti ...... 317 Impact of COVID-19 pandemic on Italian Otolaryngology Units: a nationwide study Impatto della pandemia COVID-19 sulle Unità Operative di Otorinolaringoiatria in Italia: uno studio nazionale G. Mannelli, M. Ralli, M. Bonali, P. Capasso, P. Guarino, V. Iannini, N. Mevio, G. Russo, A. Scarpa, G. Spinato, D. Topazio, G. Molteni . . . 325 Review New laboratory predictive tools in deep neck space infections Nuovi indicatori biochimici predittivi di infezioni suppurative cervicali M.L. Fiorella, P. Greco, L.M. Madami, O.V. Giannico, V. Pontillo, N. Quaranta...... 332 Head and neck Obstructive sleep apnoea after radiotherapy for head and neck cancer Apnee ostruttive del sonno dopo radioterapia per tumori del testa-collo F. Leone, G.A. Marciante, C. Re, A. Bianchi, F. Costantini, F. Salamanca, P. Salvatori...... 338 VITOM-3D assisted neck dissection via a retroauricular approach (RAND-3D): a preclinical investigation in a cadaver lab Dissezione laterocervicale mediante approccio retroauricolare assistito da sistema VITOM-3D (RAND-3D): studio preclinico in cadaver lab E. Crosetti, G. Arrigoni, A. Manca, M. Fantini, A. Caracciolo, F. Sardanapoli, G. Succo...... 343 Laryngology Modular approach in OPHL: are there preoperative predictors? OPHL modulare: esistono parametri predittivi preoperatori? A. Bertolin, M. Lionello, M. Ghizzo, E. Barbero, E. Crosetti, G. Rizzotto, G. Succo...... 352 Outcomes of balloon dilation for paediatric laryngeal stenosis Il balloon nel trattamento delle stenosi laringee in età pediatrica G. Cantarella, M. Gaffuri, S. Torretta, S. Neri, M.T. Ambrosini, A. D’Onghia, L. Pignataro, K. Sandu...... 360 Rhinology Exploring the role of nasal cytology in chronic rhinosinusitis Il ruolo della citologia nasale nella rinosinusite cronica S. Gallo, F. Bandi, A. Preti, C. Facco, G. Ottini, F. Di Candia, F. Mozzanica, L. Saderi, F. Sessa, M. Reguzzoni, G. Sotgiu, P. Castelnuovo. . . 368 Treatment of congenital nasolacrimal duct cyst: the role of endoscopic marsupialisation Il trattamento delle cisti congenite del dotto nasolacrimale: il ruolo della marsupializzazione endoscopica V. Rampinelli, M. Ferrari, S. Zorzi, M. Berlucchi...... 377 OSAHS Behavioural disorders and parental stress in children suffering from obstructive sleep apnoea syndrome: a pre- and post-adenotonsillectomy confrontation Disordini comportamentali e indice di stress genitoriale nei bambini affetti da Sindrome dell’apnea ostruttiva nel sonno: confronto pre e post adenotonsillectomia E. Sitzia, F. Pianesi, N. Mirante, G. Marini, M. Micardi, M.L. Panatta, A. Resca, P. Marsella, G.C. De Vincentiis...... 383 Otology Transmeatal microsurgery for intralabyrinthine and intrameatal schwannomas: a reappraisal Approccio transmeatale microchirurgico nei neurinomi intralabirintici e intrameatali: rivalutazione di una tecnica A. Mazzoni, E. Zanoletti, D. Cazzador, L. Calvanese, D. d’Avella, A. Martini...... 390 Letter to the Editor Current evidence on confocal laser endomicroscopy for noninvasive head and neck cancer imaging Evidenze scientifiche attuali sulla endomicroscopia confocale laser nell’imaging del tumore non invasivo del distretto testa e collo X. Yang, W. Liu...... 396

Articles in open access, information for authors including editorial standards for the preparation of manuscripts and submission and Publisher’s note available on-line: www.actaitalica.it ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:317-324; doi: 10.14639/0392-100X-N0841

COVID-19 Overview of different modified full-face snorkelling masks for intraoperative protection Panoramica delle diverse maschere snorkelling modificate per la protezione intraoperatoria Claudio Vicini1, Giovanni Cammaroto1, Giuseppe Meccariello1, Giannicola Iannella1, Marco Fragale2,3, Tommaso Cacco2,3, Claudio Sampieri2,3, Luca Guastini2,3, Eolo Castello2,3, Giampiero Parrinello2,3, Andrea De Vito4, Giampiero Gulotta5, Irene Claudia Visconti5, Pietro Abita6, Stefano Pelucchi7, Giulia Bianchi7, Michela Nicole Melegatti7, Gianluca Garulli8, Filippo Bosco9, Alessandro Gennaiotti9, Stefano Berrettini10, Massimo Magnani11, Marco Troncossi12, Giorgio Peretti2,3 1 Department of Head-Neck Surgery, AUSL Romagna, Italy - Ear Nose Throat (ENT) Unit of Forlì and Faenza, University of Ferrara and Bologna, Morgagni-Pierantoni Hospital, Forlì, Italy; 2 IRCCS Ospedale Policlinico San Martino, Unit of Otorhinolaryngology Head and Neck Surgery, Genoa, Italy; 3 Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Italy; 4 Department of Head-Neck Surgery AUSL Romagna, Italy - Ear Nose Throat (ENT) Unit, Santa Maria delle Croci Hospital, Ravenna, Italy; 5 Department of Organ of Sense, University La Sapienza, Rome, Italy; 6 Department of Adult and Development Age Human Pathology “Gaetano Barresi”, Unit of Otorhinolaryngology, University of Messina, Italy; 7 Otolaryngology Head and Neck Surgery, University Hospital of Ferrara, Italy; 8 Minimally Invasive General and Thoracic Surgery Unit, AUSL Romagna, Italy - Ceccarini Hospital, Riccione, Italy; 9 Department of Anesthesia and Intensive Care, Cisanello Hospital, University Hospital of Pisa, Italy; 10 Otolaryngology Head and Neck Surgery, Cisanello Hospital, University Hospital of Pisa, Italy; 11 Department of Head-Neck Surgery AUSL Romagna, Italy; Ear Nose Throat (ENT) Unit, Bufalini Hospital, Cesena, Italy; 12 Department of Industrial Engineering, University of Bologna, Italy

SUMMARY Objective. The COVID-19 pandemic has caused significant impact on healthcare systems Received: May 9, 2020 worldwide. The rate of infected healthcare workers is > 10% in Italy. Within this dramatic Accepted: May 23, 2020 scenario, the development of new personal protective equipment (PPE) devices is manda- Published online: September 24, 2020 tory. This study focuses on validation of modified full-face snorkel masks (MFFSM) as safe and protective equipment against SARS-CoV-2 infection during diagnostic and therapeutic Correspondence procedures on the upper aerodigestive tract. Claudio Vicini Methods. Five different MFFSM were tested during otolaryngological surgery and in anaes- Via Carlo Forlanini 34, 47121 Forlì, Italy thesia procedures. Data were collected through an online survey to assess the feedback of op- E-mail: [email protected] erators. pO2 and pCO2 monitoring values during procedures were recorded in selected cases. Results. All five MFFSM tested were easy to use and gave all operators a sound “feeling” Funding of protection. All clinicians involved had common agreement regarding safety and the user- None. friendly format. Conclusions. In the future, specific development of different type of masks for protection in the Conflict of interest operating room, intensive care units and/or office will be possible as a joint venture between clini- The Authors declare no conflict of interest. cians and developers. Goals for clinicians include better definition of needs and priorities, while developers can devote their expertise to produce devices that meet medical requirements. How to cite this article: Vicini C, Cammaroto G, KEY WORDS: COVID-19, pandemic, surgery, anesthesia Meccariello G, et al. Overview of different modified full-face snorkelling masks for intraoperative pro- tection. Acta Otorhinolaryngol Ital 2020;40:317- RIASSUNTO 324. https://doi.org/10.14639/0392-100X-N0841 Obiettivo. La pandemia di COVID-19 ha tuttora un impatto significativo sui sistemi sanitari di tutto il mondo. Il tasso di operatori sanitari italiani che hanno contratto l’infezione è superiore © Società Italiana di Otorinolaringoiatria al 10%. In questo drammatico scenario, la comunità scientifica si è impegnata nello sviluppo di e Chirurgia Cervico-Facciale nuovi dispositivi di protezione individuale. Il nostro studio si concentra sull’uso di maschere da snorkelling modificate (MFFSM) come dispositivi di protezione individuali contro l’infezione da OPEN ACCESS virus COVID-19 durante procedure diagnostiche e terapeutiche sul tratto aerodigestivo superiore. This is an open access article distributed in accordance with Metodi. Cinque diversi tipi di MFFSM sono stati testati. I dati sono stati raccolti attraver- the CC-BY-NC-ND (Creative Commons Attribution-Non- so un sondaggio online; solo per la maschera OceanReef Aria QR+ sono stati registrati i Commercial-NoDerivatives 4.0 International) license. The valori intraoperatori di pO e pCO . article can be used by giving appropriate credit and mentio- 2 2 ning the license, but only for non-commercial purposes and Risultati. Tutte le MFFSM testate si sono rivelate di facile utilizzo e tutti gli operatori hanno ri- only in the original version. For further information: https:// ferito una sensazione di comfort, mantenendo una sensazione di sicurezza durante la procedura. creativecommons.org/licenses/by-nc-nd/4.0/deed.en

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Conclusione. In futuro sarà possibile lo sviluppo di specifiche maschere per la protezione in sala operatoria e in terapia intensiva sulla base di una stretta collaborazione tra clinici e ingegneri. L’obiettivo per i medici sarà definire con precisione le loro esigenze, mentre per le industrie produttrici sarà mettere a disposizione il loro expertise per fornire dispositivi che incontrino le necessità sanitarie. PAROLE CHIAVE: COVID-19, pandemia, dispositivi di protezione individuale, maschera, chirurgia, anestesia

Introduction interface for continuous positive airway pressure (CPAP). After that, diffusion of snorkelling masks as a protective tool The COVID-19 pandemic has caused significant impact for medical and paramedical staff occurred at a worldwide on healthcare systems worldwide and is perhaps the most level. demanding challenge of the last decades. Infected health- The snorkelling mask is a single tool acting, at the same care workers represent more than 10% of all COVID-19 time, as a mouth/nose protection mask and as eye protection cases in Italy, thus highlighting the relevant involvement glasses. Moreover, the device is waterproof and capable of of this professional category 1. Unfortunately, there is lim- completely sealing the face of operators. The low price and ited knowledge about the biological behaviour, transmis- wide availability of these masks make them a potentially rapid sion and spread of the SARS-CoV-2 virus, and up to now only empirical treatments and preventive methods against and feasible solution to provide PPE during the pandemic. 11 infection have been employed 2. Direct contact (direct/in- Greig et al. were the first authors to publish a case report direct touching) and virus-containing aerosolised droplets on safety testing of a snorkeling mask, which highlighted during cough, sneezing and speaking within few metres are some interesting perspectives. believed to be the main routes of the spread of infection. The standardisation of re-usable devices would lead to a However, the hypothesis that the virus is diffuse in air, as its significant reduction of costs and to a reduced need for predecessor SARS-CoV-1, is well supported 3. disposable PPE. However, FDA or CE approval of such There is evidence that a relevant rate of droplets expired equipment is still needed, and research is expected to accelerate. containing virus become much smaller after water evapora- The aim of our multicentre prospective study is to report tion reaching 5 microns of dimension without gravitation on the use of different models of modified full-face snorkel effects and are free to travel in the air even at considerable masks (MFFSM) equipped with 3D printed adaptors distances; experimental studies show that SARS-CoV-2 for HME and FFP3 filters, evaluating several practical remains active in aerosols for at least 3 hours and on non- aspects such as safety and comfort from the perspectives porous surfaces for up to 72 hours 4-6. of surgeons and anesthesiologists. Taking into account the These pathways of viral spread and its high stability in in- demonstrated efficacy of HME and FFP3 filters, our study door environments can explain the high risk of disease trans- does not include a specific evaluation of the protective mission, causing a significant number of nosocomial infec- activity of MFFSM against infection. A brief discussion tions and consequently a high risk of exposure to the virus of the ethical and regulatory issues, with recommendations for healthcare personnel. Several other reasons, such as in- for the future, is also included. sufficient training of medical and paramedical staff, limited and partially ineffective diagnostic testing and shortage of Materials and methods personal protective equipment (PPE) 7 seem to be the main causes of the dramatic peaks of infections in hospitals. Tests of MFFSM devices were conducted from January- In particular, shortage of “second level” PPE such as N95, April 2020 in three tertiary referral centres: Otolaryngology FFP-2 and FFP-3 masks has led some authors to investi- Unit of the Morgagni-Pierantoni Hospital, Forlì, Italy, gate the possibility of re-use following feasible sterilisation Intensive Care Unit (ICU), University of Pisa, Pisa, Italy, methods 8. and Otolaryngology Unit and ICU of IRCCS Ospedale Swennen et al. 9 proposed a re-usable custom-made 3D- Policlinico San Martino, University of Genoa, Genoa, Italy. printed face mask as a valid alternative in order to reduce Five different MFFSMs were tested during anaesthesiologic the need for disposable PPEs. and head-neck surgical procedures in operating room (OR) Another recently explored solution is the use of 3D printed and endoscopic evaluations in the ICU. The first and newest adaptors that support the matching of widely used standard versions of Subea Easybreath (Decathlon, Villeneuve- anesthetic heat and moisture exchange (HME) or industrial d’Ascq, France), Seac Unica (Seac Sub, San Colombano FFP3 filters, to commercially available snorkelling masks 10. Certenoli, Genova Italy), Siropack C-Voice, (Siropack, Snorkelling masks were originally introduced in Cesenatico, Forlì - Cesena Italy), based on the Unica mask management of COVID-19 patients as an emergency model, and the OceanReef Aria QR+ (Mestel Safety, Genoa,

318 Modified full-face snorkel masks for intraoperative protection

Italy) (Figs. 1A-E). Both the first and newest versions of system that allows communication between the surgeon Decathlon masks were modified by the addition of 3D printed and/or the anaesthesiologist and the OR and ICU teams adapters that support the possibility to connect the mask to (Fig. 1D). standard anaesthesiologic filters (HME-FFP2 filter). In the The equipment of the surgeon with all different MFFSM same way, the OceanReef and Unica masks were equipped devices is shown in Figure 3. The use of MFFSM during with a patented adapter coupled to a standard HME filter and different surgical procedures is shown in Figure 4. The industrial FFP3 (Figs. 2A-E). Seac Unica mask was used only in diagnostic procedures The Siropack mask has an integrated upper filter and an in the ICU such as fibrolaryngoscopies and phoniatric internal microphone connected to an external amplification evaluations.

A B C D E

Figure 1. (A,B) first and newest versions of Decathlon Subea Easybreath mask; (C) Seac Unica mask; (D) Siropack C-Voice mask; (E) Ocean Reef Aria QR+ mask.

A B C D E

Figure 2. (A) 3D printed adapters for Decathlon Subea Easybreath; (B) Decathlon mask connected to standard anaesthesiologic filter (HME-FFP2 filter; arrow) with a 3D printed adapter; (C) adapter that allows connection of different industrial filters to the Ocean Reef Aria QR+ mask; D( ) Seac Unica 3D printed adapter; (E) industrial FFP3 filters that can be used with the OceanReef Aria QR+ mask.

319 C. Vicini et al.

A B C D

Figure 3. Surgeons wearing four different types of modified snorkelling masks; A( ) modified Decathlon mask; (B) Siropack C-Voice mask; (C) Ocean Reef Aria QR+ mask; (D) Seac Unica mask.

Information on difficulty in breathing, optical distortion, and perceived weight of each mask was collected in the survey using a Visual Analogue Scale (VAS). These parameters were evaluated with a VAS using a 1-10 numerical rating scale (1 = no impact; 10 = high impact; intermediate values with increasing degrees of impact on tested items). Comfort and fitting, ease of use, and lateral and central vision quality were evaluated with a VAS using a 1-10 numerical rating scale (1 = high impact; 10 = no impact; intermediate values with decreasing degrees of impact on tested items). Communication between members of the surgical team, due to the sound attenuation caused by the mask, was assessed using a VAS with a 1-5 score (1 = poor sound and lower verbal perception 1; 5 = excellent sound and good verbal perception; intermediate values with increasing degrees of impact on tested item). The presence of water condensation that did not allow a clear vision of the surgical field was also investigated and scored as: none, disturbing, not disturbing. Figure 4. Arrangement of the surgical team, equipped with modified full- face snorkel masks, during different surgical procedures. Finally, localised pressure or facial sores were considered as: none, slight evident, evident with painful. The subjective analysis for every model of MFFSM was based Responses were anonymously collected. Incomplete on an online survey to assess operators feedback about the responses were excluded from the analysis. mask during different types of anaesthesiologic or surgical In addition, with OceanReef mask, PO2 and PCO2 values procedures in the OR and ICU. The survey was created with were objectively monitored during surgical procedures by Google Survey (Mountain View, California, USA), so that positioning a probe on the lobe of the pinna of surgeons each participant could complete the survey only once. (SenTec V - Sign System, SenTec AG, Therwil, Basel, The survey was developed in an interactive fashion, with Switzerland). Cleaning and sterilisation of MFFSM was drafts revised by four different authors. In the final version carried out immediately after each procedure following the of the survey, there were multiple/single open-ended and institutional protocols adopted for goggles and protective closed-ended questions. visors, which took about 30 minutes to complete.

320 Modified full-face snorkel masks for intraoperative protection

Because there is no patient data, this study was exempt Table II. Operator feedback using modified full-face snorkel masks in surgi- from the need for Institutional Review Board approval. cal procedures. Mean Median Statistical analysis Ease of wearing 9.2 ± 0.8 9 Descriptive statistical analysis was made by Mann- Comfort and fitting 8.6 ± 1.5 9 Whitney U test (SPSS version 22,0; IBM Corp, Armonk, Central vision quality 8.7 ± 1.4 9 NY, USA) to compare different items investigated in three Lateral vision quality 6.7 ± 2.1 7 MFFSM devices. Since it was not used for anaesthesiologic Optical distortion of the surgical field 2.8 ± 2.1 2 and surgical procedures, data for the Seac Unica mask was Difficulty in breathing 2.7 ± 2.3 2 excluded from statistical analysis. Perceived weight of the mask 3.8 ± 2.7 2 Communication with team during surgery* 3.7 ±1 4

Results Surgeon pCO2 min** 32.7 ± 0.5 Surgeon pCO max** 37.1 ± 0.5 General results 2 Surgeon p0 mean** 96.8 ± 0.8 All procedures were performed in COVID-19 free 2 patients, confirmed by preoperative polymerase chain Localised pressure or facial sores Not evident 48 96% reaction (PCR) test on nasal and oro-pharyngeal swabs. Slight evident 2 4% ® Modified Decathlon masks (with COVIDIEN DAR Evident with painful - - HME filter) were tested in 25 surgical and anaesthesiologic * all items except “time of surgery” were scored with a numerical rating scales of VAS = 0-10; procedures in the OR, Siropack in 15, and Ocean Reef in “communication with team during surgery” was scored with a numerical rating scale of VAS = 0-5; ** values measured by operators who have tested the Ocean Reef mask; *** Seac Unica 10, respectively; Seac Unica was used in only 56 diagnostic mask was excluded from statistical analysis because it was not used in surgical procedures.

Table IA. Type of modified full-face snorkelling masks and number of proce- endoscopic evaluations in the ICU. The mean duration of dures performed in OR and ICU. surgical and anaesthesiologic procedures was 55.9 minutes Number of all procedures N = 106 (Tab. IA). Data about surgical procedures are shown in Modified Decathlon masks (HME filter) 25 (24%) Table IB. Siropack mask (HME filter) 15 (14%) Ocean Reef Aria (P3 industrial filter) 10 (9%) Operator feedback about the MFFSM during surgical Seac Unica (HME filter) 56 (53%) procedures was presented in Table II and plotted in Figure 5. Ease of wearing, comfort and fitting, achieved a Table IB. Number and type of surgical and anesthesiologic procedures in OR. median score of 9. Number of surgical and anesthesiologic procedures N = 50 Central vision quality showed a median value of 9, whereas ENT surgery 35 (70%) the median score for lateral vision was 7. Despite the mean Anaesthesiologic procedures 15 (30%) excellent outcomes, both Decathlon masks, especially the Role of surgeon/operator first model, caused optical distortion at the converging gaze Intubation 15 (30%) First surgeon 19 (38%) and was given a low score. Second surgeon 7 (14%) The absence of condensation inside the mask was reported Third surgeon 9 (18%) by 94% of operators. On the other hand, the presence of Type of anaesthesia condensation drops inside the chin valve was reported by General anesthesia 48 (96%) some operators using Decathlon masks, especially after Local anaesthesia 2 (4%) prolonged use (> 40 minutes), but did not interfere with the Type of procedures Tracheotomy 19 (38%) procedures. Ninety-six percent of testers did not complain Oro-tracheal intubation 15 (30%) of localised pressure or facial sores after use of the mask. Hemi-thyroidectomy 5 (10%) Parotidectomy 5 (10%) Total thyroidectomy 4 (8%) Operator feedback by mask Neck dissection 1 (2%) Differences in parameters between all masks used in Transoral robotic surgery 1 (2%) surgical settings are reported in Table IIIA. Mean time of surgical procedures (min)* 55.9 The quality of communication with the teams through Standard deviation 45.5 the mask showed a significant difference in terms of Higher value 180 Lower value 5 effectiveness between the Siropack vs Decathlon masks Median 40 (p = 0.04). By contrast, the Siropack model was felt to *Seac mask was excluded from statistical analysis because it was not used in surgical procedures. have a greater perceived weight compared to the others

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Figure 5. Box plot; operator feedback on the use of modified full-face snorkelling masks (Seac Unica excluded).

Table IIIA. Operator feedback: differences between modified Decathlon, Siropack, and Ocean Reef masks. Modified Decathlon mask Siropack mask Ocean Reef mask p Time of surgery 48.0 ± 55.8 55 ± 36.3 53.5 ± 18.7 > 0.05 Ease of wearing 9.4 ± 1 8.9 ± 0.7 9.5 ± 0.5 > 0.05 Comfort and fitting 8.7 ± 1.8 8.1 ± 0.7 9.1 ± 0.7 > 0.05 Central vision quality 8.8 ± 1.7 8.3 ± 2.2 9 ± 0.8 > 0.05 Lateral vision quality 7± 2.8 6.5 ± 1 6.8 ± 0.7 > 0.05 Optical distortion of the surgical field 2.9± 2.7 2.4 ± 1.1 3.1 ± 2.2 > 0.05 Difficulty in breathing 2.9 ± 2.9 2.7 ± 2.3 2.1 ± 2.4 > 0.05 Perceived weight of the mask 2.9 ± 2.4 5.8 ± 1.1 1.8 ± 0.5 0.03 * Communication with team during surgery**** 3 ± 0.9 4.1 ± 0.7 3.8 ± 0.7 0.04 ** 0.3 *** * Siropack vs decathlon and Ocean Reef mask; ** Siropack vs decathlon; *** Siropack vs Ocean Reef mask; **** all items except “time of surgery” were scored with a numerical rating scales of VAS = 0-10; “communication with team during surgery” was scored with a numerical rating scale of VAS = 0-5; Table IIIB; Operator feedback using modified Seac Unica in ICU procedures.

(p = 0.03) due to the integration of a microphone and Central vision quality with the Seac Unica mask showed external amplificatory system (Tab. IIIA). a mean value of 9.1, lateral vision quality of 9 and optical On the other hand, concerning the remaining items, no distortion of 8 (Tab. IIIB). significant differences were seen between Siropack and Table IIIB. Operator feedback using modified Seac Unica in ICU procedures. OceanReef masks. Average value Median During pO /pCO monitoring with the Ocean Reef model, 2 2 Ease of wearing 8.2 ± 2.3 9 the mean value of pO was 96.8 mmHg and the mean of the 2 Comfort and fitting 9.1 ± 1.4 9 highest pCO values recorded was 37.1 mm H O, which 2 2 Central vision quality 9.1 ± 1.2 9 was within the normal range (p < 40 mm H O). 2 Lateral vision quality 9.0 ± 1.6 9 Notably, ICU operators performed more than one procedure Optical distortion 2.0 ± 2.0 1 without removing the mask. Each procedure took a mean Difficulty in breathing 2.6 ± 2.0 2 time of 25 minutes, while the mean total wearing time Perceived weight of the mask 3.5 ± 2.4 3 was 4 hours. Condensation was reported only by operators Communication with team 4.2 ±1 4 wearing the mask for more than 4 hours, which did not, * all items were scored with a numerical rating scales of VAS = 0-10; “communication however, interfere with the procedures. with team” was scored with a numerical rating scale of VAS = 0-5.

322 Modified full-face snorkel masks for intraoperative protection

Discussion circulation in the mask. However, due to the similar structure of all devices analysed, this objective parameter is likely to be The COVID-19 pandemic, worldwide, was characterised in its similar to the other masks as well. first phase by a shortage of PPE, especially high-performance However, comparison between MFFSMs and other filtering masks FFP2 and FFP3 for healthcare workers (HCW). conventional protective devices must be carefully taken into For this reason, industrial PPE devices (mask, filters, goggles) account. FFP2-3 masks, for instance, loose their filtering are tested and commonly employed for COVID-19 patients in efficacy if they wet due to fluid penetration in the fabric; hospitals and more generally in healthcare systems. therefore, in case of incomplete face sealing, viral inhalation It is also extremely important to underline that all could not be excluded. Moreover, the need for FFP2-3 masks HCW performing trans-nasal and trans-oral endoscopic to be disposable increases both costs and problems related to examinations (i.e. pharyngo-laryngoscopy, bronchoscopy, their disposal. 6 etc.) are exposed to the highest risk of infection . Therefore, an Surgical goggles usually limit the vision inferiorly and laterally, adequate prevention of risk should be adopted, starting from often become foggy and cause significant discomfort. Face the assumption that all patients are potentially infected with shields can be cumbersome, without adequate ventilation. SARS-CoV-2 until proven otherwise. On the basis of our experience, the utilisation of a single For these reasons, the scientific community has punctually full-face protection device such as a MFFSM instead of a reported detailed international protocols and recommendations combination of a FFP2 mask and goggles seems to be more to minimise the risk of viral diffusion and infection, including user-friendly. Moreover, the respiratory fit test of the MFFSMs the observance of specific surgical and anaesthesiologic seems to be much more reliable than the respirator fit test of a procedures, new surgical team settings and constant use of conventional FFP2 mask. 12,13 adequate PPE . The wide range of responses for items related to the comfort In this dramatic scenario, the development of new PPE may reflect the less well-defined concept of “comfort” and devices is mandatory to guarantee all HCW the safest level of individual sensitivity to a claustrophobic feeling induced by protection and comfort. Our study focused on the validation prolonged use of the device, but no significant differences of MFFSMs as safe and protective equipment against SARS- were seen among the different models. CoV-2 infection, testing and both judging subjectively The optical properties of the masks may play a key role in their and objectively the efficacy and usability of these personal effective use in a surgical setting. Central vision was described and customised devices during diagnostic and therapeutic as sufficient by most operators, but the masks were rated as procedures on the upper aerodigestive tract. critical in terms of lateral view, which is much less important All tests were performed in patients who were confirmed to during intubation manoeuvers. Different amounts of optical be SARS-CoV-2 negative. The aim of the study was to test distortion were described for all the MFFSMs, such as barrel, the feasibility of the masks before using them on COVID-19 pincushion, and mustache, which is related to the different positive cases. shapes of the transparent shield of the masks. However, the All the masks tested are currently available on the market, optical distortion value was rated as non-critical for all masks. and significant differences in the quality among the devices Some breathing difficulty was reported by operators using all were not seen. types of MFFSM, which is probably related to the strength All MFFSMs tested were easy to use and gave all operators a of air flow of the respiratory system which is plugged by a sound “feeling” of protection. It is also worth mentioning that filtering membrane. The moderate increase in dyspnoea was the average score of the item related to the ease of wearing mainly related to individual sensitivity and use of a double showed a median value of 9. filter vs a single filter. The actual viral filtration capability was not tested and was not Furthermore, all MFFSM originally designed for snorkelling the goal of the present study. However, the filtering power of did not allow the use of loupes or even normal glasses. In light the system is based on the anaesthesiologic and professional of this, an integrated magnification system and lighting would filters, which are certified and widely used for a long time. The be useful, especially for specialists facing with diseases of the immediate possibility to combine commercial snorkelling masks upper airways. This issue could be overcome by customised with dedicated filters renders MFFSMs a safety emergency tool development of a new mask that is specific for clinical and than can be successfully and immediately employed. surgical needs.

The values of pCO2 were tested only for the OceanReef Another critical issue of extreme importance to be considered mask, which were always within normal ranges throughout in future is to decrease, as much as possible, the weight of the the procedure, objectively showing the stability of respiratory device, even with the integration of different accessories, to parameters that indicate correct breathing and normal air avoid discomfort and neck fatigue.

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All MFFSM evaluated are immediately available and may be Zanchini a group of very talented and enthusiastic dreamers. considered to be a practical emergency solution for personal A special mention for Siropack owners Rocco De Lucia e protection in the operating room and ICU for Head and Barbara Burioli. They provided for free most of the masks Neck and Anaesthesiologist teams during the COVID-19 included in the study. A special thanks to Eng. Gamberini, pandemic. MFFSMs could play a key role in the emergency manager of the Ocean Reef Company, a leader for individual when conventional PPE (FPP2 or FPP3, transparent shields protection systems and to Dr. Princi, Project manager for their or goggles) is not immediately available or are in shortage. support for this project. We would like to express our sincere All the teams included in the study considered MFFMs to be gratitude to Mr. Arata Daniele, President of Seac-Group for a valid and interesting alternative option, even in the case that supporting our research, providing us novel and valuable conventional PPE is available. insights for clinical practice. We are also grateful to Istituto All models provided a waterproof barrier for the eyes, nose and Italiano di Tecnologia (IIT) staff in the figures of engineer mouth, which means for the entire face. The internal sealed Michele Gesino (Senior Technician) and engineer PhD Luca respiratory space is filtered by certified devices, giving the Fiorio (Chief Technician). user a reasonable level of biological safety, awaiting official certification. Breathing in the mask seems to be perceived in References a different way by different surgeons, and sometimes with 1 Istituto Superiore di Sanità. Epicentro. Sorveglianza integrata COVID-19 some degree of discomfort. The visualisation of the surgical in Italia. https://www.epicentro.iss.it/coronavirus/sars-cov-2-sorveglianza- field with MFFMs could allow the surgeon to perform regular dati [published 17 April 2020 - accessed April 17, 2020]. activities in wide variety of surgical and anaesthesiologic 2 Morawska L, Cao J. Airborne transmission of SARS-CoV-2: the world should face the reality. Environ Int 2020;139:105730. https:// situations, including selected lengthy and demanding doi.org/10.1016/j.envint.2020.105730 surgeries. Illumination and voice communication system were 3 Fineberg HV. Rapid expert consultation on the possibility of bioaero- only available in one MFFSM, which are recommended in sol spread of the SARS CoV-2 for the COVID-19 pandemic (April 2020) In: The national Academic Press NRC. Washington DC: The the future. Nevertheless, a heavier MFFSM is the price to pay national Academic Press National Research Council; 2020. to include a double filter option and an integrated system of 4 Meselson M. Droplets and aerosols in the transmission of SARS- illumination and communication. CoV-2. N Engl J Med 2020;382:2063. https://doi.org/10.1056/NE- JMc2009324 5 van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface Conclusions stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med 2020;382:1564-7. https://doi.org/10.1056/NEJMc2004973 In addition to the required certifications, which will take 6 Meccariello G, Gallo O. What ENT doctors should know about a reasonably long time for official approval by different COVID-19 contagion risks. Head Neck 2020;42:1248-9. https://doi. authorities, all the clinicians had common agreement for org/10.1002/hed.26190 strongly recommended improvements: 7 Ranney ML, Griffeth V, Jha AK. Critical supply shortages - the need for ventilators and personal protective equipment during the 1. a more customised mask for medical and surgical needs; COVID-19 pandemic. N Engl J Med 2020;382:e41. https://doi. 2. a fundamental requisite should be the possibility to use per- org/10.1056/NEJMp2006141 sonal glasses inside the mask; 8 van Straten B, de Man P, van den Dobbelsteen J, et al. Sterilization 3. a miniaturised microphone/loudspeaker system is recom- of disposable face masks by means of standardized dry and steam sterilization processes; an alternative in the fight against mask short- mended for all medical activities; ages due to COVID-19. J Hosp Infect 2020;20:30176-6. https://doi. 4. for special activities (ENT, oral surgeons, plastic surgery, org/10.1016/j.jhin.2020.04.001 etc.), an integrated head lamp and possibly a magnifying 9 Swennen GRJ, Pottel L, Haers PE. Custom-made 3D-printed face masks in case of pandemic crisis situations with a lack of commercial- loupe system would be valuable. ly available FFP2/3 masks. Int J Oral Maxillofac Surg 2020;49:673-7. In the future, continuous cooperation and close interaction https://doi.org/10.1016/j.ijom.2020.03.015 between clinicians and engineers will offer more performing 10 Liu DCY, Koo TH, Wong JKK, et al. Adapting reusable elastomeric res- devices for different branches of the healthcare system. pirators to utilise anaesthesia circuit filters using a 3D-printed adaptor; a potential alternative to address N95 shortages during the COVID-19 pan- Clinicians will be able to better define their needs and demic. Anaesthesia 2020;75:1022-7. https://doi.org/10.1111/anae.15108 priorities, while manufacturers will focus on production of 11 Greig PR, Carvalho C, El-Boghdadly K, et al. Safety testing impro- devices that meet all medical requirements. vised COVID-19 personal protective equipment based on a modi- fied full-face snorkel mask. Anaesthesia 2020;75:970-1. https://doi. org/10.1111/anae.15085 Acknowledgements 12 European Centre for Disease Prevention and Control. https://www. ecdc.europa.eu/en/covid-19-pandemic Thanks to Mr. Salvatore Tabone, Dr. Marco Brancaleoni, Dr. 13 Società italiana di Otorinolaringologia e Chirurgia-Cervico Facciale. Filippo Bosco e Mr. Calogero Sorce, and engineer Lorenzo https://www.sioechcf.it/news-covid-19

324 ACTA OTORHINOLARYNGOLOGICA ITALICA2020;40:325-331; doi: 10.14639/0392-100X-N0832

COVID-19 Impact of COVID-19 pandemic on Italian Otolaryngology Units: a nationwide study Impatto della pandemia COVID-19 sulle Unità Operative di Otorinolaringoiatria in Italia: uno studio nazionale Giuditta Mannelli1,2, Massimo Ralli1,3, Marco Bonali1,4, Pasquale Capasso1,5, Pierre Guarino1,6, Valeria Iannini1,7, Niccolò Mevio1,8, Gennaro Russo1,5, Alfonso Scarpa1,9, Giacomo Spinato1,10, Davide Topazio1,11, Gabriele Molteni1,12 1 COVID-19 Task Force of the Young Otolaryngologists of the Italian Society of Otolaryngology Head and Neck Surgery; 2 Head and Neck Oncology and Robotic Surgery, Department of Experimental and Clinical Medicine, University of Florence, Italy; 3 Department of Sense Organs, Sapienza University of Rome, Italy; 4 Otolaryngology Head and Neck Surgery Department, University of Modena, Italy; 5 Otolaryngology, Head and Neck Surgery Unit AO dei Colli, Monaldi Hospital, Napoli, Italy; 6 Otorhinolaryngology, Head and Neck Surgery Unit “Santo Spirito” Hospital of Pescara, Italy; 7 Otolaryngology Department, Dipartimento Strutturale Ospedaliero Chirurgico di Rovigo ULSS 5, Rovigo, Italy; 8 Department of Otolaryngology Niguarda Hospital, Milano, Italy; 9 Department of Medicine and Surgery, University of Salerno, Italy; 10 Department of Neurosciences, Section of Otolaryngology and Regional Centre for Head and Neck Cancer, University of Padova, Treviso, Italy - Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, Italy; 11 Otolaryngology Department, Ospedale Mazzini, Teramo, Italy; 12 Otolaryngology, Head and Neck Surgery Unit, University Hospital of Verona Borgo Trento, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, Italy

SUMMARY Received: May 7, 2020 Objective. The aim of this study was to provide an accurate picture of the changes which Accepted: May 21, 2020 have occurred during the COVID-19 pandemic, and the contributions given by Italian Published online: September 24, 2020 Otolaryngology Units. Methods. A 29-item questionnaire was completed and returned by 154 Otorhinolaryngology Correspondence Units across Italy that investigated geographic distribution, the main changes which Giuditta Mannelli occurred in workload management and in clinical and surgical activities and screening Head and Neck Oncology and Robotic Surgery, Department of Experimental and Clinical Medicine, procedures for COVID-19 in healthcare personnel and patients. University of Florence, largo Brambillla 3, Results. Nearly half of the Otolaryngology Units that responded to the questionnaire 50134 Florence, Italy were merged with other units, while 22% were converted into COVID-19 units or Tel. +39 055 794 5489 temporarily closed. A reduction of 8.55% in the number of team members was reported, E-mail: [email protected] and about 50% of the units applied uniform work shifts for all staff. Elective activities were uniformly stopped or delayed, passing from 30,295 (pre-COVID data) to 5,684 Funding (COVID data) weekly procedures, with a mean decrease of 81.24% (p < 0.001). None. Conclusions. Most of the elective otolaryngology activities were suspended during the pandemic; the only procedures were for oncology and emergency patients. Italian Conflict of interest Otolaryngologists have demonstrated a high availability to collaborate with non-surgical The Authors declare no conflict of interest. colleagues. KEY WORDS: COVID-19, otolaryngology, SARS-CoV-2, pandemic How to cite this article: Mannelli G, Ralli M, Bo- nali M, et al. Impact of COVID-19 pandemic on Italian Otolaryngology Units: a nationwide stu- RIASSUNTO dy. Acta Otorhinolaryngol Ital 2020;40:325-331. Obiettivo. Fornire un quadro accurato dei cambiamenti che si sono verificati e dei contri- https://doi.org/10.14639/0392-100X-N0832 buti forniti dalle Unità di Otorinolaringoiatria italiane durante la pandemia COVID-19. Metodi. Un questionario di 29 domande è stato completato da 154 unità. Sono stati inve- © Società Italiana di Otorinolaringoiatria stigati la distribuzione geografica del loro coinvolgimento, i cambiamenti di gestione del e Chirurgia Cervico-Facciale carico di lavoro e delle attività clinico-chirurgiche e le procedure di screening applicate su personale sanitario e pazienti. OPEN ACCESS Risultati. Quasi la metà delle Unità che hanno risposto sono state fuse con altre unità opera- This is an open access article distributed in accordance with tive, mentre il 22% è stato convertito in unità COVID-19 o temporaneamente chiuso. È stata the CC-BY-NC-ND (Creative Commons Attribution-Non- segnalata una riduzione dell’8,55% nel numero dei membri del gruppo di lavoro e circa il 50% Commercial-NoDerivatives 4.0 International) license. The dei dipartimenti ha applicato turni di lavoro per tutto il personale. Tutte le attività elettive sono article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and state uniformemente interrotte o ritardate, passando da 30.295 (dati pre-COVID) a 5.684 (dati only in the original version. For further information: https:// COVID) procedure settimanali, con una diminuzione media dell’81,24% (p < 0,001). creativecommons.org/licenses/by-nc-nd/4.0/deed.en

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Conclusioni. La maggior parte delle attività elettive in otorinolaringoiatria, a parte le procedure oncologiche e di emergenza, sono state sospese. Gli otorinolaringoiatri italiani hanno dimostrato un’alta disponibilità a collaborare con i reparti di medicina. PAROLE CHIAVE: COVID-19, otolaringoiatria, SARS-CoV-2, pandemia

Introduction a questionnaire administered to Italian Otolaryngology Units. The ongoing pandemic of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection, also known as COVID-19, has spread rapidly worldwide since Materials and methods 1 the first cases in Wuhan, China . The first cases in Italy were This study was performed by the COVID-19 Task Force diagnosed in Rome on January 29, 2020, when two Chinese of the Italian Young Otorhinolaryngologists (GOS). On tourists tested positive for the virus and were hospitalised April 16, 2020, a 29-item questionnaire was sent by e-mail st and isolated at Spallanzani Hospital. On January 31 , the to all Otolaryngology Units in Italy (n = 296); each unit was Italian government declared a national emergency. asked to respond within 4 days and the final compilation Since the first case of an Italian patient affected by deadline was set as April 22, 2020. Data were subsequently COVID-19 in the town of Lodi, Lombardy, the number of collected and compiled anonymously in a unified dataset. patients and related deaths in Italy progressively increased 2. Duplicates, when present, were removed. In fact, despite attempts to limit the outbreak at the primary The questionnaire investigated three major aspects of cluster of infections by quarantining citizens and isolating Italian Otolaryngology Units during the pandemic: the area, similar cases were progressively diagnosed in other 1. the geographic distribution of respondent units; cities and neighboring regions, such as Veneto and Emilia- 2. the main changes in workload management and Romagna, without evidence of any epidemiologic correlation to the first case. Since then, the COVID-19 infection spread distribution in terms of outpatient and inpatient procedure across the country despite the containment measures applied volumes; by the Italian government, making Italy one of the worst 3. COVID-19 screening procedures for patients and hit countries with more than 214,457 confirmed cases and healthcare workers. 29,684 deaths reported as of May 7, 2020 3. On March 11, According to the Italian Instituto Superiore di Sanità (ISS) 9 2020, the Director-General of the World Health Organization data , Italian regions were divided into five zones based on (WHO) declared COVID-19 a pandemic 4. the total number of cases as follows: 1) > 20,000 (Lombardia, In the last two months, the Italian National Healthcare Emilia-Romagna); 2) 10,000-20,000 (Piemonte, Veneto); System has undergone multiple changes to face the 3) 3,000-10,000 (Toscana, Marche, Lazio, Provincia pandemic, with closure or conversion of many units and Autonoma di Trento, Campania, Puglia, Liguria); 4) 1,000- hospitals into units solely dedicated to the treatment of 3,000 (Abruzzo, Friuli Venezia Giulia, Umbria, Provincia COVID-19 patients 5. Most elective outpatient clinical and Autonoma di Bolzano, Sicilia, Valle D’Aosta, Sardegna); surgical procedures were delayed or suspended, allowing 5) < 1,000 (Molise, Calabria, Basilicata). the confluence of most of the resources towards Emergency Departments, Infectious Diseases Units, Respiratory Statistical analysis Disease Units and Intensive Care Units (ICUs) 6,7. Descriptive analysis was used to define the main clinical In this setting, although Otolaryngology-Head and Neck and demographic characteristics based on the responses surgeons were not in the frontline of action, they were asked to to the questionnaire. Unpaired T test was used to evaluate contribute in managing patients with upper airway impairment, differences for numeric values. A p-value less than 0.05 provide basic assistance, perform screening procedures (i.e. was considered the cutoff for statistical significance. Prism upper airway swab) and perform temporary tracheotomies in Software version 8.3.1 (GraphPad Software LLC) was used ICUs. This new arrangement implied a significant change in to perform statistical analysis. otolaryngology activities across the country 8. The aim of this nationwide study, in accordance with the Results Italian Society of Otolaryngology Head and Neck Surgery (SIOeChCF), was to provide a picture of the changes One-hundred fifty-four Otolaryngology Units (52%) and contributions of otolaryngologist specialists during completed the questionnaire; 134 (87%) units were public the COVID-19 pandemic over the last 2 months through and 20 (13%) were private and/or affiliated health facilities.

326 Geographic distribution and changes in the workload management

Geographic distribution of respondent Italian (45.5%) were merged with other units, and 10.4% were Otolaryngology Units temporarily closed. Interestingly, no changes were reported Lombardy represented the region with the highest number by 10.4% of the units, while 11.6% were converted into of Otolaryngology Units that replied to the questionnaire, COVID-19 wards. A significant reduction in hospital while the lowest response rates were registered in Trentino beds was reported by the remaining units (22.1%). Table I Alto Adige, Valle d’Aosta and Molise. Figure 1 reports the summarises the activity changes sorted by zone. geographic distribution of respondent units. Figure 2 shows A reduction in the number of team members was reported, the division of zones and the number of responses received and its percentage change during the pandemic was from each zone. Thirty-eight responses were received from compared to the pre-COVID-19 setting. A decrease of units in zone 1, 27 from units in zone 2, 60 from zone 3, 21 6.07% was recorded in the total number of otolaryngology from zone 4 and 8 from units in zone 5. specialists belonging to the 154 units, which declared Based on the responses received, the majority of units a pre-COVID staff number of 1,136 specialists which was reduced to 1,067 during the state of emergency. The difference was not statistically significant (p = 0.364). In addition, the number of residents on duty was reduced from 465 to 397 (percentage reduction: 14.6%; p = 0.054). The reduction in each unit was proportional to work shift changes applied by each zone (Tab. II). Interestingly, nearly 70% (107/154) of the respondents declared a reallocation of staff members to Internal Medicine COVID-19 Units (52/107 - 48.6%), emergency departments (20/107 - 18.7%), ICUs (9/107 - 8.4%), respiratory disease units (7/107 – 6.5%), other services (7/107 - 6.5%), Internal Medicine non-COVID-19 Units (5/107 - 4.7%), infectious disease wards (5/107 - 4.7%) and basic assistance services (2/107 - 1.9%) (Fig. 3). The highest percentage of reallocated colleagues was present in zone 1 (46.7%), and these showed a progressive reduction passing from 20.5% in zone 2 and 23.4% in zone 3, to less than Figure 1. Representation of the response rate to our questionnaire sorted by 10% in zones 4 and 5 (6.5% and 2.9%, respectively). region. The total number of responses is reported on the abscissa axis, while the ordinate axis indicates the 20 Italian regions. In this setting, 48% and 50% of reallocation changes to Internal Medicine COVID-19 Units and Emergency Departments, respectively, occurred in zone 1, while units in zone 2 reported the majority of reallocations to Internal Medicine non-COVID-19 Units (Tab. III).

Main changes in workload management and distribution in terms of outpatient and inpatient procedure volumes The questionnaire results showed a significant decrease in otolaryngology activities across the country during the pandemic with no substantial differences among the five zones. Outpatient visits showed a significant decrease in number of procedures per week (80.54%; p < 0.0001), passing from a pool of 26,035 evaluations usually performed during the pre-COVID-19 period to 5,067 registered outpatient procedures during the COVID-19 pandemic. A similar reduction (89.91%; p < 0.0001) was recorded for A B outpatient surgical procedures (i.e. surgical procedures under local anaesthesia) and for inpatient surgical Figure 2. Graphical representation of (A) the distribution of COVID-19 positive cases in Italian regions (ISS, April 16, 2020); and (B) the response rate to our ques- procedures that decreased from 2,823/week to 472/week, tionnaire sorted by the five zones identified according to the total number of cases. a reduction of 83.28% (p < 0.0001). A detailed summary

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Table I. Activity changes in Otolaryngology Units sorted by zone. Zone Changes in clinical practice in the 154 units Total No change Reduction in beds Merged with other units Converted into COVID-wards Temporarily closed 1 1 5 17 10 5 38 (24.7%) 2 4 9 9 4 1 27 (17.5%) 3 6 16 29 3 6 60 (39%) 4 5 3 10 1 2 21 (13.6%) 5 0 1 5 0 2 8 (5.2%) Total 16 (10.4%) 34 (22.1%) 70 (45.5%) 18 (11.6%) 16 (10.4%) 154 (100%)

Table II. Number of staff members sorted by zone and work shift changes. Zone Number of specialists and residents Work shifts during COVID-19 Pre- During Difference P Not Applied for Applied for Applied for Total COVID COVID (%) applied all of the members specialists only residents only 1 419 378 9.79% 0.645 16 21 0 1 38 2 330 309 6.36% 0.096 10 13 2 2 27 3 587 540 8.01% 0.217 20 28 9 3 60 4 227 203 10.57% 0.984 6 11 2 2 21 5 38 34 10.53% 0.677 4 3 1 0 8 Total 1,601 1,464 8.55% 0.069 56 (36.4%) 76 (49.4%) 14 (9%) 8 (5.2%) 100% of procedures performed per week in each zone and the Among the different types of surgery, only a small percentage corresponding percentage reduction is shown in Figure 4 of respondent units declared a reduction in head and neck and described by Table IV. and emergency surgical procedures (10.74% and 3.54%, respectively). On the other hand, the vast majority declared a drastic reduction in endoscopic sinonasal procedures (98.53%), paediatric otolaryngology surgery (97.59%) and ear surgery (94.90%). All elective surgical procedures (100%) were suspended uniformly across the country (Tab. V). In this setting, upper airway management and tracheostomy procedures were performed by 42.86% of units, while the remaining 57.14% declared that they were not involved in airway management procedures for COVID-19 patients. The vast majority of the units (70.94%) declared that the percutaneous tracheostomy technique was predominant over the surgical one in their hospitals. When asked about Figure 3. Reallocation of otolaryngology team members to other depart- the timing of tracheostomy procedures the majority of ments during the pandemic. Otolaryngology Units performed this after more than 14 days

Table III. Reallocation of physicians sorted by zone. Zone Reallocation to different departments Internal Internal Emergency Intensive Infectious Respiratory Basic Others Total Medicine Medicine Department Care Units Disease Units Disease Units assistance COVID non-COVID 1 25 0 10 6 3 3 1 2 50 (46.7%) 2 10 4 2 2 0 2 1 1 22 (20.5%) 3 11 1 6 1 1 2 0 3 25 (23.4%) 4 5 0 0 0 1 0 0 1 7 (6.5%) 5 1 0 2 0 0 0 0 0 3 (2.9%) Total 52 (48.6%) 5 (4.7%) 20 (18.7%) 9 (8.4%) 5 (4.7%) 7 (6.5%) 2 (1.8%) 7 (6.6%) 107 (100%)

328 Geographic distribution and changes in the workload management

Figure 4. The number of outpatient visits, outpatient surgical procedures, and inpatient surgical procedures comparing pre-COVID and during-COVID variation.

Table IV. Otolaryngology procedures before and during COVID-19 pandemic. Zone Otolaryngology procedures (difference %) Total (difference %) Outpatient Outpatient P Outpatient Outpatient P Inpatient Inpatient P Procedures Procedures P visits visits surgery surgery surgery surgery before during before during before during before during COVID COVID COVID COVID COVID COVID COVID COVID 1 7,702 1,341 < 0.0001 375 34 (90.9%) < 0.0001 841 123 < 0.0001 8,918 1,498 < 0.0001 (82.6%) (85.4%) (83.2%) 2 5,912 1,272 < 0.0001 303 31 (89.8%) < 0.0001 573 111 < 0.0001 6,788 1,414 < 0.0001 (78.5%) (80.6%) (79.2%) 3 8,470 1,734 < 0.0001 506 42 (91.7%) < 0.0001 1,011 164 < 0.0001 9,987 1,940 < 0.0001 (79.5%) (83.8%) (80.6%) 4 3,147 620 < 0.0001 192 33 (82.8%) 0.0013 317 69 < 0.0001 3,656 722 0.0002 (80.3%) (78.2%) (80.2%) 5 805 100 0.0006 61 5 (91.8%) 0.081 81 5 0.003 947 110 0.0203 (87.6%) (93.8%) (88.4%) Total 26,036 5,067 < 0.0001 1,437 145 < 0.0001 2,823 472 < 0.0001 30,296 5,684 < 0.0001 (80.5%) (89.9%) (83.3%) (81.2%)

Table V. Percentage of variation in different types of surgical procedures during the COVID-period in comparison to the pre-COVID period. Period Head and neck oncology Emergency Sinonasal Pediatric otolaryngology Ear Basic otolaryngology surgery procedures surgery surgery surgery surgery Pre-COVID 121 113 136 83 98 141 During COVID 108 109 2 2 5 0 Percentage 10.74% 3.54% 98.53% 97.59% 94.90% 100% reduction (%) of endotracheal intubation (38.5%), followed by 11-14 days screening procedures were performed for both patients and (27.7%), 7-10 days (26.1%) and 3-6 days (7.7%) (Fig. 5). healthcare workers, and all of the departments performed screening procedures for inpatients scheduled for surgery. COVID-19 screening procedures for patients About 20% of otolaryngology specialists in the respondent and healthcare workers units tested positive for COVID-19 screening tests; the In total, 35.71% of the respondent units declared that a highest percentages of cases were recorded in zones 1 and HUB hospital was identified in their region to treat non- 2 (34.21% and 29.63%, respectively). COVID-19 patients. In detail, 68.42% of HUBs were located in zone 1, while zones 2, 3 and 4 declared significantly Discussion smaller percentages in their regions (22.22%, 33.33% and 4.76%, respectively). Interestingly, zone 5 recorded the Since the outbreak of the COVID-19 pandemic, the Italian highest percentage of HUBs (75%), although this data may National Healthcare System abruptly reduced elective be biased by the low number of respondents from this zone. services to redirect resources to the units most affected The majority of the units (72.73%) declared that COVID-19 by the pandemic. This has translated into a significant

329 G. Mannelli et al.

A B

Figure 5. (A) surgical and percutaneous tracheostomies; and (B) timing of surgical tracheostomies (days after intubation). reorganisation of the system which required immediate changes was recorded with a superimposable percentage efforts by all workers throughout the country. reduction in staff members. On the other hand, specialist The results of this study confirm that clinical and surgical reallocations to other units were mainly recorded in zone 1, activities radically changed in Otolaryngology Units demonstrating the greater reorganisation made in the across the country. According to the responses to our Lombardy and Emilia-Romagna regions 15. questionnaire, more than one-fifth (22%) of the units were COVID-19 cases are not distributed homogenously in Italy, converted or temporary closed, with a progressive and therefore a different rate of activity change was expected in significant reduction according to the zone passing from Otolaryngology Units across the country. Instead, we did 39.5% in zone 1, to 18.5% in zone 2, 15% in zone 3, 14% not notice relevant differences in reductions in outpatient in zone 4 and 25% in zone 5. evaluations and surgical cases among units in different The consequent marked reduction in outpatient and surgical regions. This shows a great sense of responsibility by the services per week (81.24%) confirms that a significant Italian National Healthcare System, which stopped elective response to the crisis was provided by Otolaryngology activities even in less affected areas. Units; however, this also meant a reduction of nearly 80,000 Tracheostomy is a common procedure for patients admitted outpatient visits and almost 10,000 surgical procedures per to ICUs with acute respiratory distress and with difficult month. This might have dangerous consequences for the weaning. During the pandemic, many countries published health status of the population and a difficult-to-manage their own guidelines, including the Italian Society of workload in the near future 10,11. Otolaryngology and Head & Neck Surgery (SIOeChCF) 16. The activities that were guaranteed during the pandemic Nonetheless, guidelines about timing and technical were oncology and emergency procedures. In this scenario, procedures for tracheostomy are still lacking. Indications it would be fair to assume an increase in overall numbers and experiences have been published by Italian groups 17,18, of these procedures. Nonetheless, the results revealed that but many questions remain about which technique should be even these procedures decreased by nearly 10% across preferred (surgical or percutaneous) and the correct timing the country. The reduction of emergency procedures to perform tracheostomies in COVID-19 patients. Experience may be explained by the total lockdown that kept the gained from previous severe acute respiratory syndrome majority of people at home, thus reducing risk factors for coronaviruses (SARS-CoV and MERS-CoV) and from otolaryngology emergencies (abscess, bleeding, nasal bone SARS-CoV-2 demonstrated that nurses and physicians who fractures, laryngeal oedema). On the other hand, head and deal with infected patients are at high risk of infection; among neck cancer cannot be influenced by the lockdown, and physicians, otolaryngologists have been identified as having some recent articles suggest continuing treating cancer as the highest risk of contracting COVID-19 19. Tracheostomy before but including some safety measures for healthcare has been demonstrated not to change the course of the workers and patients 12-14. The reduction observed may disease and is among the most dangerous procedures be due to the reduced number of beds and personnel in for surgeons. For these reasons, many authors suggest Otolaryngology Units, and might result in more advanced- performing tracheostomy after a longer intubation time. So stage oncology cases in the near future. far, the surgical technique seems to be safer compared with Despite the five zones identified according to the total the percutaneous approach since airway opening is short and number of COVID-19 cases, a homogenous distribution of controlled with the cuffed tube placed caudally to the trachea

330 Geographic distribution and changes in the workload management

opening. Some modifications to the well-known percutaneous 3 https://COVID19.who.int techniques have been proposed to minimise the risk related to 4 WHO. Virtual press conference on COVID-19. March 11, 2020. COVID-19 infection 20. These uncertainties are reflected in https://www.who.int/docs/default-source/coronaviruse/transcripts/ who-audio-emergencies-coronavirus-press-conference-full-and-fi- Figure 5, where differences in terms of technique and post- nal-11mar2020.pdf?sfvrsn=cb432bb3_2 intubation day are revealed. Another consideration is related 5 Zangrillo A, Beretta L, Silvani P, et al. Fast reshaping of intensive care to the high volume of patients admitted to ICUs in some unit facilities in a large metropolitan hospital in Milan, Italy: facing hospitals during the first month of pandemic spread; in this the COVID-19 pandemic emergency. Crit Care Resusc 2020;22:91-4. 6 setting, an elevated number of tracheostomies was motivated Grasselli G, Pesenti A, Cecconi M. Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and fore- by the necessity for rapid weaning and transfer of patients to cast during an emergency response. JAMA 2020;323:1545-6. https:// sub-intensive care units. doi.org/10.1001/jama.2020.4031 This Italian nationwide study showed that otolaryngologists 7 Cascella M, Rajnik M, Cuomo A, et al. Features, evaluation and treat- have a high risk of contracting SARS-CoV-2. According to ment coronavirus (COVID-19). [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Avail- our data, more than 20% of Otolaryngology Units have had able from: https://www.ncbi.nlm.nih.gov/books/NBK554776/?elqTrackI physicians with positive nasal swabs; this percentage was d=acb127f200d54529bf1a65898f737ab7&elqaid=3961&elqat=2 as high as 34% in the more severely affected regions and 8 Ralli M, Greco A, de Vincentiis M. The effects of the COVID-19/ some Italian otolaryngologists have died. SARS-CoV-2 Pandemic outbreak on otolaryngology activ- ity in Italy. Ear Nose Throat J 2020:145561320923893. https://doi. org/10.1177/0145561320923893 Conclusions 9 https://www.epicentro.iss.it/coronavirus/bollettino/Bollettino-sorveg- lianza-integrata-COVID-19_16-aprile-2020.pdf Since the outbreak of COVID-19 in Lombardy and the 10 http://www.governo.it/it/faq-fasedue following WHO declaration of a global pandemic, the Italian 11 Xu K, Lai XQ, Liu Z. Suggestions for prevention of 2019 novel coro- National Healthcare System has struggled to cope with the navirus infection in otolaryngology head and neck surgery medical staff. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020;55:E001. unpredictable load of affected patients. Otolaryngology https://doi.org/10.3760/cma.j.issn.1673-0860.2020.0001 Units have been involved in treating patients who need 12 Chaves ALF, Castro AF, Marta GN, et al. Emergency changes in in- tracheostomy and guaranteeing diagnosis and treatment for ternational guidelines on treatment for head and neck cancer patients oncology and emergency patients. This nationwide study during the COVID-19 pandemic. Oral Oncol 2020;107:104734. htt- showed how prominently phase 1 of the pandemic changed ps://doi.org/10.1016/j.oraloncology.2020.104734 13 Crosby DL, Sharma A. Evidence-Based Guidelines for management the organisation and activity of Otolaryngology Units of head and neck mucosal malignancies during the COVID-19 pan- across the country. Italy is now starting phase 2 with many demic. Otolaryngol Head Neck Surg 2020;163:16-24. https://doi. questions on the strategies to adopt in the near future to org/10.1177/0194599820923623 treat patients and protect healthcare personnel 21. 14 Ansarin M. Surgical management of head and neck tumours during the SARS-CoV (Covid-19) pandemic. Acta Otorhinolaryngol Ital 2020;40:87-9. https://doi.org/10.14639/0392-100X-N0783 Acknowledgements 15 Saibene AM, Allevi F, Biglioli F, et al. Role and management of a Head and Neck Department during the COVID-19 outbreak in Lom- We heartily thank all of the personnel of the Head and bardy. Otolaryngol Head Neck Surg 2020;194599820917914. https:// Neck and Otorhinolaryngology Units who have responded doi.org/10.1177/0194599820917914 to the survey promptly and generously, and we thank our 16 SIOeCHF. La tracheostomia in pazienti affetti da COVID 19. https:// colleagues across the country for their brave commitment www.sioechcf.it/wp-content/uploads/2020/03/ 17 Mattioli F, Fermi M, Ghirelli M, et al. Tracheostomy in the COVID-19 during this unexpected crisis. pandemic. Eur Arch Otorhinolaryngol 2020;277:2133-5. https://doi. A special acknowledgement is due to Professor Mario org/10.1007/s00405-020-05982-0 Bussi, President of the Italian Society of Otolaryngology 18 Pichi B, Mazzola F, Bonsembiante A, et al. CORONA-steps for and Head & Neck Surgery (SIOeChCF), who gave us his tracheotomy in COVID-19 patients: a staff-safe method for airway management. Oral Oncol 2020;105:104682. https://doi.org/10.1016/j. trust and support, and helped to gain widespread consent oraloncology.2020.104682 and cooperation with this investigation. 19 Shiba T, Ghazizadeh S, Chhetri D, et al. Tracheostomy considerations dur- ing the COVID-19 pandemic. OTO Open 2020;4:2473974X20922528. References https://doi.org/10.1177/2473974X20922528 20 Ranganath NK, Malas J, Phillips KG, et al. Single and double lung 1 Wu F, Zhao S, Yu B, et al. A new coronavirus associated with hu- transplantation have equivalent survival for idiopathic pulmonary fi- man respiratory disease in China. Nature 2020;579:265-9. https://doi. brosis. Ann Thorac Surg 2020;109:211-7. https://doi.org/10.1016/j. org/10.1038/s41586-020-2008-3 athoracsur.2019.06.090 2 Horowitz J. Italy’s health care system groans under coronavirus - a 21 SIOeCHF. Piano strategico per la gestione del paziente orl durante warning to the world. New York Times 2020. https://www.nytimes. il periodo di transizione a seguito della pandemia covid 19. https:// com/2020/03/12/world/europe/12italy-coronavirus-health-care.html www.sioechf.it

331 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:332-337; doi: 10.14639/0392-100X-N0790

Review New laboratory predictive tools in deep neck space infections Nuovi indicatori biochimici predittivi di infezioni suppurative cervicali Maria Luisa Fiorella1, Paolo Greco1, Luigi Maria Madami1, Orazio Valerio Giannico2, Vito Pontillo1, Nicola Quaranta1 1 Unit of Otorhinolaryngology, Department of Biomedical Sciences, Neurosciences and Sense Organs, University of Bari, Italy; 2 Section of Hygiene, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy

SUMMARY Introduction. Deep neck space infections (DNSIs) are a group of infective suppurative dis- eases involving deep neck spaces and cervical fascia. Necrotising and septic evolutions are rare, but severe complications can dramatically affect the prognosis and should be promptly managed. Clinical examination often has low sensitivity, although instrumental diagnosis may delay te treatment. We investigated two laboratory tools, LRINEC (Laboratory Risk Indicator for the Necrotizing fasciitis) and NLR (neutrophil to lymphocyte ratio), in the expectation to find a rapidly available predictive indicator that may help in distinguishing necrotising complications and/or systemic septic involvement. Methods. A retrospective observational cohort study was performed on 118 patients who had underwent surgical treatment for DNSIs at our Surgical Unit. LRINEC, NLR and the product LRINEC x NLR were calculated. Results. Statistical analysis showed that these scores may have utility in rapidly predicting the risk of necrotising fasciitis and systemic involvement at an early diagnostic stage. Received: April 9, 2020 Conclusions. Further studies with a larger cohort may be necessary in order to increase the Accepted: May 20, 2020 sensitivity and specificity. Correspondence KEY WORDS: LRINEC, NLR, necrotizing fasciitis, sepsis, neck Paolo Greco Unit of Otorhinolaryngology, Department of Bio- medical Sciences, Neurosciences and Sense Organs, RIASSUNTO University of Bari, piazza Giulio Cesare 11, 70124 Introduzione. Le infezioni suppurative del collo sono un eterogeneo gruppo di patologie a Bari, Italy carico degli spazi profondi del collo e delle fasce cervicali. Al suo interno meritano partico- Tel. +39 080 5593524 lare attenzione le temibili fasciti necrotizzanti, caratterizzate dall’elevato tasso di mortalità E-mail: [email protected] e di compromissione settica. Risulta pertanto indispensabile una loro pronta diagnosi e un altrettanto tempestivo trattamento. La semeiologia clinica risulta spesso poco sensibi- Funding le, mentre l’esame TC comporta un inevitabile ritardo nella presa in carico terapeutica. None. Abbiamo quindi valutato l’applicabilità di due indicatori basati unicamente su parametri laboratoristici, quindi rapidamente disponibili: LRINEC score e NLR ratio. Conflict of interest Metodi. Abbiamo condotto uno studio retrospettivo su 118 pazienti che erano stati sottopo- The Authors declare no conflict of interest. sti a drenaggio chirurgico di ascesso cervicale c/o la nostra U.O., calcolando per ciascuno di essi LRINEC, NLR e il loro prodotto di moltiplicazione LRINEC x NLR. How to cite this article: Fiorella ML, Greco P, Risultati. L’analisi statistica dimostra un loro possibile ruolo nella diagnosi tempestiva Madami LM, et al. New laboratory predictive delle fasciti necrotizzanti e/o delle loro complicanze settiche. tools in deep neck space infections.Acta Otorhi- Conclusioni. Ulteriori studi con una maggiore numerosità campionaria potrebbero essere nolaryngol Ital 2020;40:332-337. https://doi. necessari per rafforzare sensibilità e specificità di tali score. org/10.14639/0392-100X-N0790 PAROLE CHIAVE: LRINEC, NLR, fasciti necrotizzanti, sepsi, cervicali © Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale

OPEN ACCESS Introduction This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-Non- Deep neck space infections (DNSIs) are a group of infective suppurative dis- Commercial-NoDerivatives 4.0 International) license. The eases involving deep neck spaces. They may occur at any age, although the article can be used by giving appropriate credit and mentio- 1 ning the license, but only for non-commercial purposes and mean age of onset is 49.5 years . only in the original version. For further information: https:// DNSI usually occur in patients affected by multiple comorbidities; in par- creativecommons.org/licenses/by-nc-nd/4.0/deed.en

332 LRINEC and NRL: a novel laboratory approach

ticular, diabetes may raise the risk of infection as a conse- of these indicators as predictive factors that may help in de- quence of immunological alterations or secondary micro- tecting CNFs or systemic involvement in course of DNSIs. angiopathy 2. Dental and oropharyngeal infections are the most common Materials and methods source of DNSI 3,4, even if in a fourth of cases a defined trigger cannot be found 5. Submandibular (36.26%) and A retrospective observational cohort study was performed sublingual spaces (13%) are the most frequent localisations on 118 patients who underwent surgical treatment for DN- followed by the para-pharyngeal (12%) and retropharyn- SIs at our Surgical Unit in the period between February geal spaces (3%) 5. 2008 and February 2018. Cases of peritonsillar abscess The isolated microbes in DNSIs reflect the normal flora treated by transoral incision without cervical drainage were of the upper respiratory and digestive tract, with a strong not included. Informed consent for surgery was obtained prevalence of Gram+ bacteria (Streptococcus viridans from all patients before surgery, which was performed 41.5%, Staphylococcus aureus 20.7%) 5. The presence within 48 hours after admission in all cases. All procedures of Gram- germs (Pseudomonas aeruginosa 4.07%, Kleb- were in accordance with the ethical standards of the insti- siella pneumonia 1.48%) 6 is more frequently related to tutional research committee and with the 1964 Helsinki diabetic comorbidity 2. Anaerobic bacteria (Prevotella 4%, Declaration and its later amendments or comparable ethi- Fusobacterium 5%) 7 have been demonstrated to play an cal standards. Our Ethics Committee was informed of the important role in the development of cervical necrotising retrospective data collection. fasciitis (CNF) 7,8 due to the production of specific enzymes Each patient was submitted at admission to clinical ex- involved in the necrotising process 8. Bacterial cultures amination and laboratory tests, including CBC (complete can be polymicrobial in 20.8% 5 of cases and negative in blood count), electrolytes, glycaemia, coagulation tests, 10.74% 6 of patients, probably due to the wide use of pre- liver and kidney functional tests and inflammatory markers hospitalisation antibiotic therapy or to technical difficulty (CPR, C-reactive protein and ESR, erythrocyte sedimenta- in isolating anaerobic pathogens 9,10. tion rate). A neck and chest CT was performed in all cases Especially when involving para- and retro- pharyngeal with the purpose of finding the potential focus of infection spaces, DNSI may extend by continuity and contiguity to and evaluate the extension of the suppurative process. the mediastinal and thoracic spaces. Some authors have LRINEC and NLR scores were then calculated; further- proposed the acronym DNM (descending necrotising me- more, in order to reinforce the predictive power of our diastinitis) to define a necrotising mediastinitis arising as analysis, we proposed an additive indicator, the product be- result of the secondary spread of a CNF (cervical necrotis- tween both the aforementioned scores (LRINEC x NLR). ing fasciitis) 7. LRINEC takes into account 6 laboratory values, assigning CNF, DNM and systemic septic involvement are potential a specific score to each of them, as reported in Table I. life-threatening complications of DNSIs, hence it is impor- NLR is calculated as the ratio between neutrophil and lym- tant to have a reliable tool that allows a prompt detection of phocyte percentages at CBC. these complications. LRINEC score, and consequently the product between Clinical examination allows identification of the typical NLR and LRINEC, was obtained only for a subgroup of 90 clinical signs and symptoms of CNF (e.g. crackling palpa- patients, since CRP was not routinely tested in our depart- tion, brownish or hyperaemic skin and cutaneous fistula), ment pre-operatively. but has low sensitivity (67%) 11; imaging techniques such Two outcomes were chosen: occurrence of CNF (n = 12/118) as CT can be useful, but can delay treatment. and sepsis. Detection of gas bubbles detection at CT and in- The aim of this study was to evaluate the role of two well- traoperative finding of necrosis in patients affected by CNF. known laboratory tools as predictive factors of DNSI com- Septic systemic involvement was defined on the basis of plications such as CNF and sepsis. the “The Third International Consensus Definitions for The “Laboratory Risk Indicator for NECrotizing fasciitis” Sepsis and Septic Shock (Sepsis-3)” 14. According to this, score (LRINEC) 12 was first proposed by Wong et al. 12 in sepsis can be rapidly identified in non-intensive care set- order to promptly identify a necrotising complication in tings using a new bedside clinical score termed quickSOFA case of suppurative infections, not strictly localised in the (qSOFA), when at least 2 of the following clinical criteria cervical region. On the other hand, the neutrophil to lym- are met: phocyte ratio (NLR) has been proposed for its diagnostic • respiratory rate of 22/min or greater; and prognostic role in the early and late phases of the septic • altered mentation; process 13. The present study aims to demonstrate the utility • systolic blood pressure of 100 mm Hg or less.

333 M.L. Fiorella et al.

Table I. LRINEC score calculating model. Results Variable, Unit Score 118 patients underwent a surgical intervention for DNSIs C-reactive protein (CRP), mg/L between February 2008 and February 2018 in our Unit: 73 < 150 0 males (61.86%) and 45 females (38.13%) with a mean age ≥ 150 4 of 48.39 years (range 2-83 years). Haemoglobin, g/dL Table II reports the suspected foci of infection in our co- > 13.5 0 hort. In 43.22% of cases the source was unknown as re- 11-13.5 1 ported by other authors 15. Dental infection was the most < 11 2 common cause occurring in a third of cases. Total white cell count, per mm³ In Table II, the anatomical localisations of DNSIs in our < 15 0 series are reported. The submandibular region and the 15-25 1 parapharyngeal space were involved in almost 50% of all > 25 2 cases, while multiple localisations occurred in 24 cases Sodium, mmol/L (20%). In 4 cases (3.4%), a mediastinal extension was ≥ 135 0 evident. <135 2 Seventy patients (59.32%) presented at least one major Creatinine, µmol/L comorbidity (Tab. II), mostly hypertension (21.19%) and ≤ 141 0 > 141 2 Glucose, mg/dL Table II. Clinical findings in our series. ≤ 180 0 Sources of infection N % > 180 1 Unknown 51 43.2 Odontogenic 33 27.9 Recurrent tonsillitis 11 9.3 Septic shock is defined as a subset of sepsis in which a va- Sialolithiasis 8 6.8 sopressor is required to maintain a mean arterial pressure Previous neck procedures (FNAB/surgery) 4 3.4 of 65 mm Hg or greater and serum lactate level greater Neck cysts 3 2.5 than 2 mmol/L (> 18 mg/dL) in the absence of hypovol- Lymphadenopathy 3 2.5 aemia 14. Mastoiditis 2 1.7 In accordance with these criteria, we identified 53 patients Other 3 2.5 without sepsis, 52 with sepsis and 13 with septic shock. Sites of infection N % Submandibular 34 28.81 Statistical analysis Parapharyngeal 24 20.34 Statistical analysis was performed using R 3.5.1. Statis- Parotid space 13 11.02 tical significance was reached with a P < 0.05. Categori- Oral pelvis/base of tongue 5 4.237 cal variables were reported as absolute and relative fre- Retropharyngeal 3 2.542 quencies. Numerical variables were reported as median Multiple localisations 24 20.34 and IQR and compared through Wilcoxon and Kruskall Other 15 12.71 Wallis rank sum test in order to account for non-nor- Comorbidities N % mality (evaluated through Shapiro-Wilk test) and hetero- Hypertension 25 21.19 scedasticity (evaluated through Bartlett test). Post-hoc Diabetes 16 13.56 analysis was performed through pairwise Wilcoxon rank Cardiopathy 10 8.475 sum test with Benjamini-Hochberg correction (false dis- covery rate). Autoimmune diseases 5 4.237 Six ROC curves were then fitted for the three scores (LRI- Endocrinopathy (except diabetes) 4 3.39 NEC, NLR e LRINEC×NLR) and for the two outcomes Nephropathy 4 3.39 (CNF and Sepsis Score), with the estimation of AUC (area Neoplasia 3 2.542 under the curve), optimal cut-off, sensibility, specificity, Chronic obstructive pulmonary disease (COPD) 3 2.542 positive and negative predictive value. None 48 40.68

334 LRINEC and NRL: a novel laboratory approach

Table III. Kruskal-Wallis and Wilcoxon Tests. LRINEC NLR NLR x LINREC median (IQR) median (IQR) median (IQR) Sepsis No sepsis 4.5 (3.3) 7.0 (6.9) 29.4 (43.7) Sepsis 5.0 (3.0) 10.3 (11.3) 59.2 (71.7) Septic shock 8.0 (2.0) 13.4 (8.2) 107.3 (82.6) (Kruskal-Wallis Test) P = 0.003 P = 0.001 P < 0.001 CNF Yes 8.0 (3.5) 15.0 (17.5) 86.3 (113.9) No 5.0 (3.5) 9.2 (9.5) 39.2 (72.5) (Wilcoxon Test) P = 0.020 P = 0.041 P = 0.010

diabetes (13.56%). In 11 cases (9.32%), multiple comor- Table IV. Pairwise comparison for Sepsis Score. bidities were found. Wilcoxon rank sum test P-value Surgical treatment, consisting in cervical incision with ab- LRINEC scess drainage and cervical fascia/spaces debridement and No Sepsis / Sepsis 0.039 rinsing, was performed in all cases. In 42 cases (35.59%) No Sepsis / Septic shock 0.004 the submandibular gland was removed; 4 patients (3.39%) Sepsis / Septic shock 0.039 presented suppurative mediastinitis, thus necessitating tho- NLR racic drainage; tracheotomy was performed in 21 patients No Sepsis / Sepsis 0.011 (17.79%). Twenty-four patients (20.33%) needed intensive No Sepsis / Septic shock 0.005 care. The survival rate in our series was 98.3%: 2 patients Sepsis / Septic shock 0.203 died for severe respiratory and systemic complications. In Table III, LRINEC, NLR and LRINEC x NLR values are NLRxLRINEC reported in relation to sepsis and occurrence of CNF. Sta- No Sepsis / Sepsis 0.011 tistical analysis showed significantly higher values of LRI- No Sepsis / Septic shock < 0.001 NEC, NLR and NLR x LRINEC in case of severe septic Sepsis / Septic shock 0.034 involvement (septic shock > sepsis > no sepsis) and CNF. Pairwise comparison (Tab. IV) demonstrated a potential utility of LRINEC and NLR x LRINEC in discriminating dictors of mortality and morbidity for DNSIs 8, particularly sepsis from septic shock. in case of CNF. ROC curves (Tab. V) show for both the considered out- CNF represent only 3.5% 15 of total DNSIs, but they dra- comes (sepsis and CNF) the performances of the three matically affect the prognosis of these patients, with a mor- scores, with acceptable values of AUC (between 0.6 and tality rate of 7-22%, increasing to 41% in case of thoracic 0.8). involvement and up to 64% if associated with DNM and sep- tic complications 17. This wide range is probably explained Discussion by the fact that early diagnosis requires relevant diagnostic instruments, not always available in poor resource countries, Neck spaces are bordered by cervical fascia which repre- where the prognosis is obviously worse 10. Hence, it has been sent, rather than an obstacle, a possible route of spreading stated that prompt diagnosis and surgical treatment within 12 for suppurative processes. For this reason, it is important hours 8,18 from admission are strongly advisable in order to to consider the possible dissemination of DNSIs, espe- lower the mortality rate. Clinical signs of necrosis alone have cially when evolving to CNF, to regions such as the me- been demonstrated to have a low sensitivity (67%) in detect- diastinum and thorax. In addition, the significant risk of ing CNF 11. On the contrary, CT scan is a sensitive (79%) systemic inflammatory involvement should not be ignored. and specific (94%) tool 15,19, but not always available in short Septic presentation in case of DNSIs has been frequently time frames, especially in poorer countries. For this reason, described by several authors 4,16, especially in case of CNF. the use of short-term laboratory predictors must be investi- Thus, this condition must be considered as a challenging gated in order to allow prompt diagnosis. race against time, since only early diagnosis allows well- According to Wong et al. 12, the risk of developing necrotis- timed and adequate medical and surgical treatment. In fact, ing fasciitis is distinguishable on the basis of LRINEC in: delayed diagnosis is considered to be one of the main pre- • low risk (probability less than 50%) for LRINEC-score 5;

335 M.L. Fiorella et al.

• medium risk (probability of 50-75%) for LRINEC-score 95.4%). In our study, we tried to find an application of this between 6 and 7; score as a predictor of the risk of CNF and sepsis, simi- • high risk (probability more than 75%) for LRINEC- larly to what was explained above for the LRINEC score. score ≥ 8. We found sensitivity and specificity values, respectively, of The Wong et al. 12 model considers necrotising soft tissue 50% and 84.9% (cut-off 17.5) in discriminating the risk of infections in general and CNF was only minimally repre- CNF and of 74.2% and 61.5% (cut-off 8.2) in predicting sented in their cohort. In their publication, Wong et al. dem- systemic septic involvement (Tab. V). onstrated LRINEC score to be significantly associated with Based on the these first disappointing results, in accordance the risk of necrotising fasciitis. with other authors25, we proposed a new score, LRINEC Thomas et al. 15 were the first to propose the application of x NLR (multiplication of the above-mentioned scores), LRINEC score to CNF, still achieving discouraging results. which was demonstrated to have acceptable sensitivity Sensitivity and specificity were, respectively, of 56% and (90.9% with a cut-off of 43.5) in discriminating the risk of 60% in case of value ≥ 6 (medium risk according to Wong’s CNF (Tab. V). model), 22% and 90% in case of value ≥ 8 (high risk ac- Nevertheless, LRINEC, NLR and LRINEC x NLR signifi- cording to Wong). Sandner et al. 19 found 94% sensitivity cantly differed depending on sepsis and the presence of ne- and 94% specificity in case of LRINEC score ≥ 6, with a crotising phenomena, as demonstrated by our analysis. The positive predictive value of 0.29. They concluded that LRI- research of new optimal cut-offs or the implementation by NEC score is a useful method to identify CNF cases early, the mean of correction factors may represent a line of de- especially in consideration of the easy availability of its pa- velopment for future perspectives, with the aim of increas- rameters, even at an early stage. ing the sensitivity and specificity of these scores. In our analysis, we proposed another optimal cut-off, with a sensitivity of 54.5% and a specificity of 84.8% in detect- Conclusions ing CNF for LRINEC score ≥ 7 (Tab. V). Additionally, we have investigated the utility of this score in predicting the Septic and necrotising complications rarely occur in pa- severity of systemic involvement. A cut-off of 6 was set to tients suffering from a head-neck suppurative infection, detect sepsis, but low sensitivity and specificity were found but enormously affect prognosis. Correct diagnosis is un- (respectively 42.6% and 86.1%) (Tab. V). doubtedly based on clinical presentation and instrumental Another indicator with proven clinical value in case of in- techniques (CT), but laboratory markers must be taken into fection is NLR. It has been used as inflammation marker in consideration as a prompt and valid aid. For this reason, several diseases, such as myocardial infarction 20, psoria- we propose the use of LRINEC, NLR and LRINEC x NLR sis 21, gastritis 22 and gangrenous appendicitis 23. Baglam 24 scores as predictive tools to early evaluate septic complica- was the first to apply NLR as predictive factor for DNSIs, tions and the risk of CNF in the course of DNSIs. As con- especially when occurring as a complication of acute bac- firmed by our analysis, even though with a sensitivity and terial tonsillitis in pediatric patients. An NLR cut-off of specificity values that were not encouraging, perhaps due to 5.4 was set to predict the risk of DNSI in these patients, the poor number of our cohort, these scores may have util- with a sensitivity of 96% and a specificity of 83% (positive ity in discriminating these potential life-threatening condi- predictive value of 85% and negative predictive value of tions. Further studies on a larger cohort may be helpful in

Table V. ROC indicators. Discriminating septic involvement (sepsis/septic shock) Test AUC Cut-off Sens. Spec. PV+ PV- LRINEC 0.672 7.0 42.6 86.1 82.1 50.0 NLR 0.679 8.2 74.2 61.5 71.0 65.3 NLRxLRINEC 0.716 30.4 81.5 52.8 72.1 65.5 Discriminating CNF Test AUC Cut-off Sens. Spec. PV+ PV- LRINEC 0.716 7.0 54.5 84.8 6.9 66.7 NLR 0.681 17.5 50.0 84.9 6.2 72.7 NLRxLRINEC 0.742 43.5 90.9 59.5 2.1 76.2

336 LRINEC and NRL: a novel laboratory approach

finding other implementations with the purpose of increas- 12 Wong CH, Khin LW, Heng KS, et al. The LRINEC (Labora- ing the clinical use of these scores. tory Risk Indicator for Necrotizing Fasciitis) score: A tool for distinguishing necrotizing fasciitis from other soft tissue infec- tions. Crit Care Med 2004;32:1535-41. https://doi.org/10.1097/01. Acknowledgements ccm.0000129486.35458.7d 13 Kaushik R, Gupta M, Sharma M, et al. Diagnostic and prognostic role We thank the Medical Laboratory of our Hospital for per- of neutrophil-to-lymphocyte ratio in early and late phase of sepsis. forming blood tests. We are also immensely grateful to Indian J Crit Care Med 2018;22:660-3. https://doi.org/10.4103/ijccm. IJCCM_59_18. the ‘Istituto di Igiene’ of University of Bari for statistical 14 Singer M, Deutschman CS, Seymour CW, et al. The Sepsis Defini- analysis. We would also like to show our gratitude to the tions Task Force Members. The third international consensus defini- University of Bari for the support and for providing all sci- tion for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10. entific material for the research. https://doi.org/10.1001/jama.2016.0287 15 Thomas AJ, Meyer TK. Retrospective evaluation of laboratory-based diagnostic tools for cervical necrotizing fasciitis. Laryngoscope References 2012;122:2683-7. https://doi.org/10.1002/lary.23680 16 Qu L, Liang X, Jiang B, et al. Risk factors affecting the prognosis 1 Huang TT, Liu TC, Chen PR, et al. Deep neck infection: analysis of descending necrotizing mediastinitis from odontogenic infection. of 185 cases. Head Neck 2004;26:854-60. https://doi.org/10.1002/ J Oral Maxillofac Surg 2018;76:1207-15. https://doi.org/10.1016/j. hed.20014 joms.2017.12.007 2 Lin HT, Tsai CS, Chen YL, et al. Influence of diabetes mellitus on 17 Sarna T, Sengupta T, Miloro M, et al. Cervical nectrotizing fascitis deep neck infection. J Laryngol Otol 2006;120:650-4. https://doi. with descending mediastinitis: literature review and case report. J org/10.1017/S0022215106001149 Oral Maxillofac Surg 2012;70:1342-50. https://doi.org/10.1016/j. 3 Koç A, Alakhras WM, Acipayam H, et al. Seven years of experi- joms.2011.05.007 ence in 160 patients with deep neck infection. KBB Uygulamalari 18 Cruz Toro P, Callejo Castillo A, Tornero Saltó J, et al. Cervical ne- 2016;4:22-6. https://doi.org/10.5604/01.3001.0010.5315 crotizing fasciitis: Report of 6 cases and review of literature. Eur 4 Huang TT, Liu TC, Chen PR, et al. Deep neck infection: analysis Ann Otorhinolaryngol Head Neck Dis 2014;131:357-9. https://doi. of 185 cases. Head Neck 2004;26:854-60. https://doi.org/10.1002/ org/10.1016/j.anorl.2013.08.006 hed.20014 19 Sandner A, Moritz S, Unverzagt S, et al. Cervical necrotizing fasciitis - 5 Velhonoja J, Lääveri M, Soukka T, et al. Deep neck space infections: the value of the laboratory risk indicator for necrotizing fasciitis score an upward trend and changing characteristics. Eur Arch Otorhi- as an indicative parameter. J Oral Maxillofac Surg 2015;73:2319-33. nolaryngol 2020;277:863-72. https://doi.org/10.1007/s00405-019- https://doi.org/10.1016/j.jams.2015.05.035 05742-9. 20 Dogan M, Akyel A, Bilgin M, et al. Can admission neutrophil to lym- 6 Atishkumar B, Vijayalaxmi A, Pallavi K. Deep neck space infec- phocyte ratio predict infarct-related artery patency in ST-segment ele- tion – a retrospective study of 270 cases at tertiary care center. World vation myocardial infarction. Clin Appl Thromb Hemost 2015;2:172- J Otorhinolaryngol Head Neck Surg 2016;2:208-13. https://doi. 6. https://doi.org/10.1177/1076029613515071 org/10.1016/j.wjorl.2016.11.003 21 Sen BB, Rifaioglu EN, Ekiz O, et al. Neutrophil to lymphocyte ratio 7 Karkas A, Chahine K, Schmerber S, et al. Optimal treatment of cervi- as a measure of systemic inflammation in psoriasis. Cutan Ocul Toxi- cal necrotizing fasciitis associated with descending necrotizing me- col 2014;33:223-7. https://doi.org/10.3109/15569527.2013.834498 diastinitis. British J Surg 2010;97:609-15. https://doi.org/10.1002/ 22 Farah R, Khamisy-Farah R, et al. Association of neutrophil to lym- bjs.6935 phocyte ratio with presence and severity of gastritis due to Helico- 8 Muhammad JK, Almadani H, Al Hashemi BA, et al. The value of bacter pylori infection. J Clin Lab Anal 2014;28:219-23. https://doi. early intervention and a multidisciplinary approach in the manage- org/10.1002/jcla.21669 ment of necrotizing fasciitis of the neck and anterior mediastinum of 23 Ishizuka M, Shimizu T, Kubota K. Neutrophil-to-lymphocyte ra- odontogenic origin. J Oral Maxillofac Surg 2015;73:918-27. https:// tio has a close association with gangrenous appendicitis in patients doi.org/10.1016/j.joms.2014.12.021 undergoing appendectomy. Int J Surg 2012;97:299-304. https://doi. 9 Sethi DS, Stanley RE. Deep neck abscesses - changing trends. org/10.9738/CC161.1 J Laryngol Otol 1994;108:138-43. https://doi.org/10.1017/ 24 Baglam T, Binnetoglu A, Yumusakhuylu AC, et al. Predictive S0022215100126106 value of the neutrophil-to-lymphocyte ratio in patients with deep 10 Fomete B, Agbara R, Osunde DO, et al. Cervicofacial infection in neck space infection secondary to acute bacterial tonsillitis. Int J a Nigerian tertiary health institution a retrospective analysis of 77 Ped Otorhinolaryngol 2015;79:1421-4. https://doi.org/10.1016/j. cases. J Korean Assoc Oral Maxillofac Surg 2015;41:293-8. https:// ijporl.2015.06.016 doi.org/10.5125/jkaoms.2015.41.6.293 25 Neeki MM, Dong F, Au C. Evaluating the laboratory risk indicator 11 Goldstein EJC, Anaya DA, Dellinger EP. Necrotizing soft-tissue in- to differentiate cellulitis from necrotizing fasciitis in the emergency fection: diagnosis and management. Clin Infect Dis 2007;44:705-10. department. West J Em Med 2017;18: 684-9. https://doi.org/10.5811/ https://doi.org/10.1086/511638 westjem.2017.3.33607

337 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:338-342; doi: 10.14639/0392-100X-N0895

Head and neck Obstructive sleep apnoea after radiotherapy for head and neck cancer Apnee ostruttive del sonno dopo radioterapia per tumori del testa-collo Federico Leone1, Giulia Anna Marciante1, Chiara Re1, Alessandro Bianchi1, Fabrizio Costantini1, Fabrizio Salamanca1, Pietro Salvatori1 1 Unit of Otorhinolaryngology, Head and Neck Surgery, Humanitas San Pio X, Milan, Italy

SUMMARY Objective. The aim of this study is to focus attention on obstructive sleep apnoea hypo- pnoea syndrome (OSHAS) as a sequela of non-surgical treatments of selected head and neck cancer (HNca), sharing our experience in drug-induced sleep endoscopy (DISE). To the best of our knowledge, this is the first study that documents dynamic anatomical and functional alterations during sleep in irradiated OSAHS patients by DISE. Methods. A retrospective study of patients affected by OSAHS referring to our department from January 2018 to December 2019 was carried out. Inclusion criteria were: patients who underwent radiation or chemo-radiation for HNca affecting upper airways that presented sleep-related breathing disorders after treatment. Results. 6 patients with moderate to severe OSAHS and a clinical story of previous non- surgical treatment for an HNca were enrolled. DISE showed in all patients typical anatomi- cal alterations observed in irradiated individuals. Four patients were treated with continu- ous positive airway pressure, while 2 subjects were treated with tailored minimal invasive surgery without post-operative complications. Received: May 31 , 2020 Conclusions. Our results suggest that minimal invasive surgical treatments can be a good Accepted: August 9, 2020 therapeutic option in very selected patients with post-irradiation iatrogenic OSAHS. KEY WORDS: radiotherapy, iatrogenic OSAHS, head and neck cancers, obstructive sleep Correspondence apnoea Federico Leone Unit of Otorhinolaryngology, Head and Neck Sur- gery, Humanitas, San Pio X Clinic, via Francesco RIASSUNTO Nava 31, 20159 Milan, Italy Obiettivo. Lo scopo di questo studio retrospettivo è focalizzare l’attenzione sull’OSAS E-mail: [email protected] come sequela di trattamenti non chirurgici per tumori del distretto testa-collo (HNca), con- dividendo la nostra esperienza con la “drug induced sleep endoscopy” (DISE) e la nostra Funding casistica. Per quanto ne sappiamo, questo è il primo studio che documenta alterazioni ana- None. tomiche e funzionali dinamiche mediante DISE in pazienti irradiati che hanno sviluppato OSAS. Conflict of interest Metodi. È stato condotto uno studio retrospettivo su pazienti affetti da OSAS afferenti alla The Authors declare no conflict of interest. nostra struttura da gennaio 2018 a dicembre 2019. Sono stati inclusi nello studio pazienti con anamnesi positiva per trattamento non chirurgico di HNca che hanno sviluppato OSAS How to cite this article: Leone F, Marciante dopo il trattamento. GA, Re C, et al. Obstructive sleep apnoea after Risultati. Sono stati arruolati 6 pazienti con OSAS da moderata a grave con una storia radiotherapy for head and neck cancer. Acta clinica di precedente trattamento non chirurgico per un HNca. La DISE ha mostrato in tutti Otorhinolaryngol Ital 2020;40:338-342. https:// i nostri pazienti tipiche alterazioni anatomiche osservate pazienti irradiati. 4 pazienti sono doi.org/10.14639/0392-100X-N0895 stati trattati con CPAP mentre 2 soggetti sono stati sottoposti a chirurgia mininvasiva senza complicazioni post-operatorie. © Società Italiana di Otorinolaringoiatria Conclusioni. I nostri risultati suggeriscono che i trattamenti chirurgici mini invasivi posso- e Chirurgia Cervico-Facciale no essere una buona opzione terapeutica in pazienti con OSAS iatrogena post-radioterapia ben selezionati. OPEN ACCESS PAROLE CHIAVE: apnee ostruttive del sonno, roncopatia e radioterapia, roncopatia e This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-Non- cancro, OSAS iatrogena, tumori testa-collo Commercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and only in the original version. For further information: https:// creativecommons.org/licenses/by-nc-nd/4.0/deed.en

338 OSAHS after radiotherapy for head and neck cancer

Introduction were excluded. Patients with known OSAHS before treat- ment were also excluded. Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) The diagnostic work-up included complete physical exami- is characterised by recurring events of partial or complete nation, fiberoptic endoscopic evaluation, polysomnograph- upper airway collapse during sleep. Most apnoeas and hy- ic study (PSG) and DISE. Treatment was planned taking popnoeas lead to oxygen saturation drops and therefore to into account clinical features and preferences of each pa- intermittent hypoxia (IH). IH in OSAHS is an important tient. risk factor for development of hypertension, coronary ar- Postoperative pain and dysphagia were evaluated by means tery disease, arrhythmias and other cardiovascular dis- of self-esteemed assessment questionnaires with vNRS-11 eases 1. Recent studies suggest that IH in OSAHS patients and I-EAT 10 8. might be involved in (or a cofactor for) the development of All patients were followed for a minimum of 6 months cancer 2. The relationship between OSAHS and cancer is with ENT, pneumological and PSG evaluation. Follow-up set to become an exciting area of research in the near fu- data were available for all patients and no patients were ture, although at the moment the clinical basis has not been lost to follow-up. Epidemiological and clinical data, surgi- completely demonstrated. Nevertheless, both pathophysi- ological and animal studies appear to bestow credibility on cal reports, images, complications, data on therapies and this correlation 3. follow-up information were reviewed. Finally, our results To date, data on association between OSAHS and cancer were critically analysed and discussed in light of the recent are focused on pathophysiological points of view without pertinent literature focusing on this topic. considering correlations with specific kind of tumours. Other associations can be observed focusing on head and Results neck cancers (HNca). OSAHS can develop as the first clini- From January 2018 to December 2019, 6 patients with cal presentation of a tumour (e.g. base of tongue, tonsils, moderate to severe OSAHS with a clinical history of pre- larynx), but even more frequently can be a consequence of vious non-surgical treatment for an HNca were enrolled. treatment for head and neck cancer. In fact, a higher preva- Demographic data are reported in Table I. lence of OSAHS has been observed in patients treated for A slight predominance of male was found since only 2 pa- HNca, both with surgery and radiation (RT) 4-7. The un- tients were women (33.3%), while 4 were men (66.6%); derlying mechanism consists in anatomical and functional mean age was 58 ± 8.1 years (range 47-70). Mean BMI alterations leading to narrowed upper airway and reduced was 25.2 ± 1.3 kg/m2 (range 23.4-27). All patients had compliance. A proper knowledge of this relationship be- underwent chemo-radiation therapy for HNca: 3 patients comes important for all specialists dealing with the prob- (50%) were treated for a laryngeal squamous cell carci- lem. noma (SCC), 2 (33.3%) for an oropharyngeal SCC and 1 The aim of this study is to focus attention on OSHAS as (16,6%) for an hypopharyngeal SCC. All subjects were di- a sequela of non-surgical treatments of selected HNca, agnosed with OSAHS and the mean time between end of sharing our experience in drug-induced sleep endoscopy (DISE) and a small case series of patients. To the best of the treatment and diagnosis of OSAHS was 23 ± 8 months our knowledge, this is the first study that documents dy- (range 6-28). Four (66.6%) patients were affected by severe namic anatomical and functional alterations during sleep in OSAHS, while in only 2 cases (33.3%) moderate OSAHS irradiated OSAHS patients by DISE. was found. In all patients, DISE showed typical anatomical alterations (diffused oedema, floppy exuberant mucosa at the level of arytenoid and ventricular folds, floppy epiglot- Materials and methods tis and cartilage malacia, etc.) observed in irradiated peo- This study was performed in accordance with policies ap- ple. These features were also found to be responsible for proved by the local ethics Committee. UA obstruction in these patients. In relation to treatment of A retrospective clinical study of patients affected by OS- OSAHS, 4 patients (66.6%) were treated with CPAP ven- AHS referring to the Department of Otorhinolaryngology, tilation, while 2 subjects (33.3%) were surgically treated. Humanitas San Pio X from January 2018 to December In particular, 1 patient underwent an epiglottis stiffening 2019 was carried out. Inclusion criteria were as follows: operation (ESO) sa described by Salamanca et al. 9 and 1 patients who underwent radiation or chemo-radiation for a underwent trans-oral laser microsurgery (TLM) for floppy head and neck cancer affecting the upper airways (pharynx, exuberant tissue (ventricular fold and arytenoid). No post- larynx) and who presented sleep-related breathing disor- operative complications were reported and both patients ders after treatment. Patients with a neoplastic recurrence were discharged on the 1st postoperative day substantially

339 F. Leone et al.

Table I. Preoperative data and outcomes. # Sex Age Histology Site Subsite Stage Treatment Time BMI AHI DISE Treatment AHI FU (8ed.) between (kg/m2) pre post (m) RT and OSA (m) 1 M 57 SCC O BOT cT3cN2c CHT+RT 19 24 72.1 Floppy epiglottis, CPAP 13.7 4 6 epiglottis cmH2O malacia, edema of supraglottis 2 M 70 SCC S AF cT2cN2b CHT+RT 27 25.6 62.3 Esuberant TLM:debulking 1.3 11 flapping mucosa vNRS-11: 0 of ventricular fold I-EAT10: 1 3 M 47 SCC S AF cT3cN2b CHT+RT 21 23.4 27.3 Esuberant CPAP 15 3.2 28 flapping mucosa cmH2O of ventricular fold and aritenoid, floppy and edematous epiglottis 4 F 63 SCC H PS cT2cN0 CHT+RT 15 26 32.8 Esuberant CPAP 13 3.6 25 flapping mucosa cmH2O of arytenoid, epiglottis malacia 5 M 58 SCC S E cT2cN2b CHT+RT 37 25.3 47.7 Floppy epiglottis, ESO 4.7 8 epiglottis malacia vNRS-11: 1 I-EAT10: 1 6 F 52 SCC O BOT cT3cN2c CHT+RT 17 27 24.8 Floppy epiglottis, CPAP 8 3.8 12 epiglottis cmH2O malacia, edema of supraglottis M: male; F: female; BMI: body mass index; m: months; SCC: squamous cell carcinoma; O: oropharynx; S: supraglottis; H: hypopharynx; BOT: base of tongue; AF: aryepiglottic fold; PS: pyriform sinus; E: epiglottis; CHT+RT: chemo-radiotherapy; AHI: apnoea hypopnoea index; ESO: epiglottis stiffening operation; TLM: trans-oral laser microsurgery; CPAP: continuous positive airway pressure; vNRS-11: verbal Numerical Rating Scale 11; I-EAT-10: Eating Assessment Tool 10 (Italian version); DISE: drug-induced sleep endoscopy; FU: follow up. without pain (vNRS-11: 0 and 1) and without dysphagia or point of view, several studies have shown an association aspiration (I-EAT 10: 1 and 1). Follow-up ranged between between OSAHS (particularly when evaluated by hypoxae- 6 and 28 months (mean follow-up period 15 ± 9 months) mia) and cancer incidence and mortality, although their ret- and no patients were lost. Postoperative fiberoptic evalu- rospective nature means that more in-depth and prospective ation was performed on the 7th and 30th postoperative day studies will be required before a more definitive conclusion and showed good surgical results. Moreover, all patients can be reached 1,3,10-12. underwent a PSG that confirmed resolution of OSAHS in To date, data on relationship between OSAHS and cancer all 6 patients. are focused on pathophysiological points of view without considering correlations with specific kinds of tumours. Discussion Focusing on Head and Neck cancers (HNca), we can ap- OSAHS is characterised by recurrent partial or complete preciate other kind of correlations: OSAHS can be the first upper airway narrowing during sleep. As a consequence of clinical presentation of a HNca due to a mass effect on the apnoea and hypopnoea, oxygen saturation may be altered upper airways (UA). The reduction of pharyngo-laryngeal causing IH. IH in OSAHS is an important risk factor for space can sometimes develop as a consequence of surgical development of hypertension, coronary artery disease, ar- treatment, for example after bulky flap reconstructions as rhythmias and other cardiovascular diseases 1. Recent stud- reported by Rombaux et al. 6. Furthermore, HNca patients ies suggest that IH in OSA patients might be involved in (or may experience upper airway obstruction from the anatom- a cofactor for) the development of cancer 2. From a clinical ic and functional alterations related to RT.

340 OSAHS after radiotherapy for head and neck cancer

This significant anatomic and functional heterogeneity in ment. DISE allowed us to identify the problem, but put us HNca patients partially explains the wide range in previously in front of a difficult choice. A surgical option in irradiated reported prevalence of OSAHS in this population (8-92%) 4,5,7. patient, in fact, may be risky leading to complications that Our aim was to investigate the effects of radiation therapy negatively affect the quality of life such as dysphagia. on the larynx and oropharynx during sleep in irradiated After adequate counselling, 2 patients categorically refused patients developing OSAHS after treatment. In addition to CPAP despite being aware of the surgical risks. However, some case reports 13,14, we found a study that looked specifi- if a good selection of the patients is performed, the results cally at the nonsurgical HNca patient in these two subsites. suggest that minimal invasive surgical treatments can be a In their prospective study, Huyett et al. 4 found that half of good therapeutic option in very selected cases, especially in patients with a history of RT for oropharyngeal or laryn- young patients and without other morbidity, as confirmed geal cancers demonstrated objective evidence of OSAHS, by our experience. considerably higher than in the general population. To the best of our knowledge, this is the first study documenting Conclusions dynamic anatomical and functional alterations during sleep in irradiated OSAHS patients by DISE. OSAHS is a public health problem and a very common The identification of specific site upper respiratory tract disorder, with the same prevalence as diabetes and large obstruction site(s) in OSAHS patients is important in order economic impact on public healthcare. In particular, the re- to select the best therapeutic strategy. Nowadays, among lationship between OSAHS and cancer is set to become an different diagnostic tools, DISE, although not ideal, plays exciting area of research. a key role in the decision making process 15. The introduc- As a consequence of both RT and surgical therapy, a de- tion of routinely use of DISE in OSAHS patients has been crease in the pharyngo-laryngeal space can lead to the onset reported to help the customisation of treatment demonstrat- of iatrogenic OSAHS, as suggested by a higher prevalence ing that UA obstruction results from the collapse of one or of this disorder in patients treated for HNca. Proper knowl- more pharyngeal and/or laryngeal structures 16,17. edge of this relationship becomes important for specialists Laryngeal involvement is less frequent than pharyngeal, dealing with these problems because the management of consisting in epiglottis collapse in the large majority of na- OSAHS in irradiated patients may be more challenging. ïve patients. The collapse can be described as primary (the Our results suggest that surgery can be considered in these so called “floppy epiglottis”) or secondary (when related to types of patients. Minimally-invasive surgical treatments a bulky tongue base). In our sample of irradiated patients, can be a good alternative therapeutic option in very select- the larynx was the most affected site due to typical mucosal ed patients, especially if young and without comorbidity. alterations induced by RT: massive oedema of supra-glot- In our opinion, DISE is confirmed to be a valid tool for tis structures with exuberant floppy mucosa of ventricular patient selection and should always be performed before fold, arytenoid, aryepiglottic fold, epiglottis malacia and considering surgery as the last approach. A larger case se- instability were found at the evaluation. According to our ries, hopefully a prospective multicentre study with longer findings, all these alterations (isolated or in variable combi- follow-up, is needed in order to confirm these results. nation) were responsible for obstruction in sleep. Diffuse laryngeal oedema is one of the most common side References effects of RT for HNca: 15-59% of patients develop grade 1 18 Kukwa W, Migacz E, Druc K, et al. Obstructive sleep apnea and can- > 2 laryngeal oedema within 2 years after RT . Fibrotic cer: effects of intermittent hypoxia? Future Oncol 2015;11:3285-98. changes following RT may lead to blockade of lymphatic https://doi.org/10.2217/fon.15.216 vessels, causing laryngeal oedema, particularly in the su- 2 Cao J, Feng J, Li L, et al. Obstructive sleep apnea promotes can- pra-glottis areas 19. This was the case of all patients of our cer development and progression: a concise review. Sleep Breath sample who presented the aforementioned alteration. 2015;19:453-7. https://doi.org/10.1007/s11325-015-1126-x 3 According to guidelines, CPAP ventilation should be Martínez-García MÁ, Campos-Rodriguez F, Almendros I, et al. Relationship between sleep apnea and cancer. Arch Bronconeumol the gold standard treatment for all cases of our survey 2015;51:456-61. https://doi.org/10.1016/j.arbres.2015.02.002 (AHI > 15), even if most patients do not show good com- 4 Huyett P, Kim S, Johnson JT, et al. Obstructive sleep apnea in the irra- pliance to this chronic therapy. Our decision to perform diated head and neck cancer patient. Laryngoscope 2017;127:2673-7. DISE in these patients depended on the following reasons: https://doi.org/10.1002/lary.26674 our patients were quite young (mean age 58) and were not 5 Ouyang L, Yi L, Wang L, et al. Obstructive sleep apnea in patients with laryngeal cancer after supracricoid or vertical partial laryn- obese; they had no comorbidity and according to their pref- gectomy. J Otolaryngol Head Neck Surg 2019;48:1-10. https://doi. erences we tried to propose an alternative to CPAP treat- org/10.1186/s40463-019-0347-6

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6 Rombaux P, Hamoir M, Plouin-Gaudon I, et al. Obstructive sleep 13 Steffen A, Graefe H, Gehrking E, et al. Sleep apnoea in patients after apnea syndrome after reconstructive laryngectomy for glottic car- treatment of head neck cancer. Acta Otolaryngol 2009;129:1300-5. cinoma. Eur Arch Otorhinolaryngol 2000;257:502-6. https://doi. https://doi.org/10.3109/00016480802613113 org/10.1007/s004050000267 14 Stern TP, Auckley D. Obstructive sleep apnea following treatment of 7 Loth A, Michel J, Giorgi R, et al. Prevalence of obstructive sleep head and neck cancer. Ear Nose Throat J 2007;86:101-3. apnoea syndrome following oropharyngeal cancer treatment: a pro- 15 Delakorda M, Ovsenik N. Epiglottis shape as a predictor of obstruc- spective cohort study. Clin Otolaryngol 2017;42:1281-8. https://doi. tion level in patients with sleep apnea. Sleep Breath 2019;23:311-7. org/10.1111/coa.12869 https://doi.org/10.1007/s11325-018-1763-y. 8 Schindler A, Mozzanica F, Monzani A, et al. Reliability and valid- 16 Salamanca F, Costantini F, Bianchi A, et al. Identification of ob- ity of the Italian Eating Assessment Tool. Ann Otol Rhinol Laryngol structive sites and patterns in obstructive sleep apnoea syndrome 2013;122:717-24. https://doi.org/10.1177/000348941312201109 by sleep endoscopy in 614 patients. Acta Otorhinolaryngol Ital 9 Salamanca F, Leone F, Bianchi A, et al. Surgical treatment of epiglot- 2013;33:261-6. tis collapse in obstructive sleep apnoea syndrome: epiglottis stiffen- 17 Campanini A, Canzi P, De Vito A, et al. Awake versus sleep endosco- ing operation. Acta Otorhinolaryngol Ital 2019;39:404-8. https://doi. py: personal experience in 250 OSAHS patients. Acta Otorhinolaryn- org/10.14639/0392-100X-N0287 gol Ital 2010;30:73-7. 10 Marshall NS, Wong KKH, Cullen SRJ, et al. Sleep apnea and 20-year 18 Bae JS, Roh J-L, Lee S-W, et al. Laryngeal edema after radiothera- follow-up for all-cause mortality, stroke, and cancer incidence and py in patients with squamous cell carcinomas of the larynx and hy- mortality in the Busselton Health Study Cohort. JCSM 2014;10:355- popharynx. Oral Oncology 2012;48:853-8. https://doi.org/10.1016/j. 62. https://doi.org/10.5664/jcsm.3600 oraloncology.2012.02.023 11 Shantha GPS, Kumar AA, Cheskin LJ, et al. Association between 19 Ichimura K, Sugasawa M, Nibu K, et al. The significance of arytenoid sleep-disordered breathing, obstructive sleep apnea, and can- edema following radiotherapy of laryngeal carcinoma with respect to cer incidence: a systematic review and meta-analysis. Sleep Med residual and recurrent tumour. Auris Nasus Larynx 1997;24:391-7. 2015;16:1289-94. https://doi.org/10.1016/j.sleep.2015.04.014 https://doi.org/10.1016/s0385-8146(97)00013-8 12 Sillah A. Sleep apnea and subsequent cancer incidence. Cancer Causes Control 2018;29:987-94. https://doi.org/10.1007/s10552-018-1073-5

342 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:343-351; doi: 10.14639/0392-100X-N0757

Head and neck VITOM-3D assisted neck dissection via a retroauricular approach (RAND-3D): a preclinical investigation in a cadaver lab Dissezione laterocervicale mediante approccio retroauricolare assistito da sistema VITOM-3D (RAND-3D): studio preclinico in cadaver lab Erika Crosetti1, Giulia Arrigoni1, Andrea Manca1, Marco Fantini1, Alessandra Caracciolo1, Francesco Sardanapoli1, Giovanni Succo1,2 1 Head and Neck Oncology Unit, Candiolo Cancer Institute, FPO - IRCCS, Candiolo (TO), Italy; 2 Department of Oncology, University of Turin, Orbassano (TO), Italy

SUMMARY Objective. The recent introduction of 3D exoscopic surgery has allowed interesting techni- cal improvements in head and neck surgery resulting in technical solutions that are also applicable to neck dissection. The aim is to replace robotic surgery while minimising the costs of the procedure. Methods. Based on these considerations, we conducted a preclinical investigation in the Received: March 22, 2020 cadaver lab focused on approaching conventional neck dissection using a retroauricular Accepted: August 6, 2020 incision, and evalute the applications and usefulness of the Storz 3D Exoscopic System at different stages of the surgical procedure. The acronym RAND-3D (3D exoscopic surgery) Correspondence was coined to describe the application of this optical tool in neck dissection. Erika Crosetti Results. The current study in the cadaver lab indicates that RAND-3D is an acceptable Head and Neck Oncology Unit, FPO IRCCS, Can- alternative operating technique in performing neck dissection by a retroauricular approach. diolo Cancer Institute, 10060 Candiolo (Turin) Italy Technically feasible and safe, this technique assures a complete compartment-oriented dis- Tel. + 39 011 9933663 section without damaging major vascular or nervous structures. E-mail: [email protected] Conclusions. This approach can be used in selected cases with a clear cosmetic benefit and represents a valid alternative to endoscopic- and robotic-assisted neck dissection. Funding This research was funded by: Regione Piemonte KEY WORDS: 3D, exoscope, neck dissection, 3D surgery AD FUNCTIONEM (years 2015–2018); FPRC 5xmille 2016 Ministero della Salute Progetto ARDITE; Fondi Ricerca Corrente 2020, Ministero RIASSUNTO della Salute. Obiettivo. Il recente avvento della chirurgia esoscopica 3D ha consentito, nell’ambito della chirurgia cervico-cefalica, l’introduzione di interessanti innovazioni tecnologiche, Conflict of interest risultanti in soluzioni tecniche applicabili anche alla chirurgia del collo, con l’obiettivo di The Authors declare no conflict of interest. rappresentare un’alternativa alla chirurgia robotica, minimizzando i costi della procedura. Metodi. Sulla base di queste considerazioni abbiamo recentemente condotto uno studio pre-clinico nel nostro cadaver lab, focalizzato sull’esecuzione dello svuotamento linfono- How to cite this article: Crosetti E, Arrigoni G, dale laterocervicale con approccio retroauricolare, valutando le applicazioni e l’utilità del Manca A, et al. VITOM-3D assisted neck dis- Sistema Esoscopico 3D Storz nei vari steps dell’intervento. Abbiamo coniato l’acronimo di section via a retroauricular approach (RAND- 3D): a preclinical investigation in a cadaver lab. RAND-3D (chirurgia esoscopica 3D) per descrivere l’impiego di questo tool ottico nell’e- Acta Otorhinolaryngol Ital 2020;40:343-351. secuzione di tale procedura chirurgica. https://doi.org/10.14639/0392-100X-N0757 Risultati. Il seguente studio condotto nel cadaver lab ha indicato che la tecnica RAND-3D rappresenta una valida alternativa per l’esecuzione dello svuotamento del collo con ap- © Società Italiana di Otorinolaringoiatria proccio retroauricolare. Questa metodica, tecnicamente fattibile e sicura, permette una dis- e Chirurgia Cervico-Facciale sezione compartimentale, senza danno alle principali strutture vascolo-nervose cervicali. Conclusioni. Questo approccio può essere impiegato in casi selezionati con un chiaro OPEN ACCESS finalismo estetico, rappresentando una valida alternativa alle metodiche endoscopiche e This is an open access article distributed in accordance with robotiche. the CC-BY-NC-ND (Creative Commons Attribution-Non- PAROLE CHIAVE: 3D, esoscopio, svuotamento laterocervicale, chirurgia 3D Commercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and only in the original version. For further information: https:// creativecommons.org/licenses/by-nc-nd/4.0/deed.en

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Introduction enhanced using 3D exoscopic technology in more remote Traditionally, surgery for head and neck malignancies in- areas. volves open neck approaches aimed at radical removal of The primary end point was to demonstrate the effectiveness the primary tumour together with cervical lymph nodes, al- of this technology in retroauricular or facelift approaches lowing the surgeon to obtain good control of the disease; to neck dissection. The secondary end point was to assess however, occasionally, negative post-operative aesthetic which node levels could be dissected using the 3D exo- and functional sequelae result. scopic system, the docking and setting of the procedure, The need to implement surgical approaches that minimise and the advantages and limitations of the technique. The the morbidity and impact of treatments has given great im- tertiary end point was to become familiar with a traditional petus to the development of minimally invasive techniques, technique carried out using a remote approach, to be con- such as laser surgery and robotic surgery 1,2. sidered as a rescue procedure in the case of major bleeding As far as treatment of the neck is concerned, to date, not complications during a robotic neck dissection. much has changed in terms of surgical technique, since the cervical open neck approach remains the conventional one, Materials and methods even in the case of transoral surgery on the primary tumour, and also resulting in the paradox of minimally invasive sur- Four human cadavers were obtained from the Italian Acad- gery on T and conventional surgery on N, and weakening emy of Anatomical Dissection (AIAD). Three cadavers the concept of minimal invasiveness. This has prompted were male and one was female. Dissection was carried out surgeons to try to develop minimally invasive neck dissec- bilaterally on each cadaver by two senior head and neck tion techniques using endoscopic and robotic approaches. surgeons. Endoscopic-assisted and robot-assisted neck dissection present limitations and disadvantages. Of these, the main Technology the duration of surgery, longer than the standard approach, The video telescope operating microscope (VITOM®; Karl the need for surgeons to develop skills in endoscopic and Storz, Tuttlingen, Germany) system is an exoscope with robotic techniques and the overall higher costs of the pro- 0° or 90° camera options. VITOM-3D has zoom and fo- cedures (about six times higher in the Korean experience cus functions, integrated illumination and horizontal align- using robotic neck dissection) 3-7. ment. The camera offers a magnification of 1–2× depend- The recent introduction of 3D exoscopic surgery has al- ing on the working distance and the size and resolution of lowed interesting technical improvements in head and neck the monitor used. The surgical field is visualised by a cam- surgery resulting in technical solutions that are also appli- era system which supports an output signal of 1920×1080 p cable to neck dissection, with the aim of replacing robotic and with a 16:9 image format; progressive scanning deliv- surgery but minimising the costs of the procedure 8. ers crystal-clear images with smooth motion, even if there Specifically, exoscopic surgery is based on the use of a is rapid movement. The 3-chip sensor technology in the sterile 3D optical device, called an exoscope, placed in the camera head ensures natural colour rendition. surgical field and oriented with different inclinations but The exoscope is positioned on a versatile self-supporting technically about 40 cm distant from it. The exoscope also arm, specially developed for use with the VITOM® system, illuminates the surgical field in depth, since it is equipped which allows a simple and precise positioning of the system. with two light cables with Xenon sources, and produces 4K The arm is mounted on a mobile trolley and can be trans- images on a 55″ screen positioned about 3-4 metres from ported and positioned quickly in the operating room. Thanks the surgeon. In some steps in the surgical procedure, the to its pneumatic cushioning, the arm allows weight compen- exoscope replaces the surgeon’s eyes thereby improving sation for the VITOM® system. The braking effect of each magnification. This allows the possibility to carry out the individual joint can be set individually. Furthermore, the arm neck dissection through a retroauricular incision, combin- is noted for its easy handling: the VITOM® system can be ing direct and 3D exoscopic vision and resulting in operat- easily positioned with one hand. Different directions of view ing times no longer than 20% of previous times and with a are possible depending on the surgical site being treated. comparable level of feasibility, determined by the perfect HD imaging also provides a sense of depth to improve visualisation of the surgical field even in the more remote anatomical orientation. The camera is connected to a 3D cervical areas (levels Ib–IV). monitor and 3D passive-polarised glasses, with an anti- The goal of this study is to analyse the technical details fog coating, or 3D clip-on glasses, circularly polarised, are of neck dissection in a cadaver lab carried out using a re- worn to view the monitor. An intuitive control unit with 3D mote approach in what is virtually conventional surgery but wheel (joystick) with four programmable function keys is

344 3D exoscopic surgery for neck dissection

used to control the camera. The joystick can be used with A modified retroauricular or facelift skin incision is per- the sterile coating by the surgical assistants, or without the formed without pre-auricular extension (Fig. 2). The modi- coating by other members of the surgical team not directly fied facelift incision, given its extension into the pre-au- working on the operating field. The joystick can also be ricular region, allows for more straightforward and faster used to control an instrument holding system. To increase dissection, providing a wider ‘working space’, especially the illumination of the operating field, it is possible to place for patients who need a dissection of level Ib. The median an annular illuminator device on the head of the exoscope, operating time for cutaneous flap harvesting and placement connected to a second Xenon light source. of skin retractor was 38 minutes (range 25-78 minutes). In order to carry out a hybrid procedure in which a large The median operating time for 3D exoscopic-assisted neck part of the operation is performed under direct control and dissection (levels Ib–V) was 83.2 minutes (range 73-103 only the dissection of the most distant layers from the inci- minutes). sion (levels IV and Ib) is performed under exoscopic 3D Neck dissection was successfully performed from levels I vision, the polarising lenses were adapted to the 3.5× mag- to V in all four cadavers. The skin flap is elevated under di- nification operating loupes. rect vision along a subplatysmal plane, and the inferior as- pect of the parotid gland, the great auricular nerve, and the Operating lab setting external jugular vein is identified which could be ligated The first and second surgeons are seated on the same side and sectioned as well as spared. The latter two anatomical as the neck dissection. The 55” monitor is positioned con- structures represent the anatomical landmarks used to iden- tralaterally in front of them, at a distance of about 2.5 me- tify the correct subplatysmal plane. tres. The assistant is placed at the head of the cadaver. The The anterolateral margin of the sternocleidomastoid mus- endoscopic cart is positioned at the bottom of the operating cle and the angle of the mandible are then identified. The bed with a second 3D monitor for the assistant. The first angle of the mandible, an important landmark for the man- and second surgeons also wear operating loupes over polar- dibular branch of the VIIth cranial nerve, is then marked ising clip-on lenses to view the monitor when necessary. At using a sterile pencil, over the fat tissue so as to always present, the exoscope is mounted on a mechanical holder, maintain these anatomical structures in the field of view. positioned behind the two surgeons and oriented towards The dissection proceeds with the aid of the 3D exoscope. the level to be dissected and is moved by an assistant. The We identified inferiorly the upper margin of the clavicle, latter controls the exoscope joystick. All team members medially the anterior belly of the contralateral digastric wear 3D glasses. Throughout the operation, the exoscope muscle, and laterally the anteromedial margin of the trape- is positioned behind the first two operators and directed to- wards the level to be dissected (Fig. 1).

Results The cadaver is placed in the supine passive position with neck slightly extended and turned contralateral to the side that will be operated. It is useful to identify and mark the external jugular vein on the skin, if present, and the mar- gins of the platysma/sternocleidomastoid muscle.

A B Figure 1. A) Schematic of operating lab setting. B) Operating lab setting. Figure 2. Modified retroauricular or facelift skin incision (red line).

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Figure 4. Surgical view (left side) after level IIa dissection (ECA: external ca- rotid artery; SAN: spinal accessory nerve; SCM: sternocleidomastoid muscle).

mostatic manoeuvers, carried out by the second surgeon around the hypoglossal nerve and thyrolinguofacial trunk, can benefit from exoscopic vision (Fig. 4). The neck dis- Figure 3. Surgical view (left side) after self-retaining retractor placement. section then proceeds with dissection of level IIb. The di- gastric muscle is retracted upwards by the third assistant zius muscle. A self-retaining Koh’s retractor or Mikulitz’s using an Army-Navy retractor and the spinal accessory spatula is then placed and kept raised by the third assistant nerve (SAN) is dissected (Fig. 5). Level IIb is completely (Fig. 3). In this step, the first and second surgeons work dissected under direct vision. next to each other. To better harvest the subplatysmal flap The percentage of surgery carried out under direct vision up to the clavicle inferiorly, it is preferable that the first vs 3D exoscopic vision was calculated (90% vs 10%). surgeon is positioned at the head of the cadaver or that this VITOM-3D was useful to the assistant to aid precision in step is carried out by the second surgeon. haemostatic manoeuvers. Different levels in the neck (I, IIa, IIb, III, IV, Va, Vb) are Dissection of level III then dissected as required using the traditional surgical For dissection of level III, the operation always proceeds in technique, with vascular clips and haemostatic cutting/ a medial  lateral direction. Dissection from the deep plane coagulation devices such as bipolar scissors and LigaSure and the medial-lateral shifting of the loose and fascial cellular Maryland forceps. Surgical instruments (forceps, scissors) tissue isolated so far allow the SAN and the cervical plexus to must be a minimum length of 24 cm so as to be able to be identified. The specimen is then gently pulled downwards, work in deep spaces without any difficulty. and the perivasal fasciae cut with scissors (Fig. 6). The aid provided by the 3D vision consists of useful light- ing of more distant areas of the neck and improving the visualisation of anatomic structures. The visualisation is exactly the same for both surgeons providing great preci- sion in the surgical manoeuvers. At the end of the procedure, we decided not to send the specimen to the pathologist because the main aim of our preclinical investigation was evaluation of the feasibility of the approach.

Dissection of level II To dissect this level, the first surgeon is positioned on the same side as the neck dissection while the second surgeon stands next to the first surgeon towards the patient’s head. Figure 5. Surgical view (right side): the digastric muscle is retracted upwards The dissection proceeds in a medial  lateral direction by the third assistant using an Army-Navy retractor and the spinal accessory quickly carried out under direct vision and only some hae- nerve (SAN) is dissected.

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When dissecting the lower part of level IV, to prevent any possible lymphorrhage due to damage to the thoracic duct/ great lymphatic vein, it is mandatory to place multiple vas- cular clips before cutting the fat tissue. The side of dissec- tion did not have any significant effect on the performance of neck dissection. This is undoubtedly the most challenging step in the opera- tion because, at level IV, the working space is extremely narrow and the risk of an inadvertent injury to the internal jugular vein (IJV) or thoracic duct is high. Also in this step, the exoscope is useful for sharing the same good vision among all surgeons; however, the long working distance Figure 6. Surgical view (right side): for the dissection of level III, the operation always proceeds in a medial  lateral direction, from the deep plane and the makes this dissection lengthy and difficult to manage, even medial-lateral shifting to allow the SAN and the cervical plexus to be identified. for expert surgeons. (IJV: internal jugular vein; SAN: spinal accessory nerve). To facilitate dissection of level IV, and to dramatically re- duce the risks of vascular/lymphatic injury, it is extremely useful to make a small incision (5 cm) midway between The positions of the surgeons and the exoscope are the the cricoid cartilage and sternal notch, as is currently per- same as in level II dissection. To dissect this level, the per- formed in thyroid surgery. The breadth of this incision centage of 3D exoscopic vision rose to 20%, in particular should exceed the external border of the sternocleidomas- when dissecting the lower part of this level, meaning that toid muscle by 1 cm. The concept is to create a service skin even the first surgeon can improve his accuracy. window, allowing the lateral margin of the sternocleido- mastoid muscle, the upper belly of the omohyoid muscle, Dissection of levels IV–V and the cervical vascular-nervous axis to be identified and For the dissection of levels IV and V, the first surgeon then dissecting this level upward, reaching level III (Fig. 8). moves to the head of the cadaver. Another possibility is Highlighting the phrenic nerve and the brachial plexus, dis- that the second surgeon proceeds with cervical dissection section of the inferior part of levels IV and V is completed, in this step. The dissection of level V is then carried out in certainly the most delicate and difficult to manage step a lateral  medial direction under direct vision in conven- coming from a remote behind-the-ear approach. tional mode without any particular difficulties. To dissect This surgical solution is also useful when performing thy- level IV, the retractor blade raising the skin flap is posi- roid surgery for malignancies, where neck dissection is also tioned towards the sternal notch. An assistant retracts the required due to cervical metastases, allowing an effective sternocleidomastoid muscle apart using a Richardson’s re- surgical procedure and leaving only a small visible scar. tractor. The surgical instruments are directed caudally and To dissect these levels, the rate of 3D exoscopic vision is the exoscope is directed towards the clavicle and sternal about 20% when proceeding only via a retroauricular ap- notch (Fig. 7). proach; while it is less than 5% when proceeding via the

Figure 7. Surgical view (right side): dissection of level IV (the omohyoid mus- Figure 8. Modified retroauricular or facelift skin incision and cervical median cle is retracted) (IJV: internal jugular vein). skin window.

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median skin window. In this step the VITOM-3D allows to ment of metastases of head and neck malignant tumours 9. magnify the vision of the lower part of IV level, increasing The surgical technique has changed over time with the in- the precision of the dissection and haemostatic manoeuvers troduction of more conservative approaches, curative and near the inferior cervical pedicle, phrenic nerve and major elective, allowing the preservation of anatomical structures lymphatic structures. such as the IJV, accessory spinal nerve, and sternocleido- mastoid muscle 10. Dissection of level Ib Carrying out a neck dissection using the traditional approach For dissection of level Ib, the first surgeon must be posi- does not simply mean the presence of a more or less visible tioned more caudally, directing surgical instruments crani- scar on the neck, but it can expose the patient to more easily ally. The retractor blade must be positioned medially higher acquired and more frequent complications such as cervical on the skin flap. The assistant also uses a skin hook to pull lymphoedema, fibrosis, scar retraction, keloids and wound up the skin flap. The direction of the exoscope is oriented dehiscence, that can have a negative impact on the percep- more cranially toward the upper part of the neck. tion of the body’s self, especially in young and female pa- 11 After dissecting the superficial cervical fascia, the subman- tients . In addition, since the neck dissection is performed in dibular gland is exposed, and the facial vein is identified on combination with transoral surgery in a good percentage of the surface of its posterior pole. The distal facial pedicle is cases, this partly undermines the patient’s perception of the carefully ligated 1 cm from the inferior margin, thus avoid- concept of “mini-invasiveness” of the latter. All this config- ing inadvertent damage to the mandibular branch of the ures the condition of carrying out a truly minimally invasive VIIth cranial nerve; this manoeuver is made easier by the operation on primary carcinoma, with an even greater eco- excellent 3D vision provided by the exoscope. Submandib- nomic weight linked to technological devices, keeping the ular gland removal begins from the anterior pole. Consider- aesthetic and functional cervical sequelae unchanged due to ing the working distance and the presence of blood vessels the open neck approach by dissecting the lymph node areas. In any case, the aesthetic and functional outcomes after ro- on the muscular surfaces, it can be very useful to carry out botic surgery, widely validated in terms of minimal invasive- this dissection using 24 cm LigaSure Maryland forceps, in ness and overall lower weight, justify the use of this device haemostatic mode (Fig. 9). in the transoral treatment of some primary tumours coupled Dissection of level Ib is carried out completely under 3D with a traditional open neck approach. exoscopic vision and, in our experience, was particularly In recent years, head and neck oncologic surgery has been facilitated and precise. developing various forms of minimally invasive surgical procedures to increase surgical precision as well as the Discussion satisfaction and quality of life of patients. In 2010, Kang In 1905, Crile was the first to propose a systematic clas- and colleagues first described the so-called RAND (remote sification of neck dissection. Radical neck dissection has access neck dissection), or robot-assisted neck dissection, historically been the treatment of choice for the manage- for the treatment of cervical metastases from thyroid car- cinoma using a transaxillary approach, similar to that used for total thyroidectomy 12. Based on these observations, in 2012, Koh and colleagues proposed the modified ret- roauricular and facelift approaches for performing robot- assisted neck dissection, not only of levels II, III, and IV but also I and V, highlighting the greater ease in dissecting upper and posterior cervical levels 13. The main limitation highlighted using this access route was the possibility of performing the dissection of levels IIb and Va, given the limited vision of these regions. Although these access routes cannot be literally defined as “minimally invasive”, they are not burdened by the im- pact of the scar, which is virtually invisible and not a de- cisive factor in the main sequelae of the standard cervical Figure 9. Surgical view of submandibular gland removal (right side): consid- approach; they can therefore be equated as outcomes with ering the working distance and the presence of blood vessels on the muscular surfaces, it can be very useful to carry out this dissection using a 24 cm LigaS- currently minimally invasive interventions, referring to ure Maryland forceps, in haemostatic mode. them as “remote access” interventions.

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Concerning endoscopic-assisted neck dissection, several 3D is an acceptable alternative operating technique per- drawbacks have been highlighted by many studies 14-17. forming neck dissection by a retroauricular approach. These limitations include a reduced range of motion, with Technically feasible, this technique assures a complete various collisions between first surgeon and assistant, a compartment-oriented dissection. two-dimensional view with a lack of depth perception, im- No particular difficulties were encountered during dissec- paired eye-hand coordination, minimal tactile sensation, tion of levels II and III; these steps are mainly conducted and a relatively slow learning curve. Another important dis- under direct vision with 3.5× magnification and with a advantage of endoscopic neck dissection is the need for the small percentage (10-20%) of 3D-assisted vision, which is operator to have sufficient skill in handling the endoscope. particularly useful for the second surgeon. To facilitate a The focus of recent research has been shifting towards straightforward and rapid dissection of levels IV and V, the greater implementation of the da Vinci surgical robot, as proposed solution is to combine the retroauricular incision this technique addresses some drawbacks of endoscopic with a small incision placed midway between the cricoid surgery. The robotic surgical system has the advantage of cartilage and the sternal notch, as is currently used in thy- a stable three-dimensional binocular magnification, motion roid surgery. This solution is extremely useful in reducing scaling, tremor filtration, various degrees of freedom with the operating time and could be considered an interest- wrist-like articulated movements, a shorter learning curve, ing solution during robotic-assisted neck dissection in the superior surgeon ergonomics and improved instrumental case of major bleeding which is difficult to manage in the dexterity. Although robotic surgery undoubtedly has clear lower anatomic regions of the neck. Furthermore, it results advantages, comparative studies of endoscopic- and robot- in a small median lower neck skin incision, transforming ic-assisted techniques have not been able to illustrate dif- a scar-free surgical procedure (as the purely RAND tech- ferences in terms of outcomes from a simple comparison nique offers) into one with a minor scar, but provides the of numbers such as blood loss, conversion rate, or recovery surgeons with great confidence in dissecting areas distant time 3,4,13,18. from cutaneous access and, if necessary, quickly convert to The main disadvantages of robotic-assisted neck dissection a retroauricular approach into a more comfortable proce- are the length of the operation, significantly longer than the dure without paying the price of a major scar in the neck. standard approach, the need for surgeons to develop skills It should also be noted that these operations are sometimes in the field of robotic techniques and the higher overall associated with a tracheostomy to protect the airway: the costs of the procedure. same procedure is carried out at the end of the procedure The recent advent of 3D exoscopic surgery has allowed by the same service incision. In the same way, in some bor- interesting technical improvements to be introduced in derline cases due to comorbidity, thanks to this incision, head and neck surgery, with technical solutions applicable access to the trachea can be prepared without opening it. to cervical dissection, with the aim of enhancing surgical This creates a pre-tracheotomy situation, which can be eas- vision through remote access, minimising the costs of the ily opened to the patient’s bed in the case of major bleeding procedure in comparison to robotic surgery. complications in the postoperative period. Robotic surgery and VITOM-3D have only one charac- The hybrid execution of neck dissection under direct and teristic in common: a high definition optical system (even exoscopic vision represents a valid alternative to video-as- though different in optical type and positioning with re- sisted endoscopic- and robot-assisted techniques. Undoubt- spect to the working area: in fact, one is a 3D-endoscopic edly, the need for a second skin incision could underpower device and its tip reaches near the anatomical structures, the good aesthetic results of the approach. while the second is a 3D-endoscopic device placed outside The characteristics of the VITOM-3D images can be con- the patient) allowing magnification and improved vision of sidered very comparable to those of the 3D optics of the da anatomical sites otherwise difficult to explore without a di- Vinci surgical robot, with its excellent ability to provide rect conventional approach. Based on these considerations, 3D visual information which is used to interactively con- we recently conducted this preclinical investigation in the trol the exoscope camera. Other advantages are its depth of cadaver lab focused on approaching conventional neck dis- field, magnification, and image contrast and colour, allow- section using a retroauricular incision, and evaluate the ap- ing direct manipulation of the images of anatomic struc- plications and usefulness of the Storz 3D Exoscopic Sys- tures. The most advantageous aspects are represented by tem during different stages of the surgical procedure. The the magnification of the anatomic details, for example, the acronym RAND-3D (3D exoscopic surgery) was coined to vascularisation. describe the use of this optical tool in neck dissection. The system is comfortable to use for surgeons who stay for The current study in the cadaver lab indicates that RAND- long periods in a sitting position with the screen in front of

349 E. Crosetti et al.

them at eye height: surgery carried out facing a 3D screen is during surgery, and the necessity to wear 3D glasses for not bothersome for operators, even for longer procedures. a prolonged period which can lead to headaches in some After carrying out the first procedure, the combination of cases 19-21. In our study, none of the surgeons complained direct vision and 3D exoscopic vision is very easy to work of side effects. with. In fact, adapting and placing a polarised lens over the Another important aspect to underline is that the RAND- loupes allowed us to reach a comfortable optical solution. 3D optical tool could be used in preparation for robotic- Almost without realising it, the surgeons pass from one vi- assisted neck dissection, both for the fidelity of vision and sion to another depending on the best visual alternative. for the logistics that make it more easily transportable in This continuous comparison between exoscope and loupes the cadaver lab than the robotic platform. allowed us to reach some conclusions. VITOM-3D allows to share the same vision among surgeons, placed on the Conclusions same side of the cadaver through a limited skin window, during the entire procedure. The exoscope is particularly The primary endpoint of this study was to demonstrate the useful to the second surgeon during haemostatic manoeu- effectiveness and feasibility of this technology in retroau- vers and to place multiple vascular clips in the dissection ricular or facelift approaches to neck dissection. of the lower part of IV and V level. 3D visualisation is es- The preclinical investigations on VITOM-3D-assisted neck sential during level Ib dissection to better identify each ana- dissection via a retroauricular approach (RAND-3D) have tomical structure, whereas it is almost impossible to eas- demonstrated good. This approach can be used in selected ily dissect level Ia using this approach, due to the working cases with a clear cosmetic benefit and representing a valid al- distance. ternative to endoscopic- and robotic-assisted neck dissection. Conventional surgical instruments have been used (no re- Nevertheless, we have concluded that, with the retroauricu- quirement to buy other specific instrumentation): it is only lar approach, it is possible to perform a large part of the required that the surgical instruments are of suitable length neck dissection under direct vision, even using a minimally (minimum 24 cm). Other haemostatic tools can be used invasive approach. The exoscope is useful because it allows (e.g. Focus, LigaSure, Thunderbeat) with safety deriving the second operator, seated on the same side as the first from complete visual control. These aspects are undoubt- surgeon, to have a good vision, especially during the dis- edly an advantage, in terms of immediacy, simplicity of use section of levels II and III, improving precision during hae- and lower costs in comparison to robotic surgery. mostasis. In our opinion, dissection of level IV exclusively Furthermore, the 3D exoscope provides the benefit of great through a retroauricular skin incision is quite unsafe using utility in the learning process, especially for residents, fel- this technique because the working space is extremely nar- lows, students, and OR staff, thanks to the same shared row. This is the reason why we suggest a median skin “win- visual experience being available to every operator, and al- dow” which permits better vision and greater safety in the ways with wide high-resolution monitors. Both images and dissection of vascular and lymphatic structures. video sequences can be stored in high definition, enabling The preliminary results obtained in the cadaver lab have surgeons to share videos in didactic sessions, meetings and led us to propose to the Ethics Committee of our Institute surgical technique courses. This utility applies not only to a perspective study focused on the oncological and esthetic neck dissection, but also to the treatment of primary tu- results obtained by RAND-3D with more specific evalua- mours 8. tions of costs, patient satisfaction, and learning curve. That At present, in a health policy aimed at reducing costs, it is study is currently ongoing. difficult to procure up-to-date technologies. The entire cost Moreover, we are planning an additional study to compare of the exoscopic platform is similar to that of an operat- VITOM-3D and DaVinci systems in carrying out neck dis- ing microscope with an electromagnetic brake. The cost of section with retroauricolar approach. disposables for each surgical procedure is about €40-60, composed of two sterile sheaths for the holder and the con- References troller chamber; even the cost of maintenance is consider- 1 Weinstein GS, O’Malley BW Jr, Snyder W, et al. Transoral robotic ably lower. Much of the same platform can be used daily surgery: radical tonsillectomy. Arch Otolaryngol Head Neck Surg in endoscopic surgery of the upper aero-digestive tract, the 2007;133:1220-6. https://doi.org/10.1001/archotol.133.12.1220 most frequently performed endoscopic procedure, and this 2 Weinstein GS, O’Malley BW Jr, Snyder W, et al. Tran- soral robotic surgery: supraglottic partial laryngectomy. contributes greatly to the amortisation of costs. Ann Otol Rhinol Laryngol 2007;116:19-23. https://doi. The current drawbacks are represented by the mechani- org/10.1177/000348940711600104 cal holder arm which is not always comfortable to move 3 Kim WS, Lee HS, Kang SM, et al. Feasibility of robot-assisted

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neck dissections via a transaxillary and retroauricular (“TARA”) ap- 12 Kang SW, Jeong JJ, Yun JS, et al. Robot-assisted endoscopic surgery proach in head and neck cancer: preliminary results. Ann Surg Oncol for thyroid cancer: experience with the first 100 patients. Surg Endosc 2012;19:1009-17. https://doi.org/10.1245/s10434-011-2116-2 2009;23:2399-406. https://doi.org/10.1007/s00464-009-0366-x 4 Kim WS, Byeon HK, Park YM, et al. Therapeutic robot-assisted neck 13 Koh YW, Chung WY, Hong HJ, et al. Robot-assisted selective neck dissection via a retroauricular or modified facelift approach in head dissection via modified face-lift approach for early oral tongue can- and neck cancer: a comparative study with conventional transcervical cer: a video demonstration. Ann Surg Oncol 2012;19:1334-5. https:// neck dissection. Head Neck 2015;37:249-54. https://doi.org/10.1002/ doi.org/10.1245/s10434-011-2155-8 hed.23595 14 Kang SW, Jeong JJ, Yun JS, et al. Gasless endoscopic thyroidectomy 5 Lee HS, Kim WS, Hong HJ, et al. Robot-assisted supraomohyoid neck using trans-axillary approach; surgical outcome of 581 patients. En- dissection via a modified face-lift or retroauricular approach in early- docr J 2009;56:361-9. https://doi.org/10.1507/endocrj.k08e-306 stage cN0 squamous cell carcinoma of the oral cavity: a comparative 15 Lombardi CP, Raffaelli M, Princi P, et al. Minimally invasive video- study with conventional technique. Ann Surg Oncol 2012;19:3871-8. assisted functional lateral neck dissection for metastatic papillary thy- https://doi.org/10.1245/s10434-012-2423-2 roid carcinoma. Am J Surg 2007;193:114-8. https://doi.org/10.1016/j. 6 Lewis JS Jr, Carpenter DH, Thorstad WL, et al. Extracapsular exten- amjsurg.2006.02.024 sion is a poor predictor of disease recurrence in surgically treated oro- 16 pharyngeal squamous cell carcinoma. Mod Pathol 2011;24:1413-20. Lira RB, Chulam TC, Koh YW, et al. Retroauricular endoscope- https://doi.org/10.1038/modpathol.2011.105 assisted approach to the neck: early experience in Latin Amer- ica. Int Arch Otorhinolaryngol 2016;20:138-44. https://doi. 7 Koh YW, Kim JW, Lee SW, et al. Endoscopic thyroidectomy via a org/10.1055/s-0036-1578807 unilateral axillo-breast approach without gas insufflation for unilat- 17 . eral benign thyroid lesions. Surg Endosc 2009;23:2053-60. https:// Lee S, Nam W. Comparison of retroauricular and small transcervical doi.org/10.1007/s00464-008-9963-3 approaches for endoscopic-assisted selective neck dissection: a ca- 8 daveric study. Int J Oral Maxillofac Surg 2019;48:584-89. https://doi. Crosetti E, Arrigoni G, Manca A, et al. 3D exoscopic surgery (3Des) org/10.1016/j.ijom.2018.11.008 for transoral oropharyngectomy. Front Oncol 2020;10:16. https://doi. org/10.3389/fonc.2020.00016 18 Kim CH, Chang JW, Choi EC, et al. Robotically assisted selective neck dissection in parotid gland cancer: preliminary report. Laryngo- 9 Crile GW. On the surgical treatment of cancer of the head and neck. scope 2013;123:646-50. https://doi.org/10.1002/lary.23716 With a summary of one hundred and five patients. Trans South Surg Gynecol Assoc 1905;18:108-27. 19 Garneau JC, Laitman BM, Cosetti MK, et al. The use of the exoscope in lateral skull base surgery: advantages and limitations. Otol Neurotol 10 Robbins KT, Clayman G, Levine PA, et al. Neck dissection classifica- tion update: revisions proposed by the American Head and Neck So- 2019;40:236-40. https://doi.org/10.1097/MAO.0000000000002095 ciety and the American Academy of Otolaryngology-Head and Neck 20 Chen J, Zheng H, He J. 3D laparoscopic revision thyroidectomy Surgery. Arch Otolaryngol Head Neck Surg 2002;128:751-8. https:// through an anterior chest approach: a case report. J Laparoendosc Adv doi.org/10.1001/archotol.128.7.751 Surg Tech A 2015;25:238-42. https://doi.org/10.1089/lap.2014.065 11 Terrell JE, Nanavati KA, Esclamado RM, et al. Head and neck can- 21 Capaccio P, Di Pasquale D, Bresciani L, et al. 3D video-assisted trans- cer-specific quality of life: instrument validation. Arch Otolaryngol oral removal of deep hilo-parenchymal sub-mandibular stones. Acta Head Neck Surg 1997;123:1125-32. https://doi.org/10.1001/archo- Otorhinolaryngol Ital 2019;39:367-73. https://doi.org/10.14639/0392- tol.1997.01900100101014 100X-2282

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Laryngology Modular approach in OPHL: are there preoperative predictors? OPHL modulare: esistono parametri predittivi preoperatori? Andy Bertolin1, Marco Lionello1, Marco Ghizzo1, Emanuela Barbero2, Erika Crosetti3, Giuseppe Rizzotto1, Giovanni Succo3,4 1 Otolaryngology Unit, Vittorio Veneto Hospital, Italy; 2 Otorhinolaryngology Service, University of Eastern Piedmont, Novara, Italy; 3 Head and Neck Oncology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy; 4 Department of Oncology, University of Turin, Orbassano (TO), Italy

SUMMARY Objective. Open partial horizontal laryngectomies (OPHLs) nowadays represent the first line surgical choice for the conservative treatment of locally intermediate and selected advanced stage laryngeal cancers. Among the peculiarities of OPHLs, there is the possibility of intraopera- tively modulating the procedure. It would be useful for the surgeon to recognise preoperative en- doscopic and radiological factors that can predict the possibility to modulate the laryngectomy. Methods. The present study retrospectively reviewed a cohort of 72 patients who under- went OPHL for glottic LSCC, in order to identify preoperative (endoscopic and radiologi- cal) parameters that are able to predict modulation surgery. Results. The hypoglottic extension of the glottic tumour was the preoperative finding that was most informative in predicting OPHL modulation. However, it had no significant im- pact on oncological outcomes. Conclusions. Patients affected by tumours with hypoglottic extension and eligible for OPHL type II should be preoperatively informed about the possibility of an intraoperative switch towards OPHL type III. Received: April 3, 2020 KEY WORDS: OPHL, partial laryngectomy, modular, laryngeal carcinoma, hypoglottic Accepted: May 19, 2020 extension Correspondence Marco Lionello RIASSUNTO Otolaryngology Unit, Vittorio Veneto Hospital, via Obiettivi. La laringectomia parziale orizzontale open (OPHL) rappresenta al giorno d’oggi Forlanini 71, Vittorio Veneto, Treviso, Italy la scelta chirurgica di prima linea per il trattamento conservativo del carcinoma squamoso E-mail: [email protected] laringeo (LSCC) in stadio intermedio e di selezionati casi in stadio localmente avanzato. Fra le peculiarità della OPHL c’è la possibilità di modulare intraoperatoriamente la procedura. Funding Sarebbe utile al chirurgo riconoscere parametri preoperatori endoscopici e/o radiologici che None. possano predire la possibilità di modulare intraoperatoriamente la laringectomia. Metodi. Il presente studio ha considerato retrospettivamente una popolazione di 72 pazien- Conflict of interest The Authors declare no conflict of interest. ti sottoposti ad OPHL per LSCC, al fine di identificare parametri preoperatori (endoscopici e radiologici) in grado di predire la modulabilità della OPHL. Risultati. L’estensione ipoglottica del tumore è risultata essere il parametro preoperatorio How to cite this article: Bertolin A, Lionello M, più informativo nel predire la modulazione della OPHL. Tale condizione, tuttavia, non Ghizzo M, et al. Modular approach in OPHL: impattava in maniera significativo sull’outcome oncologico. are there preoperative predictors? Acta Otorhi- Conclusioni. I pazienti affetti da tumori con estensione ipoglottica e candidabili ad OPHL nolaryngol Ital 2020;40:352-359. https://doi. tipo II dovrebbero essere informati preoperatoriamente sulla possibilità di uno switch in- org/10.14639/0392-100X-N0782 traoperatorio verso una OPHL tipo III. © Società Italiana di Otorinolaringoiatria PAROLE CHIAVE: OPHL, laringectomia parziale, modulare, carcinoma laringeo, e Chirurgia Cervico-Facciale estensione ipoglottica OPEN ACCESS

This is an open access article distributed in accordance with Introduction the CC-BY-NC-ND (Creative Commons Attribution-Non- Commercial-NoDerivatives 4.0 International) license. The Open partial laryngectomies have undergone worldwide diffusion from the article can be used by giving appropriate credit and mentio- th ning the license, but only for non-commercial purposes and second half of the 20 century thanks to the efforts of some excellent surgeons. only in the original version. For further information: https:// Alonso described supraglottic laryngectomy, indicated for tumours limited to creativecommons.org/licenses/by-nc-nd/4.0/deed.en

352 Modulated OPHL

the supraglottic region 1. A few years later Meyer, Piquet derwent salvage OPHL; iii) patients with a follow-up < 24 and Labayle standardised supracricoid laryngectomies months; iv) a final histology other than LSCC. with and without conservation of the suprahyoid epiglot- Laryngeal tumours were staged according to the 8th clas- tis, respectively 2,3. These became the most performed open sification of the Union Internationale Contre le Cancer and partial laryngectomies worldwide, given their satisfying the American Joint Committee on Cancer 7. and reproducible results. In the 1970s, Serafini described a Preoperative diagnostic work-up included laryngeal indi- near-total laryngectomy, defined by a supratracheal caudal rect flexible video-endoscopy, contrast-enhanced neck CT resection 4, that was subsequently revised by Rizzotto who scan or MRI, chest X-ray; under general anaesthesia laryn- codified the tracheohyoidopexy as a supracricoid laryngec- goscopy was then performed using rigid 0°, 30° and 70° tomy that extended toward the cricoid 5. The requisite for telescopes in white light and narrow band imaging to com- the functional success of this technique was the possibility plete the diagnostic work-up. of sparing at least one crico-arytenoid unit (CAU). All patients preoperatively signed an informed consent Open partial laryngectomies nowadays represent the first form for modular surgery and total laryngectomy. line surgical choice for conservative treatment of locally in- All procedures performed were in accordance with the termediate and selected advanced stage laryngeal cancers. ethical standards of the institutional Ethics Review Board According to the most recent guidelines of the European and with the 1964 Helsinki declaration and its later amend- Laryngological Society (ELS), OPHL represents the cur- ments or comparable ethical standards. rent classification of horizontal partial laryngectomies 6. Both classifications are characterised by distinction of Surgery surgical subcategories according to the level of the caudal Indications to perform OPHL were: i) selected cases of ear- horizontal resection. We can therefore distinguish supra- ly glottic cancer (cT2) not fit for transoral laser microsur- glottic laryngectomies (OPHL type I), supracricoid laryn- gery (TLM), and ii) selected cases of locally intermediate- gectomies (OPHL Type II) and supratracheal laryngecto- advanced disease (cT3-4a) with at least one disease-free mies (OPHL type III). CAU, no massive extralaryngeal spread (i.e. a limited dif- Among the peculiarities of OPHLs, there is the possibility fusion to prelaryngeal tissues without invasion of the thy- to intraoperatively modulate the procedure. roid gland or of the infrahyoid muscles) and iii) acceptable It would be useful for the surgeon to identify preoperative general conditions and comorbidities. endoscopic and radiological factors that can predict the pos- General patient-related contraindications to OPHL includ- sibility to modulate the laryngectomy. These factors should ed alcohol and drug abuse, or major comorbidities (heart be considered and mentioned during preoperative counseling failure, lung diseases, mellitus diabetes, or severe neuro- in order to allow the patient to participate in the therapeutic cognitive decay). choice. The open partial laryngectomies were performed and re- The main aim of the present study was to investigate, in corded according to the ELS classification 6. According to a cohort of glottic LSCC patients undergoing OPHL, the the “modular” approach, the patients with glottic LSCC preoperative factors that are related to modulation of the were initially approached with supracricoid resection; the procedure. Secondary aims were to analyse the oncologi- procedure could intraoperatively change to supratracheal cal outcomes of the cohort and the prognostic relevance of laryngectomy, according to macroscopic extension of the clinical, surgical and pathological parameters. tumour and microscopic findings at frozen sections (posi- tive or negative status of mucosal margins), with progres- Methods sive widening of the resection, sparing at least one crico-ar- ytenoid unit. All margins were also checked postoperatively Patients on final histology and classified as positive/close/negative. From 2015 to 2017, 119 patients underwent OPHL for A radical or modified radical neck dissection (RND and glottic LSCC at the Otolaryngology Service of Vittorio MRND, respectively) were performed in the event of clinical- Veneto Hospital, and the Otolaryngology Service of San ly or radiologically proven lymph node involvement. Selec- Luigi Gonzaga University Hospital in Turin (Italy). Clini- tive neck dissection (SND) of levels II-III-IV was performed cal charts were retrospectively reviewed. electively for cT3-4a N0 disease, or with curative intent for Exclusion criteria were: i) patients with supraglottic cancer clinically or radiologically limited node metastases. Bilateral treated with supraglottic laryngectomy (OPHL I), since the neck dissection was routinely performed in cases of supra- primary aim of our study was to examine the factors influ- glottic spread. An ipsilateral paratracheal neck dissection was encing modularity in glottic cancer; ii) patients who un- used in the event of disease extending to the hypoglottis.

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Postoperative radiotherapy (RT) was considered in locally The cases of LSCC were classified as follows: cT2 in 16; advanced cases (pT3-T4a) with positive margins or multi- cT3 in 49; and cT4a in 8. Regional node status was classi- ple node metastases (pN2-3); chemo-radiotherapy (CRT) fied as: cN0 in 56 cases; cN1 in 7; cN2 in 7; and cN3 in one. was scheduled in cases with extranodal extension, and an- The pathological classification was: pT1 in 3 cases; pT2 in gio-vascular or perineural invasion. 6; pT3 in 44; and pT4a in 19. The pathological classifica- tion of cervical nodes was: pNX-0 in 56 cases; pN1 in 7; Statistical analysis pN2 in 5; and pN3 in 4. Fisher’s exact test was used to calculate the association be- An ipsilateral neck dissection was performed in 63 cases, tween different clinical and pathological parameters with while a bilateral neck dissection in 4 cases with lesions OPHL modulation and disease recurrence rate. The log- crossing the midline. There was evidence of extranodal dis- rank test and Kaplan-Meier survival function were used to semination in 6 cases. Eleven patients received postopera- calculate disease-free survival (DFS) for patients stratified tive radiotherapy or CRT. by the selected variables. A multivariate logistic model (Wald test) was applied to Pathological findings the same parameters (Fisher’s exact test, p < 0.10) to iden- At pathology, 10 patients had positive surgical margins, 45 tify independent prognostic factors in relation to recurrence negative and 17 closed. The positive margin was lateral (on rate and modulation surgery, and the relative 95% confi- the side of the spared arytenoid) in 6 cases, deep in 4, and cau- dence intervals were calculated. dal in 1 case. Vascular and perineural invasion were detected A p-value < 0.05 was considered significant. The STATA in 38 and 27 cases, respectively. As for pathological grade, 14 statistical package (Stata Corp., College Station, TX) this was well differentiated in 12 cases, moderately differenti- was used for all analyses. ated in 28, poorly differentiated in 24 and indeterminate in 8.

Results Oncological outcomes Sixty-two patients had no relapse of disease, while 10 pa- Open partial horizontal laryngectomies tients (13%) experienced a disease recurrence after 15 ± 6 In this study a cohort of 72 LSCC patients (62 men and 10 months. The mean follow-up was 34 ± 6 months (range women; mean age 61.1 ± 8.6 years, median 62) met the 26-71 months). At latest follow-up, 61 patients (85%) were inclusion criteria. alive and disease-free, 7 (9%) were alive with disease, 2 An OPHL type II was performed in 49 cases, while a type (3%) died of their disease and 2 (3%) died with no evidence III was carried out in 23 cases. of disease. The final overall and disease-specific survival OPHL was modulated (from type II to type III) in 6 cases. rates were 94% and 97%, respectively. Table I shows the distributions of preoperative clinical pa- Considering the 10 cases with positive margins, 3 patients rameters in relation to the modulation of surgery. Hypo- underwent postoperative radiotherapy, chemo-radiotherapy glottic tumour extension was the preoperative parameter was scheduled in 1 case with neck metastasis, while close that was significantly related with OPHL modulation. follow-up was adopted in the remaining 6 cases. Two of the 10 patients experienced a local recurrence of disease and were submitted to total laryngectomy: one patient died Table I. Distributions of modulated OPHLs according to preoperative clinical of disease, the other was disease free at last follow-up. The (endoscopic/radiological) parameters. OPHL was modulated in 1 patient, with caudal positive Parameter Modulated OPHL p* margin, who experienced no recurrence of disease. Posterior glottis 5/36 0.19 Anterior glottis 1/36 Univariate and multivariate analysis of prognostic factors Impaired/absent arytenoid motility 5/44 0.39 Results of the univariate analysis are shown in Table II. Pa- Normal arytenoid motility 1/28 tients with lymph node metastases had significantly higher Radiological TCAS invasion 5/47 0.65 recurrence rates and shorter DFS compared with pN0 pa- No radiological TCAS invasion 1/25 tients. Statistical analysis found that patients who under- Radiological CAU invasion 5/30 0.07 went OPHL type III and those with CAU involvement had No radiological CAU invasion 1/42 significantly lower DFS compared with patients undergone Hypoglottic extension 6/32 0.00 OPHL type II and those without CAU involvement by the No hypoglottic extension 0/40 tumour. These patients had also higher recurrence rates, al- * Fisher’s exact test though no significant p values emerged from our analysis.

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Table II. Distribution of recurrence rate and disease-free survival (months) by main clinical and pathological parameters. No. of patients Recurrence rate p * DFS p ** (%) (%) (Mean ± SD) Age Age ≥ 65 24 4 (16%) 0.72 22 ± 21 0.83 Age < 65 48 5 (10%) 43 ± 6 Pathological T classification pT1 3 2 (22%) 0.60 24 ± 31 0.35 pT2 6 pT3 44 8 (12%) 47 ± 30 pT4a 19 Pathological N classification pNX-0 56 7 (12%) 0.05 49 ± 4 0.06 pN1 7 3 (18%) 17 ± 9 pN2 5 pN3 4 Resection margins Negative 62 10 (16%) 0.66 31 ± 22 0.95 Positive 10 2 (20%) 39 ± 8 Vascular invasion Negative 34 4 (11%) 0.73 43 ± 4 0.86 Positive 38 6 (15%) 40 ± 10 Perineural invasion Negative 45 7 (15%) 0.73 29 ± 25 0.44 Positive 27 3 (11%) 43 ± 13 OPHL type II 49 4 (8%) 0.06 40 ± 9 0.05 III 23 6 (26%) 12 ± 15 Anterior vs posterior Posterior glottis 36 8 (22%) 0.08 22 ± 1 0.04 Anterior glottis 36 2 (5%) 34 ± 8 Arytenoid motility Impaired/absent arytenoid motility 45 9 (20%) 0.02 16 ± 6 0.07 Normal arytenoid motility 27 0 (0%) 18 ± 8 TCAS involvement Radiological TCAS invasion 47 8 (17%) 0.47 17 ± 8 0.43 No radiological TCAS invasion 25 2 (8%) 27 ± 1 CAU involvement Radiological CAU invasion 30 7 (23%) 0.08 31 ± 11 0.04 No radiological CAU invasion 42 3 (7%) 25 ± 4 Hypoglottic extension Endoscopic hypoglottic extension 32 7 (21%) 0.09 20 ± 4 0.10 No endoscopic hypoglottic extension 40 3 (7%) 26 ± 4 * Fisher’s exact test; ** Log-rank test

Patients with normal arytenoid motility experienced sig- mediate-advanced stage disease (pT3-4), positive margins, nificantly lower recurrence rates compared with patients posterior glottic tumours and radiological involvement of with impaired/absent motility. Patients with locally inter- thyro-crico-arytenoid space (TCAS) and hypoglottic region

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had a higher recurrence rate and shorter DFS, although the It is worth noting that every type of conservative surgery, differences were not significant. including OPHL, necessarily needs a very accurate pre- Multivariate analysis confirmed that hypoglottic extension operative diagnostic work-up in order to analyze the real of the tumour was the only independent predictive factor extension of the tumour, as well as intraoperative confirma- for surgical modulation (Wald test, p = 0.05; odds ratio 2.1; tion of surgical margins with frozen sections. In the case 95% confidence interval 1.25-4.35). The pathological find- of modular surgery, the role of histological examination is ing of neck metastasis was an independent negative prog- even more relevant since it determines modulation towards nostic factor in terms of recurrence rate (Tab. III). the more radical procedure. In the present study, a relatively high number of positive Discussion margins was reported (13.9%). This could be related to: i) the discrepancy between intraoperative and definitive Modular surgery is a patient- and tumour-tailored surgical results of the pathological examination, ii) the final posi- approach that is gaining increasing importance in modern tivity of deep margins, since we intraoperatively sent only surgery. Considering laryngeal cancer, OPHL is the modu- superficial mucosal margins, and iii) to the high number of lar procedure par excellence. As previously reported, when locally advanced tumours (pT3-T4a: 63 cases, 87%). approaching an OPHL, the surgeon should refer to a surgi- The possibility to modulate the level of the caudal resection cal plan rather than to a single procedure 8. represents a peculiarity and one of the main advantages of Modular surgical approaches to organ resection, related to partial horizontal laryngectomies. The diffusion and the the tumour site and extension, have already been proposed standardisation of OPHL are due to ELS, and in particular for other cancers, including gastric, liver and pancreatic to the efforts of Succo and coworkers 6. cancers 9-13. In dermatological surgery, Mohs micrographic This surgical modular approach was demonstrated to be a surgery (MMS) has become the gold standard for treatment valid and effective therapeutic choice for selected patients of cutaneous malignancies. It consists with removal of the with glottic or transglottic laryngeal cancer with subglottic neoplasm, in a step-by-step fashion, with progressive tis- extension, not only in terms of oncologic results, but also in sue exeresis checked with frozen sections, up to complete terms of functional outcomes 15,16. removal of the lesion. Histopathologic examination is key However, OPHL type II had been demonstrated to warrant to the high cure rates achieved with MMS 14. overall better functional results and lower complication

Table III. Multivariate analysis of main clinical and pathological parameters. Odds ratio p * 95% confidence interval p ** Pathological N classification pN+ 2.35 0.05 Reference group 0.05 1.55-7.85 OPHL type III 1.80 0.06 Reference group 0.07 0.85-2.35 Anterior vs posterior Posterior glottis 1.50 0.08 Reference group 0.08 1.15-5.55 Arytenoid motility Impaired/absent arytenoid motility 3.20 0.02 Reference group 0.07 1.35-15.5 CAU involvement Radiological CAU invasion 2.30 0.08 Reference group 0.10 1.65-3.35 Hypoglottic extension Endoscopic hypoglottic extension 1.55 0.09 Reference group 0.25 0.65-8.55 * Fisher’s exact test; ** Wald test

356 Modulated OPHL

rates. In 2017, Lucioni et al. reported that postoperative la- cedure can even be converted to total laryngectomy. In most ryngeal obstruction of the neoglottis after OPHL occurred cases, however, correct preoperative staging can predict the in 49 of 446 patients who had OPHL type II (11%) and in possibility of conservative surgery, rather than the need for 36 of 105 patients who had OPHL type III (34%). Such a radical laryngectomy. For the same reasons, OPHL type I is complication in most cases can be managed with transoral not usually part of the modularity issue, since correct endo- laser microsurgery (TLM) to resolve the neolaryngeal ste- scopic and radiological diagnostic work-up can exclude the nosis. Also, the number of procedures necessary to treat involvement of the glottis by a supraglottic cancer. the stenosis differed between the procedures. Actually, the To our knowledge, on the other hand, there are no clear authors reported that 1.6 ± 1.2 TLM procedures were nec- predictive parameters of the modulation of OPHL. In the essary to manage the stenosis after OPHL type II, while present study, we investigated the relevance of clinical (en- 2.2 ± 1.8 were necessary after OPHL type III. The final doscopic and radiological) parameters to predict the modu- decannulation rate after OPHL type II was 92% vs 86% lation of the OPHL. after OPHL type III 17. Univariate and multivariate analysis found that hypoglottic In 2015, Schindler and coworkers published an exhaustive extension of the tumour was the most significant preopera- comparison of functional outcomes of OPHL type IIa and tive parameter to predict the possibility of intraoperatively IIIa, in terms of swallowing, voice and quality of life. Their modulating the OPHL. results, showing the effectiveness of OPHL type IIIa, de- In cases with endoscopic and radiological suspicion of noted a trend toward better functional outcomes of OPHL the hypoglottic region, OPHL lets the surgeon start with IIa, although significant differences were found in swal- a supracricoid approach, with the possibility to lower the lowing only for residue with solids and for voice intelligi- resection, modulating the procedure to a supratracheal lar- bility 18. yngectomy, according to the results of intraoperative frozen All patients must be preoperatively informed about the sections. eventuality of shifting from supracricoid to supratracheal Clearly, the possibility to modulate the OPHL must not laryngectomy. Specific consent including all possible ex- reduce the importance of a scrupulous preoperative stag- tensions of the procedure, to be signed by the patient, is ing. In the present study, all patient underwent preopera- thus needed 8. At our Institution, patients are routinely in- tive flexible endoscopy in an outpatient setting, contrast- formed about the possibility of intraoperative modulation enhanced neck MRI, if available, or CT scan and direct of partial laryngectomy and that, in extreme cases, the pro- laryngoscopy under general anaesthesia using rigid 0°, 30°

A B C

Figure 1. A. Opening the larynx during supracricoid approach to assess the tumour extension. B. After frozen sections results, the caudal incision is lowered under the cricoid cartilage (supratracheal resection). C. Removal of the cricoid ring en bloc with the specimen. Captions. c: cricoid ring; g: glottis; h: hypoglottis; lcau: left crico-arytenoid unit; t: trachea; *: tumour.

357 A. Bertolin et al. and 70° telescopes in white light and narrow band imaging Acknowledgements to assess the mucosal margins of the neoplasm 19. The authors thank all the medical and paramedical staff On the other hand, the hypoglottic extension did not sig- at the Otolaryngology Unit - Vittorio Veneto Hospital, for nificantly impact oncological outcomes (Tab. II). This is collecting the follow-up data, and the Association “Amici probably due to the good tumour control by OPHL type III della voce” (Friends of the Voice) for support in preparing in cases with initial hypoglottic extension of the tumour. the manuscript. Moreover, the only patient with caudal positive margins who had modulation of the OPHL did not experience local recurrence of the disease. References The recent literature is focusing on the negative prognostic 1 Alonso JM. Functional surgery in cancer of the larynx; subtotal hori- relevance of posterior spreading of the glottic tumour 20-25. zontal laryngectomy. Ann Otolaryngol 1957;74:75-80. 2 This finding was confirmed by our results (Tab. II), although Piquet JJ, Desaulty A, Decroix G. La crico-hyoido-épiglottopexie. Tecnique opératoire et résultats fonctionnels. Ann Otolaryngol Chir only the posterior glottic localisation and the impaired/ab- Cervicofac 1974;91:681-90. sent arytenoid mobility were related to significantly lower 3 Labayle J, Bismuth R. Total laryngectomy with reconstitution. Ann DFS (p = 0.04) and higher recurrence rate (p = 0.02), re- Otolaryngol Chir Cervicofac 1971;88:219-28. spectively. Interestingly, our results ruled out glottic locali- 4 Serafini I. Reconstructive laryngectomy. Rev Laryngol Otol Rhinol sation (anterior vs posterior), arytenoid mobility and the (Bord) 1972;93:23-38. 5 Rizzotto G, Succo G, Lucioni M, et al. Subtotal laryngectomy radiological finding of TCAS or CAU involvement as pre- with tracheohyoidopexy: a possible alternative to total laryngec- dictors of OPHL modulation. This could be related to the tomy. Laryngoscope. 2006;116:1907-17. https://doi.org/10.1097/01. preoperative selection of cases. Actually, patients with en- mlg.0000236085.85790.d5 doscopic evidence of posterior glottic lesions or impaired/ 6 Succo G, Peretti G, Piazza C, et al. Open partial horizontal laryn- gectomies: a proposal for classification by the working committee absent arytenoid mobility were directly approached with on nomenclature of the European Laryngological Society. Eur Arch OPHL type III because of the high risk of crico-arytenoid Otorhinolaryngol 2014;271:2489-96. https://doi.org/10.1007/s00405- joint involvement by the tumour. Similarly, in case of radi- 014-3024-4 ological suspicion of TCAS or CAU invasion, these struc- 7 Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours. 8th ed. Chichester, UK: John Wiley and Sons; tures were directly sacrificed (OPHL type III). 2017. In the present study, multivariate analysis (Tab. III) con- 8 Giordano L, Di Santo D, Crosetti E, et al. Open partial horizontal firmed that only a pathological finding of neck metastasis laryngectomies: is it time to adopt a modular form of consent for the was an independent negative prognostic factor in terms of intervention? Acta Otorhinolaryngol Ital 2016;36:403-7. https://doi. org/10.14639/0392-100X-769 recurrence rate (p = 0.05), consistent with the current litera- 9 Chang YR, Han SS, Park SJ, et al. Surgical outcome of pancre- 26 ture on laryngeal cancer . On the other hand, the impaired atic cancer using radical antegrade modular pancreatosplenectomy arytenoid motility, CAU invasion and need for OPHL type procedure. World J Gastroenterol 2012;18:5595-600. https://doi. III were not independent negative prognostic factors. Once org/10.3748/wjg.v18.i39.5595 10 again, this is reasonably due to the fact that all these situ- Brar S, Law C, McLeod R, et al. Defining surgical quality in gas- tric cancer: a RAND/UCLA appropriateness study. J Am Coll Surg ations are possible in case of posterior glottic localisation 2013;217:347-57.e1. https://doi.org/10.1016/j.jamcollsurg.2013.01.067 of the tumour. 11 Masiak-Segit W, Rawicz-Pruszyński K, Skórzewska M, et al. Surgi- cal treatment of pancreatic cancer. Pol Przegl Chir 2018;90:45-53. https://doi.org/10.5604/01.3001.0011.7493 Conclusions 12 Li M, Wang XA, Wang L, et al. A three-step method for modular lym- phadenectomy in gastric cancer surgery: the ability to retrieve suf- OPHL represents the modular surgery par excellence to ficient lymph nodes and improve survival. Am J Surg 2018;215:91-6. approach the glottic LSCC. The endoscopic and radio- https://doi.org/10.1016/j.amjsurg.2017.01.042 logical finding of hypoglottic extension is the preoperative 13 Wu X, Rao J, Zhou X, et al. Partial ALPPS versus complete ALPPS parameter that is most informative in predicting intraop- for staged hepatectomy. BMC Gastroenterol 2019;19:170. https://doi. erative OPHL modulation. Patients affected by tumours org/10.1186/s12876-019-1090-1 14 Tolkachjov SN, Brodland DG, Coldiron BM, et al. Understanding with hypoglottic extension and eligible for OPHL type II Mohs micrographic surgery: a review and practical guide for the should be preoperatively informed about the possibility of nondermatologist. Mayo Clin Proc 2017;92:1261-71. https://doi. an intraoperative switch towards OPHL type III. Patients org/10.1016/j.mayocp.2017.04.009 with posterior glottic lesions or impaired/absent arytenoid 15 Succo G, Crosetti E, Bertolin A, et al. Benefits and drawbacks of open partial horizontal laryngectomies, Part B: Intermediate and selected mobility should be directly approached with OPHL type III advanced stage laryngeal carcinoma. Head Neck 2016;38(Suppl or total laryngectomy. 1):E649-57. https://doi.org/10.1002/hed.24064.

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16 Succo G, Fantini M, Rizzotto G. Supratracheal partial laryngec- 22 Succo G, Cirillo S, Bertotto I, et al. Arytenoid fixation in laryngeal tomy: indications, oncologic and functional results. Curr Opin Oto- cancer: radiological pictures and clinical correlations with respect to laryngol Head Neck Surg 2017;25:127-32. https://doi.org/10.1097/ conservative treatments. Cancers (Basel) 2019;11:360. https://doi. MOO.0000000000000344 org/10.3390/cancers11030360 17 Lucioni M, Bertolin A, Lionello M, et al. Transoral laser microsurgery for 23 Del Bon F, Piazza C, Lancini D, et al. Open partial horizontal lar- managing laryngeal stenosis after reconstructive partial laryngectomies. yngectomies for T3-T4 laryngeal cancer: prognostic impact of an- Laryngoscope 2017;127:359-65. https://doi.org/10.1002/lary.26056 terior vs. posterior laryngeal compartmentalization. Cancers (Basel) 18 Schindler A, Pizzorni N, Fantini M, et al. Long-term functional results 2019;11:289. https://doi.org/10.3390/cancers11030289 after open partial horizontal laryngectomy type IIa and type IIIa: A 24 Crosetti E, Bertolin A, Molteni G, et al. Patterns of recurrence after comparison study. Head Neck 2016;38(Suppl 1):E1427-35. https:// open partial horizontal laryngectomy types II and III: univariate and doi.org/10.1002/hed.24254 logistic regression analysis of risk factors. Acta Otorhinolaryngol Ital 19 Crosetti E, Pilolli F, Succo G. A new strategy for endoscopic staging 2019;39:235-43. https://doi.org/10.14639/0392-100X-2409 of laryngeal carcinoma: multistep endoscopy. Acta Otorhinolaryngol 25 Lucioni M, Lionello M, Guida F, et al. The thyro-cricoarytenoid Ital 2012;32:175-81. space (TCAS): clinical and prognostic implications in laryngeal 20 Succo G, Crosetti E, Bertolin A, et al. Treatment for T3 to T4a la- cancer. Acta Otorhinolaryngol Ital 2020;40:106-12. https://doi. ryngeal cancer by open partial horizontal laryngectomies: prognos- org/10.14639/0392-100X-N0373 tic impact of different pathologic tumor subcategories. Head Neck 26 Bradford CR, Ferlito A, Devaney KO, et al. Prognostic factors in la- 2018;40:1897-908. https://doi.org/10.1002/hed.25176 ryngeal squamous cell carcinoma. Laryngoscope Investig Otolaryn- 21 Lucioni M, Lionello M, Machin P, et al. Sclerosis of the arytenoid gol 2020;5:74-81. https://doi.org/10.1002/lio2.353 cartilage and glottic carcinoma: A clinical-pathological study. Head Neck 2019;41:72-8. https://doi.org/10.1002/hed.25372

359 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:360-367; doi: 10.14639/0392-100X-N0830

Laryngology Outcomes of balloon dilation for paediatric laryngeal stenosis Il balloon nel trattamento delle stenosi laringee in età pediatrica Giovanna Cantarella1,2, Michele Gaffuri2, Sara Torretta1,2, Simona Neri3, Maria Teresa Ambrosini3, Alessandra D’Onghia1,2, Lorenzo Pignataro1,2, Kishore Sandu4 1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Otolaryngology and Head and Neck Surgery, Milan, Italy; 2 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 3 Unit of Pediatric Anesthesiology and Intensive Care, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 4 Airway Sector; Department of Otolaryngology, Lausanne University Hospital CHUV, Switzerland

SUMMARY Objective. Balloon dilation (BD) is a minimally invasive endoscopic treatment for paediat- ric laryngeal stenosis (LS) with reduced morbidity compared to open surgery. We retrospec- tively describe our experience in a cohort of children with chronic LS. Methods. Fourteen children (median age: 28.5; range: 2-81 months) with chronic LS (mul- tilevel in 8) were treated with tubeless total intravenous anaesthesia under spontaneous ventilation. Results. Grade III LS was preoperatively detected in 12 children; the remaining 2 had grade IV stenosis. Six had prior tracheotomy, and one received it during the first interven- tion. Dilation laryngoplasty was the primary treatment in 11 children and was used as an Received: May 5, 2020 adjuvant treatment in 3 after open reconstructive surgery. The median number of dilations Accepted: July 28, 2020 was 2 (range: 1-6). There were no postoperative complications. At the end of the follow-up (median: 20.5; range: 2-46 months), detectable laryngeal lumen widening and/or respira- Correspondence tory improvement occurred in 12 children. Two of 7 patients with tracheostomy were de- Sara Torretta cannulated. Department of Clinical Sciences and Community Conclusions. Balloon laryngoplasty is a valuable therapeutic option to improve laryngeal Health, Università degli Studi di Milano, Fondazio- patency in children with chronic multilevel LS, both as a primary and secondary adjuvant ne IRCCS Cà Granda Ospedale Maggiore Policlini- treatment after reconstructive surgery. co, Via F. Sforza 35, 20122 Milano, Italy Tel. +39 02 50320245. Fax +39 02 50320248 KEY WORDS: balloon dilation, paediatric, laryngeal stenosis, dyspnea, children E-mail: [email protected]

RIASSUNTO Funding Obiettivi. Descrivere retrospettivamente la nostra esperienza con dilatazione laringea con None. balloon (DB) per il trattamento della stenosi laringea (SL) cronica in età pediatrica. Metodi. Quattordici bambini (età mediana: 28,5; range: 2-81 mesi) con SL cronica (multi- Conflict of interest livello in 8 casi) sono stati sottoposti a DB in ventilazione spontanea in assenza di intuba- The Authors declare no conflict of interest. zione orotracheale con anestesia endovenosa esclusiva. Risultati. Dodici bambini presentavano pre-operatoriamente una SL di grado III, i rima- How to cite this article: Cantarella G, Gaffuri nenti una SL di grado IV. Sei pazienti erano portatori di tracheotomia mentre un paziente M, Torretta S, et al. Outcomes of balloon dilation è stato sottoposto a tracheotomia durante la prima DB. La DB è stata eseguita come trat- for paediatric laryngeal stenosis. Acta Otorhi- tamento primario in 11 bambini e come adiuvante a chirurgia ricostruttiva in 3 casi. Il nolaryngol Ital 2020;40:360-367. https://doi. numero mediano di BD eseguite è 2 (range: 1-6). Non si sono verificate complicanze post- org/10.14639/0392-100X-N0830 operatorie e, al termine del follow-up (mediana: 20,5; range: 2-46 mesi), in 12 bambini è stato obiettivato un ampliamento del lume laringeo e/o un miglioramento respiratorio. Due © Società Italiana di Otorinolaringoiatria dei 7 pazienti con tracheotomia sono stati decannulati con successo. e Chirurgia Cervico-Facciale Conclusioni. La DB risulta efficace e sicura per migliorare in bambini con SL cronica multi-livello sia come trattamento primario che come trattamento adiuvante. OPEN ACCESS This is an open access article distributed in accordance with PAROLE CHIAVE: dilatazione con balloon, pediatria, stenosi laringea, dispnea, bambini the CC-BY-NC-ND (Creative Commons Attribution-Non- Commercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and only in the original version. For further information: https:// creativecommons.org/licenses/by-nc-nd/4.0/deed.en

360 Balloon dilation for paediatric laryngeal stenosis

Introduction Study subjects The study involved the charts of children who had been Laryngeal stenosis (LS) in neonatal and paediatric age treated with BD for chronic LS between February 2016 and groups is a potentially life-threatening condition and has a October 2019. All patients underwent endoscopic treatment severe impact on the quality of life of children and families. and subsequent postoperative follow-up in our tertiary out- It can be congenital or acquired, but the latter is most fre- patient clinic. The authors GC, MG and LP performed all quent, mainly due to prolonged endotracheal intubation in the procedures with collaborative guidance of KS. All pa- neonatal intensive care for severe prematurity 1,2. The most tients underwent transnasal flexible high-definition video commonly involved sites in LS are the subglottis and the laryngoscopies on their initial presentation and during fol- posterior glottis, as the cricoid, the medial aspects of the low-up visits. arytenoid cartilage and the posterior commissure are the The diagnosis of LS was confirmed by direct laryngotra- areas in the airway with a major risk of developing intuba- cheoscopy under general anaesthesia, and patients breathed tion injuries 1. spontaneously. The degree of LS before and after BD was Three main types of procedures have been proposed to treat scored according to the Myer-Cotton grading scale 6. established cicatricial LS: expansion of the airway with LS was defined as chronic if symptoms were present for costal cartilage, resection of the stenotic part of the airway more than 3 months. and dilation by means of rigid dilators or by inflatable bal- loons. Balloon dilation (BD) has been proposed since 1984 Interventions to treat tracheal and bronchial stenoses and is appropri- The retrospective chart review included demographic data ate only if the cartilaginous skeleton of the airway is pre- and clinical histories. The clinical histories included all served. A balloon is used under direct endoscopic vision possible conditions predisposing to the development of and allows the application of radial pressure on the airway LS, including prolonged intubation, intensive-care unit stricture, thus theoretically reducing the risk of shearing the stay, prematurity, syndromic disease or defined genetic ab- mucosa with consequent possible restenosis. normalities, previous cardiac surgery and previous airway Recently, there has been an increase in the number of re- ports highlighting the important role of balloon laryn- surgery. History of respiratory distress, stridor, voice im- goplasty in avoiding tracheotomy in acute and subacute pairment, failure to thrive, or swallowing impairment were airway obstruction and in improving airway patency in im- recorded. mature or mature scarring with limited extension and thick- In the children without tracheotomy, BD was performed ness 4,5. The procedure is minimally invasive and can avoid under tubeless total intravenous anaesthesia (TIVA) with the intra- and postoperative risks of major reconstructive spontaneous ventilation and supplemental oxygen adminis- surgery. tration dispensed by an uncuffed silicone endotracheal tube This paper aims to retrospectively describe our experience placed through the nasal fossa and left in the hypopharynx with BD in a cohort of children affected by LS. The pe- with its bevel facing the airway. A second similar uncuffed culiarity of the described series is related to the extension tube was prepared on a 2.7 mm Storz (Germany) rigid 0° of stenosis - multilevel in most cases - and to the chronic endoscope ready to be used in case of the need for emer- nature of the lesion, as the majority of patients were symp- gency intubation to allow rapid introduction under direct tomatic for several months or years. endoscopic vision. The anaesthetic technique was stand- ardised as reported in Table I. Heart rate, blood pressure, pulse oximetry, Bispectral Index (BIS) level, transcutane- Materials and methods ous CO2 (TcCO2), respiratory rate and temperature were recorded intraoperatively. Study design and setting Lidocaine was sprayed into the larynx under direct laryn- This study is a retrospective chart review of prospectively goscopic vision at a dose of 2-4 mg/kg. Then, an appropri- recruited children with LS, and it was carried out at the ately sized Lindholm or Parson laryngoscope was placed Otolaryngology Division of Milan University’s Depart- to expose the larynx under suspension. First, a 0° rigid ment of Clinical Sciences and Community Health in De- 2.7- or 4-mm telescope was introduced to examine the vo- cember 2019. cal cords, anterior and posterior commissures, subglottis, The protocol was approved by our local Ethics Commit- trachea, carina and mainstem bronchi. Once the stenosis tee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore was assessed, triamcinolone acetate (KenacortR 40 mg/ml, Policlinico and was conducted in accordance with the prin- Bristol-Myers Squibb s.r.l.) was injected into the stenotic ciples of good clinical practice. and scarred areas. If concentric stenosis was found, 3-4 ra-

361 G. Cantarella et al.

Table I. Description of the anaesthetic protocol for balloon dilation. Superpulse). Next, an appropriately selected balloon was Anaesthetic procedures placed in the stenotic tract of the airway under direct tel- Premedication: intranasal dexmedetomidine (3 mcg/kg), 30 minutes before escopic or microscopic vision. An angioplasty balloon the procedure (Boston Scientific PTCA Dilatation Catheter) was utilised Mask induction with sevoflurane to for intravenous access placement for the first 26 dilations, while the TRACOE Aeris® Bal- Anaesthetic maintenance with propofol (target-controlled infusion model; loon Dilation Catheter was available for the 4 dilations per- 3-4 mcg/ml) and remifentanil (0.07-0.15 mcg/kg/min) formed in cases 13 and 14. The balloon size was selected Propofol infusion titrated to a clinically adequate level of anaesthesia, guided by the BIS (target 40-60) and remifentanil infusion titrated to by adding 1 mm for the larynx and 2 mm for tracheal ste- respiratory rate (target >10 breaths per min) to avoid apnoea and nosis to the outer diameter of the age-appropriate endotra- desaturation cheal tube size for the patient 7,8. Careful laryngoscopy and 2% lidocaine spray to the vocal cords (2-4 mg/kg) Balloon inflation was performed and maintained for 2 min Supplemental oxygen administered through a Portex Blue Line tube or until oxygen saturation decreased to less than 90%. It positioned through a nostril into the hypopharynx was repeated 2-3 times for one min in patients who desatu- Propofol bolus to induce apnoea during balloon inflation, followed by hand- rated early. In cases of severe stenosis or fragile mucosa, mask ventilation or endotracheal intubation until spontaneous breathing was resumed the duration of each dilation was 20-30 sec to avoid mu- cosal shearing and/or development of an ischaemic lesion. In syndromic children, we used a balloon smaller than the dial incisions were performed using a microlaryngoscopy age-appropriate balloon and reduced the dilation time to disposable sickle knife (Medtronic) mounted on a handle 20-30 sec for each inflation to minimise the risk of collat- (Microfrance). In the case of posterior glottic stenosis, a eral mucosal damage under the assumption that a congeni- single median sagittal incision was performed either by a tally small cricoid might not safely tolerate an excessive or sickle knife or by the digital AcuBlade CO2 laser (Lumenis, prolonged pressure that might cause cartilage damage.

Table II. Demographic and clinical characteristics of patients (Part I). Table II. Demographic and clinical characteristics of patients (Part II). Case Age (months) Gender Comorbidities Previous surgery Site of stenosis Cause of stenosis Type of Pre-op. grade No. of Post-op. Tracheotomy Clinical condition after Follow-up (months) No. treatment of stenosis* endoscopic grade of treatment treatments stenosis* Predilation Post dilation 1 48 Male Severe prematurity No Posterior glottis and Acquired Primary III 2 I Yes No Asymptomatic 25 subglottis 2 76 Male Severe prematurity No Subglottis and posterior Acquired Primary III 2 I No No Mild fatigue at maximal 25 glottis effort 3 20 Male Head, neck, chest burns No Subglottis Acquired Primary III 1 I No No Asymptomatic 16 4 30 Male Down’s syndrome PCTR and LTR Subglottis, glottis. Mixed Adjuvant III 2 III Yes Yes Phonatory valve 19 5 27 Male Severe prematurity LTR Glottis, subglottis Acquired Adjuvant III 3 II Yes No Asymptomatic 46 6 81 Male Prematurity No Subglottis Acquired Primary III 1 I No No Asymptomatic 45 7 14 Male Prematurity Endoscopic surgery Glottis, subglottis Mixed Primary III 1 III Yes Yes Requires EPCTR 42 8 7 Female Genetic disease with No Subglottis Acquired Primary III 1 I No No Asymptomatic 25 multiple malformations 9 51 Male Severe prematurity - LTR Glottis, subglottis, and Acquired Adjuvant IV 6 III Yes Yes Phonatory valve 24 h 22 trachea 10 6 Male Down’s syndrome and No Subglottis Mixed Primary IV 3 III Yes Yes Phonatory valve 12 previous cardiac surgery (daytime) 11 20 Male Severe prematurity No Glottis and subglottis Mixed Primary III 2 III No Yes Phonatory valve 13 (daytime) 12 64 Female Down’s syndrome. and No Subglottis Mixed Primary III 2 I No No Asymptomatic 6 previous cardiac surgery 13 2 Male DiGeorge syndrome No Glottis Mixed Primary III 3 I No No Improved++ 6 14 43 Male Severe prematurity No Glottis and subglottis Acquired Primary III 1 II No No Improved++ 2 PCTR: partial cricotracheal resection; LTR: laryngotracheal reconstruction; EPCTR: extended partial cricotracheal resection. * according to the Myer-Cotton classification6 ; PCTR: partial cricotracheal resection; LTR: laryngotracheal reconstruction; EPCTR: extended partial cricotracheal resection. * according to the Myer-Cotton classification6 ; ++ no longer dependent on noninvasive ventilation. ++ no longer dependent on noninvasive ventilation.

362 Balloon dilation for paediatric laryngeal stenosis

Noninvasive ventilation (CPAP) was given in the immedi- are given as absolute numbers and percentages or median ate postoperative period along with temporary adrenaline values with ranges. and budesonide aerosols. Dexamethasone (1 mg/kg), cefa- zoline (25 mg/kg) and proton pump inhibitors were admin- Results istered in the operating room and were continued during the postoperative period. Children were admitted to the This case series comprised 14 children – median age: 28.5 months, range: 2-81 months; 12 boys and 2 girls; and 8 paediatric intensive care unit for at least one night after the (57.1%) patients with severe prematurity and 5 (35.7%) with surgery. If additional dilations were needed, repeated pro- syndromic or genetically-defined disease. Patients had a his- cedures were performed at 2-6-week intervals. tory of prolonged intubation for severe prematurity (8/14, The effectiveness of the procedure was defined by three 57.1%), respiratory distress at birth (3/14, 21.4%), previous main outcome measures: cardiac surgery (2/14, 14.3%) and severe burns extending to • Stable improvement of airway patency with a reduction the lower face, neck and chest (1/14, 7.1%). The detailed de- in the grade of stenosis according to the Myer-Cotton mographic and clinical characteristics are reported in Table II. grading scale Dilation laryngoplasty was the primary treatment in 11 • Clinical improvement and use of a phonatory valve that children; among them, acquired LS was documented in 8, was not possible prior to dilation while mixed-type stenosis was found in 3 syndromic chil- • Decannulation or tolerating a fully capped tracheostomy dren (cases 10, 12, 13). A congenital membranous glot- cannula tic web (Cohen type 2) 9 affected case 13, but his stenosis became symptomatic after intubation for cardiac surgery Statistical analysis (ventricular septal defect correction), adding mild acquired Descriptive statistics were used to summarise the demo- stenosis to the existing congenital stenosis. He was treated graphic and clinical characteristics of patients. The results with sickle knife lysis of the web, followed by dilation. In 3

Table II. Demographic and clinical characteristics of patients (Part I). Table II. Demographic and clinical characteristics of patients (Part II). Case Age (months) Gender Comorbidities Previous surgery Site of stenosis Cause of stenosis Type of Pre-op. grade No. of Post-op. Tracheotomy Clinical condition after Follow-up (months) No. treatment of stenosis* endoscopic grade of treatment treatments stenosis* Predilation Post dilation 1 48 Male Severe prematurity No Posterior glottis and Acquired Primary III 2 I Yes No Asymptomatic 25 subglottis 2 76 Male Severe prematurity No Subglottis and posterior Acquired Primary III 2 I No No Mild fatigue at maximal 25 glottis effort 3 20 Male Head, neck, chest burns No Subglottis Acquired Primary III 1 I No No Asymptomatic 16 4 30 Male Down’s syndrome PCTR and LTR Subglottis, glottis. Mixed Adjuvant III 2 III Yes Yes Phonatory valve 19 5 27 Male Severe prematurity LTR Glottis, subglottis Acquired Adjuvant III 3 II Yes No Asymptomatic 46 6 81 Male Prematurity No Subglottis Acquired Primary III 1 I No No Asymptomatic 45 7 14 Male Prematurity Endoscopic surgery Glottis, subglottis Mixed Primary III 1 III Yes Yes Requires EPCTR 42 8 7 Female Genetic disease with No Subglottis Acquired Primary III 1 I No No Asymptomatic 25 multiple malformations 9 51 Male Severe prematurity - LTR Glottis, subglottis, and Acquired Adjuvant IV 6 III Yes Yes Phonatory valve 24 h 22 trachea 10 6 Male Down’s syndrome and No Subglottis Mixed Primary IV 3 III Yes Yes Phonatory valve 12 previous cardiac surgery (daytime) 11 20 Male Severe prematurity No Glottis and subglottis Mixed Primary III 2 III No Yes Phonatory valve 13 (daytime) 12 64 Female Down’s syndrome. and No Subglottis Mixed Primary III 2 I No No Asymptomatic 6 previous cardiac surgery 13 2 Male DiGeorge syndrome No Glottis Mixed Primary III 3 I No No Improved++ 6 14 43 Male Severe prematurity No Glottis and subglottis Acquired Primary III 1 II No No Improved++ 2 PCTR: partial cricotracheal resection; LTR: laryngotracheal reconstruction; EPCTR: extended partial cricotracheal resection. * according to the Myer-Cotton classification6 ; PCTR: partial cricotracheal resection; LTR: laryngotracheal reconstruction; EPCTR: extended partial cricotracheal resection. * according to the Myer-Cotton classification6 ; ++ no longer dependent on noninvasive ventilation. ++ no longer dependent on noninvasive ventilation.

363 G. Cantarella et al.

children, balloon laryngoplasty was an adjuvant treatment er grade of LS in 11 patients (78.6%). In 2 of the remain- following reconstructive surgery (Tab. II). ing 3 children, subjective improvement occurred, and these Grade III LS was preoperatively detected in 12 of 14 (85.7%) children currently tolerate the use of a phonatory valve over children; the remaining 2 patients presented with grade IV a down-sized cannula. stenosis. In one case of grade IV stenosis, a Down’s syn- Six children had an initial tracheotomy, and one was tra- drome patient had a cranio-caudal length of 3 mm and was cheotomised at the time of the first dilation (Tab. III). affected by mixed-type stenosis; in the other patient, recur- Two were decannulated (cases No. 1 and 5) after BD, rence of grade IV stenosis was observed with a size of ap- and 5 remained tracheotomised. The benefit achieved by proximately 5 mm after a second attempt at airway expansion BD procedures in cases No. 4, 9, 10 and 11 did not al- by cartilage grafts. Two patients with grade III stenosis and low decannulation but the use of a phonatory valve was 1 patient with grade IV stenosis had previously undergone tolerated all day long. Case 7 had no benefit at all: he major surgical treatment (laryngotracheal reconstruction in was an extremely premature child with severe multilevel 2 cases and partial cricotracheal resection followed by laryn- fibrotic stenosis resulting from several endoscopic laser gotracheal reconstruction in 1 case). In most treated patients procedures performed elsewhere. After failing BD, he (8/14, 57.1%), multiple sites of obstruction were detected. underwent a successful reconstructive procedure with A total of 30 dilation procedures were performed; the me- subsequent decannulation. A detailed description of the dian number of dilation procedures was 2 (range: 1-6). clinical characteristics and outcomes in the subset of tra- Only in one child (No. 11), affected by severe grade III cheotomised patients is reported in Table III. glotto-subglottic stenosis, was a tracheotomy performed on BD laryngoplasty established a clearly detectable widening the day of his first dilation to establish a secure distal air- of the laryngeal lumen and respiratory improvement in 12 way. All the other dilation procedures were well tolerated (85.7%) of the 14 children. without any immediate or late complications. We continued Figures 1-3 show the results achieved in 3 patients. to use BD only if we found that there was clinical and en- doscopic improvement compared to prior the endoscopy. Discussion Postoperatively, the patients had a median follow-up of 20.5 months, ranging from 2-46 months. Residual grade I The use of BD is becoming progressively widespread in LS was documented in 8 of 14 (57.1%) patients; grade II several surgical fields and is considered a valid and mini- and grade III LS were found in 1 (7.1%) and 5 (45.4%) pa- mally invasive alternative to major open surgical proce- tients, respectively. Follow-up laryngoscopy showed a low- dures. The morbidity associated with airway dilation is low

Table III. Detailed description of clinical characteristics and outcomes in the subset of tracheotomised patients. Case No. Comorbidities Previous procedures Clinical staging* Outcome (elsewhere) (before balloon dilation) 1 Severe prematurity Multiple unsuccessful Multisite grade III LS Decannulated decannulation attempts (elsewhere) 4 Down’s syndrome PCTR; LTR Multisite grade III LS Non-decannulated but using phonatory valve 5 Severe prematurity Approximately 18 endoscopic Multisite grade III LS Decannulated laser procedures (elsewhere); LTS 7 Severe prematurity Multiple endoscopic laser Multisite grade III LS Decannulated after reconstructive procedures (elsewhere) procedure 9 Severe prematurity 2 LTRs (1 elsewhere) Multisite grade IV LS Non-decannulated but using phonatory valve 10 Down’s syndrome and cardiac Multiple unsuccessful extubation Subglottic grade IV LS Non-decannulated but using surgery attempts phonatory valve (elsewhere) 11 Severe prematurity and prolonged Multiple unsuccessful extubation Multisite grade III LS Tracheotomy at the first dilation; endotracheal intubation attempts non-decannulated but using (elsewhere) phonatory valve. Waiting for reconstructive surgery LS: laryngeal stenosis; PCTR: partial cricotracheal resection; LTR: laryngotracheal reconstruction; * according to the Myer-Cotton classification6 .

364 Balloon dilation for paediatric laryngeal stenosis

A B A B

C D C D

Figure 1. A: Grade III subglottic stenosis in a 20-month-old male intubated Figure 2. Multilevel obstruction in a 76-month-old male, severe prematurity, with several failed attempts of extubation elsewhere, due to diffuse burns to with a history of prolonged invasive ventilation. A: Posterior glottic stenosis due head, neck and chest. B: Radial incisions of the concentric stenosis. Note the to inter-arytenoid scarring and associated subglottic stenosis. B: View of the naso-oropharyngeal tube. C: Laryngoscopic view soon after dilation. D: La- subglottic stenosis. C: Subglottic result achieved after a single dilation, a sec- ryngoscopy performed 4 months later shows a stable scar and a sub-optimal ond dilation is performed together with median incision of the posterior glottic airway. scar, and intralesional injection of triamcinolone; D: final result.

if the procedure is cautiously performed and if the indica- A B tions and contraindications are correctly respected 4,5,9-11. In our opinion, BD is mainly indicated for grade I-III ste- nosis (Cotton-Myer classification) and in rare cases of thin diaphragm-like grade IV stenosis. Conversely, long and thick stenoses, narrow congenital cricoid malforma- tions, associated airway malacia, inflammation and multi- site dense stenoses require open operations such as airway expansion (laryngotracheal reconstruction with cartilage C D grafts) or airway resection and anastomosis (cricotracheal resection-CTR or an extended CTR); BD can be used as a complementary procedure to enhance open surgical results. Reconstructed multi-planar 3-D CT scans can be useful in multi-site airway stenosis. However, precise interpretation of laryngotracheal stenosis on CT scan in small children can be challenging. A dedicated dynamic and rigid endoscopy is more valuable Figure 3. Multilevel obstruction in a 64-month-old female, affected by Down in detecting the exact site(s), length of the stenosis and ex- syndrome, with prior history of cardiac surgery. A: Subglottic mixed type con- tent of remaining normal trachea 17. The quality of airway centric stenosis and posterior glottic stenosis. B: Immediate result after radial mucosa is critical and a CT scan cannot detect this informa- incisions of the stenosis and dilation by 6 mm balloon. C: Laryngoscopic view 4 weeks later showing that the improvement in patency is maintained; a second tion. Additionally, stagnated secretions at the stenotic sites incision and dilation treatment with 8 mm balloon is performed; D: final result. will exaggerate the stenosis. We prefer doing CT/MRI scan in cervico-mediastinal vascular anomalies, though virtual bronchoscopy could be useful in complete airway stenosis Most patients with correct selection criteria can undergo that will not allow passing of endoscopes. laryngeal BD without needing tracheotomy. In our series,

365 G. Cantarella et al.

only one of the 8 non-tracheotomised patients (a child with proving airway patency. A small hypoplastic cricoid and a history of severe prematurity, affected by severe stridor severe hypertrophy of subglottic submucosal glands with and chest retractions at rest) needed a tracheotomy on the an added intubation insult respond best to cricotracheal day of his first dilation. All the remaining 7 patients under- resection and anastomosis 17. Similarly, an elliptic cri- went dilation procedures without tracheotomy, obtaining coid malformation with minor intubation sequelae is best immediate and persistent improvements in airway patency; treated with cartilage graft(s) expansion cricoplasty 17. these patients are currently asymptomatic despite their co- In syndromic children, we used a balloon smaller in size morbidities. than the age-appropriate balloon and reduced the dilation The type of anaesthesia adopted is of crucial importance time to 20-30 seconds for each inflation to minimise the for both diagnostic assessment and the endoscopic proce- risk of mucosal ulceration and ischaemia, as a congeni- dure, as spontaneous breathing under intravenous anaes- tally smaller cricoid might not safely tolerate excessive or thesia provides an unobstructed surgical field and excellent prolonged pressure. evaluation of the dynamic airway function and the grades Our results, attesting to the effectiveness of BD in approx- of obstruction. We strongly advocate the use of noninva- imately 86% of children with chronic LS as both primary sive ventilation in the immediate postoperative period. The and adjuvant treatment, corroborate the results of previous continuous airway pressure acts like a pneumatic stent and studies. In particular, Wentzel et al. 18 in 2014 reported a promotes satisfactory airway epithelisation. success rate of 77% after BD in a cohort of 60 children, Eight of our patients had a history of severe prematurity. including 44 with subglottic stenosis; most of the cases Recent advances in neonatal care have greatly improved were acquired after prolonged intubation. This result was the survival rates of premature infants who often require further confirmed by a systematic literature review per- intubation and mechanical ventilation. Currently, only a formed by the same authors 18. The overall success rate, small percentage of intubated babies develop LS, although defined as symptomatic improvement, a decrease in the the majority of paediatric LS cases are acquired because of Myer-Cotton LS grade, decannulation, or the avoidance prolonged intubation (Figs. 1,2). of reconstructive surgery, was slightly lower in their study LS can be associated with some syndromes, and its treat- (64%) than in ours. ment may be challenging if comorbidities are severe. One More recently, Wenzel and coworkers 4 evaluated the im- of the 8 patients without tracheotomy in our series was af- pact of balloon laryngoplasty on the management of acute fected by 22q11 microdeletion syndrome. He needed non- subglottic stenosis in 23 children and reported a success invasive ventilation without oxygen supplementation for rate of approximately 83%. Tracheotomy was required in several months after dilation, as two previous thoracoto- 3 patients, and open laryngotracheal reconstruction was mies for cardiac surgery subsequently weakened his chest required in one case. wall. The effectiveness of BD in mature severe laryngo (tra- Most of the current literature regarding airway BD claims cheal) stenosis has been previously documented in a small the efficacy of BD mainly in cases of acute/subacute case series of 8 children and adolescents by Guarisco and stenosis 12-15 or membranous chronic stenosis with lim- Yang 5, as an open surgical procedure was required in only ited vertical extension. In both cases, a prerequisite for a one patient. They simultaneously applied laryngeal stent- successful procedure is the integrity of the cartilaginous ing in the 4 tracheotomised patients, who were all sub- laryngotracheal skeleton. Our small series suggests that sequently decannulated. None of the remaining patients the dilation procedure can be safely attempted in care- required tracheotomy. In our opinion, an important fac- fully selected cases of acquired or congenital LS and that tor that determines success after BD is the cranio-caudal a minor congenital subglottic malformation might not be length of LS, which has not been well elucidated in many an absolute contraindication. It is known that Down’s syn- publications. The vertical extent of the stenosis is calcu- drome might be associated with underdevelopment and/or lated using a rigid, long and thin telescope that can go malformation of the cricoid cartilage 16 with consequent beyond the stenotic segment. The distal and proximal airway narrowing. The frequent association of heart de- points of the stenosis are ink-marked on the telescope at fects in these patients will prompt early cardiac surgery, the level of the incisor. The cranio-caudal length is then and the subsequent prolonged intubation will add oedema measured on a caliper ruler. In our opinion, any grade of and/or scar tissue, thus worsening congenital stenosis. thin diaphragm-like stenosis that is less than 5 mm in a This was the case in 2 of our patients affected by Down’s non-collapsing airway could respond to BD, although this syndrome. Despite congenital stenosis, cautious dilation needs to be confirmed with prospective and larger multi- might solve the acquired component, significantly im- centric studies. Open surgery must be considered when

366 Balloon dilation for paediatric laryngeal stenosis there is no change or when there is progression of stenosis References after 1-3 trials of BD, as well as in cases of severe carti- 1 Smith MM, Cotton RT. Diagnosis and management of laryngotrache- lage malformations It is difficult to decide the appropriate al stenosis. Exp Rev Resp Med 2018;12:709-17. https://doi.org/10.10 period when adjuvant BD can be performed safely after 80/17476348.2018.1495564 an open neck surgery. At the senior authors’ institution, 2 Choi SS, Zalzal GH. Changing trends in neonatal subglottic stenosis. Otolaryngol Head Neck Surg 2000;122:61-3. https://doi.org/10.1016/ BD is done only after 6 weeks following laryngotracheal S0194-5998(00)70145-8 reconstruction or cricotracheal resection and anastomosis. 3 Cohen MD, Weber TR, Rao CC. Balloon dilatation of tracheal and We did not find any difference between the angioplasty bronchial stenosis. Am J Roentgenol 1984;142:477-8. https://doi. balloons and the Tracoe balloon. However, our experience org/10.2214/ajr.142.3.477 4 Wenzel AM, Schweiger C, Manica D, et al. Impact of balloon lar- with the Tracoe Aeris balloon is not sufficient to make any yngoplasty on management of acute subglottic stenosis. Eur Arch definite conclusions. Otorhinolaryngol 2018;275:2325-31. https://doi.org/10.1007/s00405- The importance of choosing patients wisely, of adequate 018-5064-7 training in endoscopy and all types of open airway surger- 5 Guarisco JL, Yang CJ. Balloon dilation in the management of severe air- way stenosis in children and adolescents. J Pediatr Surg 2013;48:1676- ies, of anesthesia strategies and of postoperative manage- 81. https://doi.org/10.1016/j.jpedsurg.2012.12.035 ment cannot be overemphasised. The first choice of treat- 6 Myer CM 3rd, O’Connor DM, Cotton RT. Proposed grad- ment, whether endoscopic or open, is the best chance to ing system for subglottic stenosis based on endotracheal tube cure patients with LS. Additional collateral damage due to sizes. Ann Otol Rhinol Laryngol 1994;103:319-23. https://doi. org/10.1177/000348949410300410 a wrongly chosen intervention might worsen the original 7 Avelino M, Maunsell R, Jube Wastowski I. Predicting outcomes stenosis and should be avoided. Surgical treatment of LS of balloon laryngoplasty in children with subglottic stenosis. Int J must be tailored depending on the patient’s clinical condi- Pediatr Otorhinolaryngol 2015;79:532-6. https://doi.org/10.1016/j. ijporl.2015.01.022 tion, including the grade and type of stenosis and the pres- 8 Sharma SD, Gupta SL, Wyatt M, et al. Safe balloon sizing for endo- ence of concomitant disease. Complex, multi-site stenosis scopic dilatation of subglottic stenosis in children. J Laryngol Otol with additional cricoarytenoid ankyloses is best treated by 2017;131:268-72. https://doi.org/10.1017/S0022215117000081 open approaches 17. 9 Cohen SR: Congenital glottic webs in children. A retrospective re- An important limitation of our study is the relatively view of 51 patients. Ann Otol Rhinol Laryngol Suppl 1985;121:2-16. 10 Hulstein S, Hoffman H. Technique for improved safety in the en- small number of patients. Nevertheless, to the best of our doscopic management of subglottic stenosis. Am J Otolaryngol knowledge, this is the first Italian report on the system- 2016;37:490-2. https://doi.org/10.1016/j.amjoto.2015.10.009 atic use of BD laryngoplasty for treating paediatric LS. 11 Maresh A, Preciado DA, O’Connell AP, et al. A comparative analysis The present results encourage the use of BD as a primary of open surgery vs endoscopic balloon dilation for pediatric subglot- tic stenosis. JAMA Otolaryngol Head Neck Surg 2014;140:901-5. or adjuvant treatment to obtain adequate patency of the https://doi.org/10.1001/jamaoto.2014.1742 airway with the aim of avoiding tracheotomy when fea- 12 Axon PR, Hartley C, Rothera MP. Endoscopic balloon dilatation sible and reducing the necessity of major reconstructive of subglottic stenosis. J Laryngol Otol 1995;109:876-9. https://doi. surgery. org/10.1017/s0022215100131561 13 Durden F, Sobol SE. Balloon laryngoplasty as a primary treatment for subglottic stenosis. Arch Otolaryngol Head Neck Surg 2007;133:772- Conclusions 5. https://doi.org/10.1001/archotol.133.8.772 14 Bakthavachalam S, McClay JE. Endoscopic management of subglot- Our results confirm the efficacy of BD as a minimally inva- tic stenosis. Otolaryngol Head Neck Surg 2008;139:551-9. https:// sive technique and as the first therapeutic option in selected doi.org/10.1016/j.otohns.2008.07.024 cases of chronic and multilevel LS with an intact laryn- 15 Hebra A, Powell DD, Smith CD, et al. Balloon tracheoplasty in chil- dren: results of a 15-year experience. J Pediatr Surg 1991;26:957-61. gotracheal cartilaginous framework. Failure of this first- https://doi.org/10.1016/0022-3468(91)90843-i line upfront endoscopic procedure does not compromise 16 Hamilton J, Yaneza MM, Clement WA, et al. The prevalence of airway the chances of success of subsequent major reconstructive problems in children with Down’s syndrome. Int J Pediatr Otorhi- surgery. nolaryngol 2016;81:1-4. https://doi.org/10.1016/j.ijporl.2015.11.027 17 This limited series also confirms the validity of dilation lar- Monnier P. Pediatric airway surgery. Berlin, Germany: Springer; 2011. 18 Wentzel JL, Ahmad SM, Discolo CM, et al. Balloon laryngoplasty for yngoplasty as an adjuvant treatment to improve and stabi- pediatric laryngeal stenosis: case series and systematic review. Laryn- lise the results of previous reconstructive surgeries. goscope 2014;124:1707-12. https://doi.org/10.1002/lary.24524

367 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:368-376; doi: 10.14639/0392-100X-N0711

Rhinology Exploring the role of nasal cytology in chronic rhinosinusitis Il ruolo della citologia nasale nella rinosinusite cronica Stefania Gallo1,2, Francesco Bandi1, Andrea Preti3,4, Carla Facco5, Giorgia Ottini5, Federica Di Candia2, Francesco Mozzanica3,6, Laura Saderi7, Fausto Sessa5, Marcella Reguzzoni4, Giovanni Sotgiu7, Paolo Castelnuovo1,2 1 Department of Otorhinolaryngology, University of Insubria and ASST Sette Laghi, Varese, Italy; 2 Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy; 3 Department of Otorhinolaryngology, IRCCS Multimedica, Milano, Italy; 4 Department of Medicine and Surgery, University of Insubria, Varese, Italy; 5 Department of Pathology, University of Insubria and ASST Sette Laghi, Varese, Italy; 6 Department of Biomedical and Clinical Sciences, University of Milan, Italy; 7 Clinical Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, University of Sassari, Italy

SUMMARY Objective. Characterising the eosinophilic profile represents the main step in chronic rhi- nosinusitis (CRS) endotyping. The aim of the study is to verify the correlation between different methods for tissue eosinophilia quantification. Methods. 33 CRS patients undergoing endoscopic sinus surgery and 30 controls undergo- ing non-CRS surgeries were enrolled. Blood venous sampling, nasal biopsy on uncinate process (UP), nasal cytology on inferior turbinate (IT) and middle meatus (MM) were per- formed. Results. Differences in eosinophil count in blood (P=0.0001), UP (P<0.0001), IT (P = 0.01) and MM (P = 0.0006) were significant between CRS cases and controls. A weak correlation Received: February 25, 2020 was found between UP and blood eosinophil count (r = 0.34, P = 0.006) and between UP Accepted: May 11, 2020 and IT eosinophil count (r = 0.30, P = 0.017). Moderate correlation between UP and MM (r = 0.51, P < 0.0001) was shown. ROC analysis predicted eosinophilic CRS with an over- Correspondence all low sensitivity. Once allergic patients were excluded from the analysis, the sensitivity Stefania Gallo decreased for sampling on IT and increased for MM sampling. Clinica Otorinolaringoiatrica, ASST Sette Laghi e Conclusions. This study suggests that MM cytology gives more accurate information on Università degli Studi dell’Insubria, via Guicciardi- ni 9, 21100 Varese, Italy the degree of tissue eosinophilia. Replication in wide and unbiased cohorts is necessary to Tel. +39 0332 278426. Fax +39 0332 278945 verify these results and define accurate thresholds. E-mail: [email protected] KEY WORDS: rhinosinusitis, nasal polyps, rhinitis, eosinophilia, biomarker, cytology Funding None. RIASSUNTO Obiettivi. L’identificazione del profilo eosinofilico è uno step fondamentale nell’endoti- Conflict of interest pizzazione della rinosinusite cronica (RSC). Lo scopo dello studio è verificare il grado di The Authors declare no conflict of interest. correlazione tra le diverse metodiche di quantificazione dell’eosinofilia. Metodi. Sono analizzati, per 33 pazienti RSC candidati a chirurgia endoscopica nasosinu- How to cite this article: Gallo S, Bandi F, sale e 30 controlli sottoposti a chirurgia non RSC-correlata, un campione di sangue venoso Preti A, et al. Exploring the role of nasal cy- periferico, una biopsia del processo uncinato (PU), un citologico sul turbinato inferiore tology in chronic rhinosinusitis.Acta Otorhi- (TI) e un citologico nel meato medio (MM). nolaryngol Ital 2020;40:368-376. https://doi. Risultati. Differenze tra RSC e controlli negli eosinofili su sangue periferico (P = 0,0001), org/10.14639/0392-100X-N0711 PU (P < 0,0001), TI (P = 0,01) e MM (P = 0,0006) sono risultate statisticamente signifi- cative. È stata dimostrata una correlazione debole tra sangue periferico e PU (r = 0.34, © Società Italiana di Otorinolaringoiatria P = 0,006) e tra PU e IT (r = 0,30, P = 0,017), e una correlazione moderata tra PU e MM e Chirurgia Cervico-Facciale (r = 0,51, P < 0,0001). Le curve ROC hanno predetto forme di RSC eosinofila con una sensibilità globalmente bassa. Escludendo i pazienti allergici la sensibilità si riduce ulte- OPEN ACCESS riormente per TI mentre aumenta per MM. This is an open access article distributed in accordance with Conclusioni. Il presente studio suggerisce di eseguire il prelievo citologico nel MM al fine the CC-BY-NC-ND (Creative Commons Attribution-Non- Commercial-NoDerivatives 4.0 International) license. The di identificare le RSC eosinofile. Sono necessari studi più ampi per verificare i risultati e article can be used by giving appropriate credit and mentio- definire valori limite adeguati. ning the license, but only for non-commercial purposes and only in the original version. For further information: https:// PAROLE CHIAVE: rinosinusite, polipi nasali, rinite, eosinofilia, biomarker, citologia creativecommons.org/licenses/by-nc-nd/4.0/deed.en

368 A correlational study of tissue eosinophilia

Introduction ECRS in presence of differently matched clinical criteria 7. Much less widespread among rhinologists is assessment Chronic rhinosinusitis (CRS) is a generic term for different of the degree of eosinophilia through nasal cytology. This disease entities, each representing the downstream conse- technique has been reported as an efficient method to dif- quence of a specific immune-mediated inflammatory mech- ferentiate among various forms of non-allergic rhinitis 8. anism. This is why a blanket treatment approach has been However, it is still debated if it might be of interest in defin- 1 proven unsuccessful in some cases . The phenotypic di- ing CRS inflammatory profiles. Controversies are related chotomy of CRS with and without nasal polyps (CRSwNP to both sampling site and method of analysis, and only few and CRSsNP, respectively) is progressively being replaced reports have examined the cellular inflammatory pattern of by a more complex biomolecular classification of subtypes different endonasal subsites in CRS. 2 (or endotypes) . In light of these premises, we wished to verify in a sample Although the current therapeutic strategy is focused on im- population (including CRS patients and controls) the exist- munomodulation (i.e., monoclonal antibodies), more sci- ence of a correlation among the degree of tissue, blood and entific evidence is needed to find accurate predictive mo- cytological eosinophilia. Moreover, standard cytological lecular markers of CRS endotypes to better tailor effective data was integrated with analysis of a cytological sample regimens. obtained from the middle meatus region. Lastly, by sort- To date, biological agents tested or in use for moderate/se- ing the study population into cases (patients with CRS) and vere inflammatory disorders of the airways and skin target controls, we investigated the existence of significant differ- the T helper 2 (Th2) pathway. Conversely, few treatments ences in the degree of eosinophilia and association with the 3 are available for non-Th2 and non-eosinophilic cascades . most typical clinical features related to CRS. However, based on the rate of non-responders to biological therapies, clinical translation of the endotyping process is urgently needed 3. Currently, the eligibility for these treat- Materials and methods ments depends on the demonstration of an eosinophilic in- An observational prospective study was conducted accord- flammatory profile (i.e., blood eosinophil count and serum ing to the declaration of Helsinki and was previously ap- IgE). However, cut-off values are not clearly defined, with proved by the Institutional Review Board of the hospital. the only exception being thresholds applied in clinical tri- als 4. Study population All these premises are even more vague when applied to Clinical data were obtained from patients affected by CRS CRS. A basic attempt of CRS endotyping is based on the who underwent endoscopic sinus surgery (ESS) at the same identification of the predominant immune cells in the in- tertiary care center in the period between January 2018 and flamed sinonasal mucosa; in particular, it is key the distinc- July 2018. tion between eosinophilic and non-eosinophilic mediated CRS was diagnosed according to the latest European guide- CRS (ECRS and non-ECRS, respectively) 2. The clinical lines 9. Each CRS case was assessed by SNOT-22 question- interest in ECRS arises as it generally shows a poor re- naire for symptoms, Lund Kennedy (LK) and Lund Mackay sponse to medical and surgical therapies 5. The therapeutic (LM) scores to assess the endonasal status and the degree impact would be significant, as cases with intense eosino- of opacification of the sinuses, respectively, and skin prick philia would justify higher dosage of steroids and, theoreti- test to investigate allergic sensitisation to common inhal- cally, selected biological antagonists of type 2 inflamma- ants. Data on asthma, aspirin sensitivity and smoking hab- tion 6. its were self-reported by patients. Exclusion criteria were Although no unanimous histopathological criteria exist for genetic syndromes, congenital or acquired immunodefi- discriminating between ECRS and non-ECRS, it is current ciency, malignancy or history of the head and neck cancers, practice to define western ECRS when tissue eosinophil systemic autoimmune diseases, and drug abuse. count > 5 cells/HPF 5. Moreover, a tissue eosinophil count Patients scheduled for other non-CRS surgeries (septo- > 10 cells/HPF correlates with poorer outcomes 5. Diagno- plasty and dacryocystorhinostomy) in the same time-lapse sis requires obtaining tissue for histopathological analysis. served as control group. Each control was assessed by As sinus mucosa needs to be collected, biopsies may not be SNOT-22 questionnaire as well as LK and LM scores to straightforward or performed under local anaesthesia. This exclude CRS. Control patients affected by asthma and as- is why different, less invasive, surrogates have been tested pirin sensitivity were excluded a priori. Lastly, skin prick to improve their reliability to predict tissue eosinophilia. tests were performed to investigate allergic sensitisation to It is worth mentioning the JESREC score, which defines common inhalants.

369 S. Gallo et al.

All cases and controls were considered eligible for enrol- absolute and relative frequencies. Mean and standard de- ment only after a washout period of 15 days from oral and viation (SD) or median and interquartile range (IQR) were topical steroids and 1 month from oral antibiotics. used for quantitative variables with a parametric and non- All collected data were entered in a specific CRS database parametric distribution, respectively. Chi-squared or Fish- as previously reported 10. er’s exact test were used to detect significant differences for qualitative variables. Student’s t and Mann-Whitney Sampling steps tests were used for quantitative variables following their At the beginning of the surgical procedure under general parametric or non-parametric distribution. Spearman’s cor- anesthesia, the following sampling steps were taken. relation was used to assess the relationship between the dif- A peripheral blood venous sample from antebrachial vein ferent measurements of eosinophils. P values < 0.05 was was collected for blood and leukocyte formula counts. considered statistically significant. Stata 15 statistical soft- White blood cells (WBC) were expressed both as absolute ware was used for each statistical computation. count (cell x 109/L) and percentage of the total WBC count. A nasal cytological sampling was performed under en- Results doscopy along the inferior turbinate (IT) and the middle meatus – lateral nasal wall (MM) mucosa. The procedure A total of 33 CRS patients and 30 controls were recruited. consisted in swiping gently a disposable plastic nasal cu- Baseline characteristics are shown in Table I. The CRS rette (Rhinoprobe®), equipped with a small distal collection group included 21 (63.6%) CRSwNP and 12 (36.4%) chamber, on the mucosal surface. Samples were swiped on CRSsNP. Allergic sensitisation was diagnosed in 13 cases the central area of a slide and smeared with May Grun- (39.4%), asthma in 14 (42.4%), and aspirin intolerance in 3 wald-Giemsa as described by Gelardi et al. 11. Slides were (9.1%). Sixteen (48.5%) CRS patients had underwent pre- observed through an optical microscope (Nikon Eclipse vious surgery elsewhere. Median baseline SNOT-22 score 600®) at different magnifications (100x, 200x, and 400x). was 30. Mean baseline LK and LM scores were 6.1 and Observed cells included intact respiratory epithelial, flak- 13.5, respectively. ing, and immune cells (i.e., eosinophils, neutrophils, mast- Only 5 (16.7%) controls showed allergic sensitisation to cells, macrophages, and plasma cells) and were counted in inhalants. 10 consecutive fields at 400x. Eosinophils were expressed The median blood eosinophil count was 0.3x109/L in CRS both as mean of eosinophil cells per high-power field (HPF) group (min 0.03, max 1.14) and 0.2x109/L in control group 400x and percentage of eosinophils on total immune cells. (min 0.01, max 0.36) [P = 0.0001]. The median percentage This latter parameter was intended to incorporate also the of blood eosinophils was 3.9% (min 0.4, max 13.3) and 2% effect of the neutrophilic degree of infiltration of the speci- (min 0.2, max 6) in CRS and control group, respectively men. [P = 0.0008]. A mucosal biopsy was collected on the uncinate process Increased overall degree of inflammation was found in UP (UP) at the same side of the cytological sampling. All sam- CRS samples [P = 0.003]. Eosinophil counts in UP sam- ples, sized > 0.4 mm, were fixed in 10% buffered formalin, ples were significantly different between cases and controls dehydrated by alcohol passages with increasing concentra- [P < 0.0001]. In detail, among CRS group, the eosinophil tions of ethanol, clarified in BioClear® and embedded in count was <5 cells/HPF in 18 (54.5%) cases, 5-10 cells/ paraffin. Histological sections, with a thickness of 3 mm, HPF in 3 (9.1%), and > 10 cells/HPF in 12 (36.4%); in con- were stained with haematoxylin-eosin. A conventional trol samples, the eosinophil count was < 5 cells/HPF in 29 morphological evaluation was carried out according to the (96.7%) cases and 5-10 cells/HPF in 1 (3.3%). 2017 WHO classification criteria. Additional histopatho- Similarly, cytological analysis showed higher overall in- logic features were taken into consideration as reported by flammatory infiltration in CRS cases, confirmed at both IT Snidvongs et al. 12. Moreover, an immune cell count was (P = 0.01) and MM scraping (P = 0.0006). Median IT eo- performed in 5 HPF using a 400x objective corresponding sinophil count was 0.5 cells/HPF in CRS group and 0 cells/ to an area of 1 mm2. Tissue eosinophil count was graded in HPF in control group [P = 0.0002]. Median IT eosinophil three classes: < 5 cells/HPF, 5-10 cells/HPF and > 10 cells/ percentage was 4.2% and 0% in CRS and control group, HPF 12. respectively [P = 0.002]. Median MM eosinophil count was 0.3 cells/HPF in CRS group and 0 cells/HPF in control Statistical analysis group [P = 0.006]. Median MM eosinophil percentage on An ad hoc electronic database was created to collect all total immune cells was 1.9% and 0% in CRS and control study variables. Qualitative data were summarised with group, respectively [P = 0.01]. On the whole, these data

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Table I. Demographic data of control and CRS groups.

Control group CRS group P value N = 30 N = 33 Males, n (%) 17 (56.7) 8 (24.2) 0.009 Mean (SD) age, years 52.1 (16.8) 52.7 (15.5) 0.88 CRS with nasal polyps, n (%) - 21 (63.6) - Previous surgery for CRS, n (%) - 16 (48.5) - Allergy, n (%) 5 (16.7) 13 (39.4) 0.05 Asthma, n (%) 0 (0.0) 14 (42.4) < 0.0001 Aspirin intolerance n (%) 0 (0.0) 3 (9.1) 0.24 Smoker, n (%) Nonsmoker 29 (96.7) 24 (72.7) Smoker 1 (3.3) 4 (12.1) 0.03 Former 0 (0.0) 5 (15.2) Median (IQR) SNOT-22 score - 30 (25-42) - Mean (SD) LK score - 6.1 (2.8) - Mean (SD) LM score - 13.5 (5.7) - SD: standard deviation; CRS: chronic rhinosinusitis; IQR: inter-quartile range; LK: Lund-Kennedy; LM: Lund-Mackay; SNOT-22: Sino-nasal outcome test 22 showed a significant difference in terms of eosinophilic in- phil count (MM eosinophils/HPF 400x, P = 0.003; MM filtrate between CRS cases and controls (Tab. II). eosinophil percentage, P = 0.005) (Tab. IV). The absence A weak correlation was seen between UP eosinophil count of a significant difference for asthma, aspirin intolerance and blood eosinophil count (r = 0.34, P = 0.006), and be- and polyp phenotype might be justified by the small size tween UP and IT eosinophil count (r = 0.30, P = 0.017), of the sample. whereas a moderate correlation was observed between UP ROC curve analysis on IT eosinophil count predicted ERCS and MM eosinophil count (r = 0.51, P < 0.0001). Subgroup with a sensitivity of 51.5% and specificity of 90% [posi- analysis showed that in the control group only the correla- tive predictive value (PPV) 85%; negative predictive value tion between UP and IT cytology was confirmed, whereas (NPV) 62.8%; area under the curve (AUC) 0.76, range the opposite was seen in the CRS group (loss of correlation 0.65-0.87], on IT eosinophil percentage on total immune between UP eosinophil count and IT cytology and con- cells with a sensitivity of 48.5% and specificity of 80% firmed correlation between UP eosinophil count and MM (PPV 72.7%; NPV 58.5%; AUC 0.72, range 0.59-0.84), cytology) (Tab. III). on MM eosinophil count with a sensitivity of 42.4% and No significant differences were observed in terms of tissue specificity of 90% (PPV 82.4%; NPV 58.7%; AUC 0.69, eosinophilia (blood, UP, IT, MM eosinophil count) across range 0.57-0.81), on MM eosinophil percentage on total different clinical parameters, including sex, age, presence immune cells with a sensitivity of 42.4% and specificity of of nasal polyps, previous surgery, allergy, asthma and 87.7% (PPV 77.8%; NPV 57.8%; AUC 0.67, range 0.55- smoking habit. Similarly, no significant differences were 0.80). Once allergic patients were excluded from the CRS evident comparing UP, IT, MM eosinophil count and clini- population, ROC curve analysis on IT eosinophil count cal staging scores (SNOT-22, LK score, LM score). Con- predicted ERCS with a sensitivity of 11.1% and specificity versely, higher levels of blood eosinophilia were associated of 90.9% (PPV 50%; NPV 55.6%; AUC 0.53, range 0.27- with an increase in endoscopic and radiological scores (LK 0.80), on IT eosinophil percentage on total immune cells score, P = 0.03; LM score, P = 0.01). with a sensitivity of 11.1% and specificity of 81.8% (PPV The CRS group was then classified in ECRS and non- 33.3%; NPV 52.9%; AUC 0.51, range 0.24-0.77), on MM ECRS on the basis of the histopathological threshold eosinophil count with a sensitivity of 33.3% and specificity (ECRS, eosinophil count ≥ 5 cells/HPF; non-ECRS, eo- of 90.9% (PPV 75%; NPV 62.5%; AUC 0.81, range 0.61- sinophil count < 5 cells/HPF). The analysis of different 1), on MM eosinophil percentage on total immune cells clinical and biological parameters showed only a signifi- with a sensitivity of 55.6% and specificity of 81.8% (PPV cant difference between the two groups for MM eosino- 71.4%; NPV 69.2%; AUC 0.85, range 0.67-1).

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Table II. Blood, histological and cytological features of control and CRS groups. Statistical difference is expressed as p value; significant results (P < 0.05) are highlighted in bold. Control group CRS group P value Peripheral blood eosinophilia Median (IQR) blood eosinophil count, 109/L 0.2 (0.1-0.2) 0.3 (0.2-0.4) 0.0001 Median (IQR) blood eosinophils, % 2.0 (1.1-3.2) 3.9 (2.4-5.8) 0.0008 Uncinate process (UP) histological features Overall degree of inflammation, n (%) Absent 14 (46.7) 5 (15.2) Mild 16 (53.3) 22 (66.7) 0.003 Moderate 0 (0.0) 6 (18.2) Inflammatory predominance, n (%) Lymphoplasmacytic 16 (53.3) 27 (81.8) Absent 14 (46.7) 5 (15.2) 0.01 Eosinophilic 0 (0.0) 1 (3.0) Neutrophilic infiltrate, n (%) 4 (13.3) 4 (12.1) 1.0 Eosinophil count, n (%) < 5/HPF 29 (96.7) 18 (54.5) 5-10/HPF 1 (3.3) 3 (9.1) < 0.0001 10/HPF 0 (0.0) 12 (36.4) Inferior turbinate (IT) cytological features Median (IQR) eosinophils/HPF 400x 0 (0.0-0.2) 0.5 (0.0-1.3) 0.0002 Median (IQR) eosinophil percentage on total immune cells 0 (0.0-0.6) 4.2 (0.0-12.5) 0.002 Eosinophil grading, n (%) < 5%, 24 (80.0) 20 (60.6) 5-19% 3 (10.0) 9 (27.3) 0.05 20-50% 3 (10.0) 1 (3.0) 50% 0 (0.0) 3 (9.1) Median (IQR) mast cell count 0 (0-1) 3 (1-8) < 0.001 Median (IQR) neutrophil count 8 (2-43) 46 (8-300) 0.06 Median (IQR) macrophage count 2 (1-3) 3 (1-4) 0.25 Median (IQR) plasma cell count 0 (0-0) 0 (0-0) 0.17 Median (IQR) total immune cells 12 (4-50) 80 (20-409) 0.01 Middle meatus (MM) cytological features Median (IQR) eosinophils/HPF 400x 0 (0.0-0.2) 0.3 (0.0-3.5) 0.006 Median (IQR) eosinophil percentage on total immune cells 0 (0-4) 1.9 (0-30) 0.01 Eosinophil grading, n (%) < 5%, 24 (80.0) 18 (54.6) 5-19% 4 (13.3) 4 (12.1) 0.04 20-50% 0 (0.0) 6 (18.2) 50% 2 (6.7) 5 (15.2) Median (IQR) mast cell count 1 (0-1) 3 (1-12) < 0.0001 Median (IQR) neutrophil count 3 (2-13) 19 (4-200) 0.04 Median (IQR) macrophage count 1 (1-2) 3 (2-6) 0.001 Median (IQR) plasma cell count 0 (0-0) 0 (0-0) 0.33 Median (IQR) total immune cells 7 (4-18) 95 (13-253) 0.0006 IQR: interquartile range; UP: uncinate process; IT: inferior turbinate; HPF: high power field; MM: middle meatus

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Table III. Spearman’s rank-order correlation between histological samples, blood tests and cytology. Statistical difference is expressed as p value; significant results (P < 0.05) are highlighted in bold. Uncinate process (UP) eosinophil count Spearman’s rho rho P value Total population (n = 63) Blood eosinophil count, 109/L 0.34 0.006 Blood eosinophils, % 0.26 0.038 IT eosinophils/HPF 400x 0.30 0.017 IT eosinophil percentage on total immune cells 0.20 0.111 MM eosinophils/HPF 400x 0.51 < 0.0001 MM eosinophil percentage on total immune cells 0.48 < 0.0001 Control group (n = 30) Blood eosinophil count, 109/L -0.17 0.36 Blood eosinophils, % -0.07 0.69 IT eosinophils/HPF 400x 0.40 0.03 IT eosinophil percentage on total immune cells 0.26 0.16 MM eosinophils/HPF 400x 0.19 0.32 MM eosinophil percentage on total immune cells 0.11 0.56 CRS group (n = 33) Blood eosinophil count, 109/L 0.20 0.26 Blood eosinophils, % 0.11 0.56 IT eosinophils/HPF 400x 0.04 0.83 IT eosinophil percentage on total immune cells -0.06 0.74 MM eosinophils/HPF 400x 0.53 0.002 MM eosinophil percentage on total immune cells 0.51 0.002 UP: uncinate process; IT: inferior turbinate; HPF: high power field; MM: middle meatus; CRS: chronic rhinosinusitis

Table IV. Blood, histological, cytological and clinical differences between non-ECRS and ECRS group. Statistical difference is expressed as P value; significant results (P < 0.005) are highlighted in bold. CRS group Non-ECRS ECRS P value N = 18 N = 15 Median (IQR) blood eosinophil count, 109/L 0.3 (0.2-0.4) 0.4 (0.2-0.6) 0.19 Median (IQR) blood eosinophils, % 3.7 (2.3-5.4) 3.9 (2.4-8.0) 0.42 Median (IQR) IT eosinophils/HPF 400x 0.4 (0.1-0.8) 0.7 (0-1.8) 0.66 Median (IQR) IT eosinophil percentage on total immune cells 4.6 (3-9.1) 3.4 (0-15) 0.94 Median (IQR) MM eosinophils/HPF 400x 0.05 (0-0.2) 3.3 (0.4-10.3) 0.003 Median (IQR) MM eosinophil percentage on total immune cells 0.2 (0-7.7) 23.3 (1.9-68.8) 0.005 Asthma, n (%) 8 (44.4) 6 (40.0) 0.80 Allergy, n (%) 7 (38.9) 6 (40.0) 0.95 Aspirin intolerance, n (%) 2 (11.1) 1 (6.7) 1.0 CRSwNP, n (%) 12 (66.7) 9 (60.0) 0.69 IQR: interquartile range; IT: inferior turbinate; HPF: high power field; MM: middle meatus; CRS: chronic rhinosinusitis

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A cut-off of ≥ 1.9% of MM eosinophil percentage provided eosinophil count is > 5 cells/HPF. Moreover, a tissue eosin- the best sensitivity and specificity (88.9% and 81.8%, re- ophil count > 10 cells/HPF was demonstrated to correlate spectively) (Tab. V). with poorer outcomes and overall prognosis 5. To overcome the aforementioned disadvantages of biopsy, Discussion other types of biological samples have been considered as possible indirect assessments of tissue eosinophilia. A The term ECRS was introduced to identify a subgroup of number of studies demonstrated that there is an association patients with CRS and eosinophilic infiltration of nasal between peripheral eosinophilia and tissue eosinophilia in polyps, likely to occur consequent to eosinophil dysregula- paranasal sinuses. Our study confirmed this correlation, al- tion 13. The aetiology of ECRS encompasses a wide variety beit weak (r = 0.341). The cut-point of > 0.3 x 109/L or of stimuli and overlapping pathogenic mechanisms 13. There 4.4% of WBC is that adopted for administration of biologi- is evidence that ECRS is associated with greater symptom cal agents in asthma, though still within the normal range. severity 14, extensive sinus disease and comorbidities (asth- Other thresholds have been proposed to gain better diag- ma), with intermittent acute exacerbation of secondary bac- nostic reliability. However, their broad variability prevents terial infections 5. Moreover, ECRS patients seem to have drawing firm conclusions 13. Blood eosinophil count shows a poorer response to medical and surgical treatments with low specificity depending on other comorbidities (para- high polyp recurrence rate and severely impaired quality sitic infections, allergy, autoimmune disorders, adverse of life 5. Therefore, early detection of ECRS, preferably in drug events, etc.); moreover, local eosinophilic activation outpatient settings, is key to guide overall long-term man- is often independent on blood eosinophils 14. It is reason- agement and improve prognosis. able that on-site biomarkers might provide a more specific In daily practice, diagnostic criteria for ECRS are based overview on cellular inflammatory pattern. In some studies, on clinical features. Traditional traits include asthma (late- indeed, asthma subtypes are defined on induced sputum, a onset), nasal polyps, aspirin intolerance, high serum eosin- non-invasive well standardised procedure of bronchial cy- ophilia and IgE. Although the presence of polyps predicts tological assessment, able to sort asthma into eosinophilic, high tissue eosinophilia, a remarkable number of CRSs- neutrophilic, mixed-granulocytic or pauci-granulocytic NP show the same degree of eosinophilic inflammation subtypes 16. Similarly, the degree of nasal eosinophilia, (19%) 12. For this reason, the most reliable way to diagnose together with other inflammatory cells, can be measured ECRS remains histopathological assessment. However, re- by cytological analysis. Numerous techniques have been lying on biopsy as the main diagnostic tool of ECRS opens described to obtain nasal specimen for cytological assess- several issues. 1) Unless adequately aware, the pathologist’s ment. Among them, nasal scraping, performed along the report often concludes generically with “chronic inflamma- medial aspect of the inferior turbinate, has shown several tion” 12. 2) Diagnosis requires obtaining sufficient tissue advantages 8. Although the technique has been validated as for histopathological analysis. As sinus mucosa needs to be a semi-quantitative analysis for diagnosis of cellular rhini- collected, and not just nasal polyp samples, biopsies may tis and correlations have been demonstrated between nasal not be straightforward or performed under local anaesthe- and bronchial inflammatory cytological patterns, its role in sia. Moreover, biopsy – due to its intrinsic invasiveness – CRS has not been clarified 17. One controversial issue is is not an early step in the CRS diagnostic workup. 3) To linked to the sampling site. Some studies debate its use- date, the definition of eosinophilia in CRS has not reached fulness when performed along the inferior turbinate. For consensus among researchers 5. This controversy concerns example, De Corso et al. reported that inferior turbinate both the method and interpretation of the results. Actually, eosinophilic inflammation represents an early marker for it is accepted practice to define western ECRS when tissue severe CRSwNP 18. Similarly, Gelardi et al. showed that the

Table V. Sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of cytology performed on the inferior turbinate and middle meatus in the non- allergic CRS population. N = 20 Best cut-off Sensitivity, % Specificity, % LR+ LR- Correctly classified, % IT eosinophil count in 10 consecutive HPF 400x ≥ 7 66.7 54.6 1.5 0.6 60.0 IT eosinophil percentage on total immune cells ≥ 1.3 66.7 45.5 1.2 0.7 55.0 MM eosinophil count in 10 consecutive HPF 400x ≥ 5 88.9 72.7 3.3 0.2 80.0 MM eosinophil percentage on total immune cells ≥ 1.9 88.9 81.8 4.9 0.1 85.0 IT: inferior turbinate; HPF: high power field; MM: middle meatus; LR+: positive likelihood ratio; LR-: negative likelihood ratio

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association of eosinophilic-mast cell inferior turbinate in- plied to patients clinically suspect for ECRS, this test might filtration and the presence of asthma and aspirin sensitivity confirm diagnosis and drive treatment selection. Lastly, it is correlated with an increased risk of polyp relapse 19. Our is reasonable to think that the degree of neutrophilic infil- analysis confirmed the existence of a significant degree of tration also produces an effect in terms of CRS classifica- correlation between tissue eosinophilia and IT cytological tion. Thus, a more comprehensive grouping should account eosinophilic count (r = 0.30, P = 0.017). To make matters for mixed-granulocytic and pauci-granulocytic CRS cases, complicated, She et al. demonstrated a lack of significant apart from the classical ECRS and non-ECRS subtypes. correlation between the total and individual inflammatory Of course, the study is somewhat limited. It represents a cell counts in inferior turbinate versus paranasal sinus mu- preliminary exploration of the role of nasal cytology in cosa, questioning the diagnostic value of nasal cytology CRS in a relatively small population. The technical choice for CRS 20. If it is true that the term CRS has been coined has fallen upon nasal scraping because it was the only precisely to express that every sinus inflammation trans- available in our center. Nonetheless, the literature concern- lates contextually into an inflammation of the nasal mucosa ing this topic is limited and extremely variable in terms of (and therefore also of the inferior turbinate) and that tran- sampling site and processing techniques, which makes it scriptomic studies showed a substantially overlapping gene difficult to carry out comparisons and draw solid conclu- expression profile of various nasal subsites 21,22, it is also sions. true that clinical practice teaches that the phenotypic mani- festations of CRS usually spare the mucosa of the inferior Conclusions turbinates 23. This aspect is the inspiring concept underly- ing the recent “reboot approach” 24. Moreover, this region, In summary, assuming that a re-classification of CRS is a in addition to a different embryological origin, shows a pressing clinical need, as well as the identification of re- morpho-histological structure that is not identical to that of liable biomarkers, nasal cytology conceptually represents the middle meatus 22,25. an interesting tool. In the same way as bronchial cytology She et al. demonstrated that 66% of CRS patients with CRS for asthma, nasal cytology can allow for cellular profiling show marked inflammation in the inferior turbinate, but that of CRS which, albeit in its initial stages, is a step forward the inflammation is much more intense in maxillary sinus the endotyping process and the thoughtful application of mucosa 20. Furthermore, the inflammatory response in the innovative biological therapies. Additionally, it shows sev- ethmoid sinus seems even more severe than in maxillary eral practical advantages, such as good tolerability and sinus or inferior turbinate in other series of patients with compliance, limited costs and an easy-to use approach. It chronic sinusitis 26. Taken together, these findings suggest is reasonable to think that nasal cytology in the MM might that the paranasal sinuses, especially ethmoid, possibly provide more accurate information on the degree of tissue play a pivotal role in CRS. It follows that sampling a typi- eosinophilia in CRS. The next steps would be to verify cal site of CRS manifestation might be more representative these results across other wide and unbiased cohorts (even- of CRS-related inflammatory profile; moreover, the cel- tually comparing different sampling methods) and to define lular inflammatory pattern of the inferior turbinate can be thresholds values with the best accuracy. However, at pre- clearly influenced by the coexistence of allergic and non- sent, its semi-quantitative nature, the lack of standard cut- allergic rhinitis. Furthermore, as reported by Armengot et offs and the discrepancy of reported results limit its sys- al., a significant correlation exists between ethmoid tissue tematic use in CRS workup, while remaining undisputed its eosinophilia and MM cytological eosinophilia 27; the same role in chronic rhinitis. moderate correlation emerged from our data (r = 0.51, P < 0.0001). However, the estimated accuracy of nasal Acknowledgements cytology seems limited because overall sensitivity values Andrea Preti is a PhD student of the “Sperimental and are low. Interestingly, once allergic patients were excluded translational medicine” course at University of Insubria. from the analysis, the sensitivity further decreased for cy- A special thanks goes to Daniele Sabatino, technician of tological sampling on IT and slightly increased for cyto- the Pathology Department, for his precious collaboration in logical MM sampling. This fact suggests that the allergy the preparation of the histopathological samples analysed comorbidity can act as a confounding factor and should be in the present study. taken into account when interpreting nasal cytology find- ings. These results, moreover, lead to further reflection. Ap- parently, nasal cytology might not be the ideal screening References test for ECRS due to its low sensitivity. However, when ap- 1 Van der Veen J, Seys SF, Timmermans M, et al. Real-life study show-

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La- 2018;38:222-4. https://doi.org/10.14639/0392-100X-1993 ryngoscope 2016;126:E179-83. https://doi.org/10.1002/lary.25791 11 Gelardi M, Iannuzzi L, Quaranta N, et al. Nasal cytology: practical 24 Bachert C, Zhang N, Hellings PW, et al. Endotype-driven care path- aspects and clinical relevance. Clin Exp Allergy 2016;46:785-92. ways in patients with chronic rhinosinusitis. J Allergy Clin Immunol https://doi.org/10.1111/cea.12730 2018;141:1543-51. https://doi.org/10.1016/j.jaci.2018.03.004 12 Snidvongs K, Lam M, Sacks R, et al. Structured histopathology pro- 25 Pezato R, Voegels RL, Stamm AC, et al. Why we should avoid using filing of chronic rhinosinusitis in routine practice. Int Forum Allergy inferior turbinate tissue as control to nasal polyposis studies. Acta Rhinol 2012;2:376-85. https://doi.org/10.1002/alr.21032 Otolaryngol 2016;136:973-5. https://doi.org/10.3109/00016489.20 13 Lou H, Zhang N, Bachert C, et al. Highlights of eosinophilic chronic 16.1166262 rhinosinusitis with nasal polyps in definition, prognosis, and ad- 26 Kamil A, Ghaffar O, Lavigne F, et al. Comparison of inflammato- vancement. Int Forum Allergy Rhinol 2018;8:1218-25. https://doi. ry cell profile and Th2 cytokine expression in the ethmoid sinuses, org/10.1002/alr.22214 maxillary sinuses, and turbinates of atopic subjects with chronic si- 14 Yao Y, Xie S, Yang C, et al. Biomarkers in the evaluation and man- nusitis. Otolaryngol Head Neck Surg 1998;118:804-9. https://doi. agement of chronic rhinosinusitis with nasal polyposis. Eur Arch org/10.1016/S0194-5998(98)70273-6 Otorhinolaryngol 2017;274:3559-66. https://doi.org/10.1007/s00405- 27 Armengot M, Garín L, de Lamo M, et al. Cytological and tissue 017-4547-2 eosinophilia correlations in nasal polyposis. Am J Rhinol Allergy 15 Gallo S, Russo F, Mozzanica F, et al. Prognostic value of the Sinonasal 2010;24:413-5. https://doi.org/10.2500/ajra.2010.24.3549

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Rhinology Treatment of congenital nasolacrimal duct cyst: the role of endoscopic marsupialisation Il trattamento delle cisti congenite del dotto nasolacrimale: il ruolo della marsupializzazione endoscopica Vittorio Rampinelli1, Marco Ferrari1,2, Silvia Zorzi1, Marco Berlucchi3 1 Unit of Otorhinolaryngology-Head and Neck Surgery, University of Brescia, ASST Spedali Civili of Brescia, Italy; 2 Section of Otorhinolaryngology-Head and Neck Surgery, Department of Neurosciences; University of Padua, Italy; 3 Unit of Pediatric Otorhinolaryngology, ASST Spedali Civili of Brescia, Italy

SUMMARY Objective. Congenital nasolacrimal duct cyst (NLDC) is a rare disorder, which can present with ophthalmological and nasal signs and symptoms. The authors analyse their personal experience to identify diagnostic criteria for NLDC, which were treated by endoscopic transnasal procedure. Methods. Clinical records of patients with a diagnosis of NLDC were retrospectively re- viewed. All patients underwent rhinoscopy and ophthalmologist evaluation before surgery, whereas imaging was performed in selected cases. All neonates underwent transnasal endo- scopic marsupialisation after failure of conservative medical therapy. Results. Five patients were included in the study. One patient presented bilateral NLDC. In Received: March 23, 2020 3 cases, CT scan of the sinus was carried out. A total of 6 marsupialisation procedures were Accepted: May 21, 2020 performed and a bi-canalicular lacrimal stent was positioned in 1 case. Complete remission of symptoms was observed in all cases. Correspondence Conclusions. Nasal endoscopy is mandatory to diagnose NLDCs, and, in some cases, it can Vittorio Rampinelli be complemented by radiological procedures. When symptoms persist after systemic and Unit of Otorhinolaryngology-Head and Neck topical therapy, nasal endoscopic marsupialisation is the treatment of choice. This surgical Surgery, Department of Medical and Surgical procedure is effective, safe and can be repeated if needed. Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili KEY WORDS: nasolacrimal duct, children, nasal surgical procedures, minimally invasive di Brescia, 25121 Brescia, Italy surgical procedures Tel. +39 030 3995319. Fax +39 030 3995212 E-mail: [email protected] RIASSUNTO Obiettivo. La cisti congenita del dotto nasolacrimale (CDNL) è una condizione rara, che Funding None. si manifesta con segni e sintomi oftalmologici e nasali. Gli autori analizzano la propria esperienza al fine di identificare criteri diagnostici per la CDNL, trattata con procedura endoscopica transnasale (ET). Conflict of interest The Authors declare no conflict of interest. Metodi. È stata eseguita un’analisi retrospettiva dei dati clinici dei pazienti affetti da CDNL. I pazienti sono stati sottoposti ad endoscopia nasale (EN) e valutazione oculistica prima dell’intervento, l’imaging è stato eseguito in casi selezionati. Tutti i neonati sono How to cite this article: Rampinelli V, Ferrari M, stati sottoposti a marsupializzazione ET dopo fallimento di terapia medica. Zorzi S, et al. Treatment of congenital nasolacri- Risultati. Cinque pazienti sono stati inclusi nello studio. Un paziente ha presentato CDNL mal duct cyst: the role of endoscopic marsupiali- bilaterale. In 3 casi, è stata eseguita TC del massiccio facciale. Sono state eseguite 6 pro- sation. Acta Otorhinolaryngol Ital 2020;40:377- cedure di marsupializzazione; uno stent lacrimale bi-canalicolare è stato posizionato in 1 382. https://doi.org/10.14639/0392-100X-N0759 caso. La remissione completa dei sintomi è avvenuta in tutti i casi. © Società Italiana di Otorinolaringoiatria Conclusioni. L’EN è chiave per la diagnosi di CDNL e può essere integrata con procedure e Chirurgia Cervico-Facciale radiologiche. Quando i sintomi persistono dopo terapia sistemica e topica, la marsupia- lizzazione ET rappresenta il trattamento di scelta. Questa procedura chirurgica è efficace, OPEN ACCESS sicura e può essere se necessario ripetuta. This is an open access article distributed in accordance with PAROLE CHIAVE: dotto nasolacrimale, pediatrico, procedure chirurgiche nasali, the CC-BY-NC-ND (Creative Commons Attribution-Non- procedure chirurgiche mininvasive Commercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and only in the original version. For further information: https:// creativecommons.org/licenses/by-nc-nd/4.0/deed.en

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Introduction Pediatric Otorhinolaryngology, Spedali Civili of Brescia, Brescia - Italy, from January 2010 to January 2019 were Congenital nasolacrimal duct (NLD) obstruction is a com- retrospectively reviewed. mon disorder. Cassady reported incomplete canalisation of Informed consent was systematically acquired at time of NLD in more than 70% of newborns 1, with Hasner’s valve hospitalisation. Ethical approval was not required due to being the most frequent site of stenosis 2,3. The majority of the retrospective nature of the study and anonymisation of cases resolve spontaneously during the first weeks of life 4,5, all data. while persistent epiphora is observed in 6-20% of infants 5,6. All patients underwent preoperative flexible nasal endosco- Several malformations have been attributed to persistent py and ophthalmologist evaluation. Before January 2013, epiphora in young patients. The term “inferior mucocele” all patients underwent CT scan of sinuses to confirm diag- or “NLD cyst” (NLDC) refers to an unperforated Hasner’s nosis; thereafter, our diagnostic strategy changed, in order valve showing an inferior prolapse and therefore occupying to avoid redundant radiological exams. We utilised the fol- the inferior meatus and nasal cavity 7. NLDC associated lowing diagnostic criteria for NLDC: with dacryocystocele, which consists of a cystic enlarge- • nasal obstruction; ment of lacrimal sac 8, is reported in 0.1% of infants dur- • epiphora; ing the first year of life 5. The dacryocystocele may resolve • nasal endoscopy revealing a translucent, cystic lesion spontaneously, but frequently becomes infected and rapidly centered on the anterior portion of the inferior turbinate progresses to acute dacryocystitis, lacrimal sac empyema and obstructing the nasal fossa; and preseptal/orbital cellulitis 9. • no suspicion of orbital complications at ophthalmologist Diagnosis of NLDC is usually based on clinical symptoms, evaluation; endoscopic appearance and imaging. The typical clinical • no suspicion of another pathological condition (i.e., cho- presentation includes epiphora, history of relapsing dacryo- anal atresia, pyriform aperture stenosis, nasopharyngeal cystitis, and unilateral nasal obstruction. When the malfor- teratoma, and meningoencephalocele) at flexible nasal mation is bilateral, clinical presentation emulates adenoid endoscopy. hypertrophy, with different respiratory issues consisting of chronic snoring respiration, difficulties in sleeping and If all the above criteria were satisfied, a clinical diagno- feeding, and severe respiratory distress associated with sis was made and CT and/or magnetic resonance imaging cyanosis and/or intercostal retraction. At nasal endoscopic (MRI) were deemed unnecessary. All patients underwent evaluation, NLDC appears as a mucosal translucent protru- surgery after failure of conservative treatments (i.e., mas- sion stemming from the inferior meatus, in proximity to the sage of the medial cantus, antibiotic and steroid eye drops, area of Hasner’s valve. If associated with dacryocystocele, systemic antibiotic therapy) for at least 3 weeks. Signs of a blue swelling at the level of the ipsilateral medial cantus acute inflammation of the nasolacrimal duct system were is usually noticeable. CT scan of the sinuses confirms diag- considered a temporary contraindication to surgery, which nosis, above all when the nasal fossa is not clearly explor- was postponed after resolution of inflammation-related able and/or other associated conditions are suspected 10. symptoms. Management of NLDC includes conservative and non- conservative treatments. The former comprises massage of Surgical technique and postoperative management the lacrimal sac, topical antibiotics and steroids and sys- The surgical procedure was performed under general anaes- temic antibiotic therapy. The latter, which usually follows thesia. After mucosal decongestion with pledgets soaked an unsuccessful conservative strategy, consists of a surgical with adrenalin (1:100,000), a rigid nasal 0° endoscope 2.7 procedure, ranging from nasolacrimal probing to intrana- diameter, 11 cm long (Karl Storz, Tuttlingen, Germany) sal endoscopic marsupialisation 2. The aim of the present connected with high definition camera and xenon-175-watt single-institution study is to analyse clinical outcomes of cold light illumination source (HD 3 CCD camera, Karl children who underwent transnasal endoscopic marsupi- Storz, Tuttlingen, Germany) was placed intranasally to alisation of NLDC and to identify clinical and endoscopic identify and analyze the extent of NLDC. The NLDC was diagnostic criteria to diagnose congenital NLDC. marsupialised by removing the anteromedial wall of the cyst by cold sharp instruments that are commonly em- ployed for otosurgery. In one case, a microdebrider was Materials and methods used to perform partial marsupialisation of NLDC. Once Patients and preoperative workup valve patency was checked with a 30° scope (Karl Storz, Clinical records of patients who underwent transnasal Tuttlingen, Germany), antibiotic ointment (Mupirocin) was endoscopic marsupialisation of a NLDC at the Unit of applied in the inferior meatus. Bilateral NLDCs were oper-

378 Endoscopic marsupialisation of congenital nasolacrimal duct cyst

Table I. Relevant data of the present series (Pt: patient; CT: computed tomography; DCC: dacryocystocele).

Patient Age/ Unilateral/ Imaging Associated Breastfeeding Breathing Hospitalisation days Gender bilateral findings difficulties difficulties 1 5 months/F Unilateral CT DCC No No 3 2 18 days/M Unilateral CT None No No 2 3 12 days/F Unilateral CT None Yes No 2 4 45 days/F Bilateral No None Yes No 2 5 2 months/M Unilateral No None No No 1 ated on concurrently with a bilateral procedure. No nasal packing was applied after surgery. Patients underwent systemic antibiotic therapy (amoxi- cillin) for 1 week and nasal irrigation twice per day for 1 month after surgery. The first postoperative outpatient control with nasal flexible endoscopy was scheduled at 1 week. Patients were closely followed for 3 months after surgery, until appropriate healing of the surgical site was endoscopically demonstrated. The last control was sched- uled at 12 months after surgery. According to Lueder 9, the procedure was considered successful if both symptoms and signs attributable to lacrimal obstruction or inflammation completely recovered.

Results Five patients were included in the study. Transnasal endo- scopic marsupialisation of the NLDC was the primary sur- gical treatment for all patients. Relevant data of the series Figure 1. Endoscopic appearance of congenital nasolacrimal duct cyst (as- are summarised in Table I. Two patients were male and 3 terisk) in left nasal fossa. Inferior turbinate (IT) is displaced laterally and supe- were females, with a mean age of 26 days (range: 12 days riorly. NS – Nasal septum. to 4 months). All children had normal development with no other relevant comorbidities. No case of acute respira- tory distress was observed. In all patients, ophthalmologic bital canthus was observed. A concomitant dacryocystocele evaluation documented the presence of epiphora associated was identified in a single case. No other malformations or with at least one episode of dacryocystitis, presenting with associated conditions were detected. eyelid oedema and purulent secretions from lacrimal cana- Following the abovementioned diagnostic criteria, 2 cases liculi. Medial canthal swelling was observed in 1 patient, were treated based on clinical and endoscopic diagnosis af- who had a concomitant dacryocystocele. ter January 2013. Nasal endoscopy showed a cystic lesion centered on the Six endoscopic marsupialisation procedures were per- area of Hasner’s valve in all patients. The cyst filled the formed (4 unilateral and 1 bilateral surgeries). Intraopera- inferior meatus and nasal fossa, occluding the ipsilateral tive probing of the nasolacrimal system was avoided. In the nasal respiratory space (Fig. 1). The middle meatus was patient with a dacryocystocele, a bi-canalicular lacrimal usually patent or partially narrowed due to cranial displace- stent was positioned and removed 6 months later under ment of the inferior turbinate. general anaesthesia. CT scan of sinuses was performed in the 3 cases treated No perioperative complication was observed. All patients before January 2013, showing an enlarged NLD that was were discharged within the first and third postoperative in continuity with a cystic lesion within the nasal cavity. day. Endoscopic outpatient medications and follow-up In all these cases, the NLDC was occupied by hypodense evaluations were performed at 1 week, and 1, 2, 3, and 12 material and hypertrophy of soft tissues of the medial or- months after surgery. Simple local anaesthesia without se-

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dation was employed during outpatient evaluation. Com- served in our series, anterior rhinoscopic examination should plete recovery of symptoms was observed in all patients. be included in routine newborn examination, especially when newborns or neonates present obstructive symptoms 14. Discussion The lacrimal system connects the orbital and nasal com- plexes; therefore, multidisciplinary management of its The present retrospective observational study reviewed 5 pathological conditions is recommended. Hence, all pa- patients undergoing endoscopic transnasal marsupialisa- tients in our series underwent ophthalmologist evalua- tion for NLDC at a single institution between 2010 and tion to exclude proximal stenosis, orbital complications, 2019. The aim of the study was to identify clinical and en- or other malformations. The role of imaging in diagnostic doscopic features that allow diagnosis of NLDC. Moreo- work-up is ill-defined. CT and dacryocystographic findings ver, an overview of the management strategy for this ex- of patients affected by dacryocystocele and NLDCs have ceedingly rare clinical entity, focusing on postoperative been described by several authors 15,16. The presence of a results of endoscopic treatment, was performed. To the cystic lesion of the anterior-inferior-lateral portion of the lat- best of our knowledge, only a few case reports or limited eral nasal wall, medial displacement of the inferior turbinate, case series on the transnasal endoscopic marsupialisation and pronounced distention of NLD possibly associated with of NLDC can be found in the literature. Moreover, some lacrimal sac dilation are the main signs raising suspicion for of confusion has emerged around this pathological entity, NLDC. Castillo et al. 16 diagnosed NLDC using CT to evalu- especially concerning its distinction from similar diseases ate 2 newborns who presented with acute respiratory distress such as dacryocystocele. immediately after birth. Both were found to have bilateral The pathogenesis of both NLDC and dacryocystocele con- soft-tissue masses beneath the inferior turbinates. MRI has sists of mucosal obstruction of the NLD, which leads to in- also been used in evaluation of dacryocystoceles 17, by virtue creasing pressure and subsequent dilatation of the lacrimal of its optimal contrast resolution on soft tissue, which allows system in areas that are not completely surrounded by bone characterisation of the cyst content. The primary advantage (i.e. Hasner’s valve and the lacrimal sac, respectively). of MRI over CT is the avoidance of exposure to ionising The level of obstruction on a craniocaudal axis determines radiation. On the other hand, MRI requires sedation of the whether the cystic swelling appears as a dacryocystocele newborn and provides poorer depiction of bony surfaces. or a NLDC: cysts located in proximity to Hasner’s valve We performed CT scan in the first 3 cases we handled to exhibit an intranasal cystic mass with possible retrograde study the anatomical region and confirm diagnosis. Based dilation of the NLD, while more cranial obstruction does on our experience and the literature 2, we thought that clini- not show relevant nasal changes 11. cal and endoscopic evaluation could be sufficient for di- Infantile dacryocystocele and many cases of paediatric agnosis. Thus, after January 2013, we introduced clinical acute dacryocystitis are associated with NLDC 9. Barham diagnostic criteria in our practice. If satisfied, an exclusive- et al. 4 even hypothesised that the coexistence of the two ly clinical diagnosis was deemed reliable to proceed with entities (dacryocystocele and NLDC) is unvarying. On the treatment, and imaging was avoided. Unfortunately, the other hand, many cases of NLDCs are not associated with a small number of patients due to rarity of the disease does congenital dacryocystocele, nor to epiphora or other distur- not permit to perform statistical analysis. Consequently, we bances referable to the lacrimal sac 2,12. In the present series, hope that present study could stimulate a multicentre trial which includes 4 monolateral and 1 bilateral NLDCs, all that confirms this hypothesis. patients experienced at least 1 episode of acute dacryocyst- However, CT and/or MRI should be considered to corrobo- itis, whereas a dacryocystocele was present in a single case. rate diagnosis when the nasal fossa is not clearly explorable The slight female predisposition reported by Levin et al. 13 or other/associated conditions are suspected: choanal atre- and Brachlow et al. 14 was confirmed in our series, with a sia, pyriform aperture stenosis, nasopharyngeal teratoma male-to-female ratio of 2:3. and meningoencephalocele 2,10. Diagnosis is based on history, clinical examination and nasal Sundry treatment approaches have been described for man- endoscopy: nasal obstruction, epiphora, medial canthal swell- agement of NLDCs: massage, warm compresses, topic, en- ing, eyelid oedema and purulent secretions from lacrimal teral or parenteral antibiotics, nasolacrimal probing, laser mu- canaliculi are the most frequent clues, with nasal endoscopy cosal vaporisation, silastic stenting, and intranasal endoscopic revealing a translucent, cystic lesion centered on the anterior cyst marsupialisation. Our management consisted first of portion of the inferior turbinate and obstructing the nasal fos- medical therapy associated with delicate massage of the me- sa. As bilateral NLDCs can be associated with complete nasal dial canthus. If these therapeutic procedures failed, transnasal obstruction and severe respiratory distress, although never ob- endoscopic marsupialisation of the cyst was performed.

380 Endoscopic marsupialisation of congenital nasolacrimal duct cyst

Though limited to a small sample size, endoscopic transna- diagnosis of nasal obstruction associated with epiphora in sal marsupialisation showed optimal results in the present newborns and infants. Multidisciplinary management by series: all 5 patients, for a total of 6 procedures, experi- both an otorhinolaryngologist and ophthalmologist is rec- enced complete remission of symptoms after surgery, in ommended. The suggestive clinical picture associated with line with what reported in the literature 2,9,13,18. Some au- a complete nasal endoscopy could be sufficient for diag- thors have suggested probing the NLD to verify its patency nosis. On the other hand, cross-sectional imaging should after marsupialisation 2,18. In our experience, lavage of the be considered in case of uncertain diagnosis or suspect for lacrimal pathway is sufficient to demonstrate the patency concomitant malformations. Our experience, even if lim- of NLD. With the intent of avoiding inflammation-related ited to 5 NLDC cases, suggests that endoscopic marsu- complications, an endoscopic procedure was performed pialisation without NLD stenting is an effective and safe when signs of acute inflammation resolved with medical procedure. However, a multicentre, prospective study is therapy. However, other authors highlighted that in cases of needed to establish whether this treatment is significantly acute infection resistant to antibiotic therapy prompt surgi- preferable over other surgical techniques alongside more cal management should be considered to prevent disease precisely quantify the morbidity of surgery. progression 9. In line with Natesh et al. 7, we consider the use of powered instrumentation (e.g. microdebrider) a wise References option to achieve sharp and precise dissection of the cyst. 1 Cassady JV. Developmental anatomy of nasolacrimal duct. AMA During resection of redundant mucosa, attention should Arch Ophthalmol 1952;47:141-58. https://doi.org/10.1001/ar- be paid to avoid injury of Hasner’s valve and the inferior chopht.1952.01700030146003 turbinate, which could lead to nasolacrimal air reflux and 2 Dogan E, YükseL NG, Ecevit MC, et al. Microdebrider assisted en- doscopic marsupialization of congenital intranasal nasolacrimal duct excessive scar tissue formation, respectively. cysts. Int J Pediatr Otorhinolaryngol 2012;76:488-91. https://doi. Some authors have used prolonged silicone stenting of the org/10.1016/j.ijporl.2011.12.031 NLD to prevent recurrence after marsupialisation of the 3 Bansal S, Gupta AK. Endoscopic management of pediatric nasol- cyst 19,20. We positioned a bi-canalicular lacrimal stent in acrimal anomalies. Clin Rhinol An Int 2014;7:16-9. https://doi. org/10.1016/j.otc.2006.07.004 only the first patient we treated. In subsequent cases, we 4 Barham HP, Wudel JM, Enzenauer RW, et al. Congenital nasolacri- chose to avoid canal stenting, further reducing the invasive- mal duct cyst/dacryocystocele: An argument for a genetic basis. Al- ness of the procedure 2,9. However, lacrimal stenting could lergy Rhinol (Providence) 2012;3:e46-49. https://doi.org/10.2500/ be considered in patients with bone/mucosal malforma- ar.2012.3.0024 tions associated with NLDC and recurrent disease. 5 MacEwen CJ, Young JD. Epiphora during the first year of life. Eye (Lond) 1991;5:596-600. https://doi.org/10.1038/eye.1991.103 Postoperative meticulous management, including nasal ir- 6 Guerry D 3rd, Kendig EL Jr. Congenital impatency of the nasolac- rigations and repeated endoscopic medications, was prob- rimal duct. Arch Ophthal 1948;39:193-204. https://doi.org/10.1001/ ably the key of the overall success of treatment. Of note, the archopht.1948.00900020198006 anterior position of the surgical wound allowed avoidance 7 Natesh BG, Patil S, Nilssen E, et al. Endonasal microdebrider assisted of sedation during medications, otherwise required for en- excision of congenital intranasal nasolacrimal duct cyst or inferior mucocele. Indian J Otolaryngol Head Neck Surg 2016;68:115-7. htt- doscopic posterior procedures in non-cooperating patients. ps://doi.org/10.1007/s12070-015-0948-y Recently, bedside nasal endoscopy with cyst marsupialisa- 8 Harris GJ, DiClementi D. Congenital dacryocystocele. Arch tion under local anaesthesia have been proposed as an ef- Ophthalmol 1982;100:1763-5. https://doi.org/10.1001/ar- fective primary treatment option 21,22. Although feasibility chopht.1982.01030040743006 9 Lueder GT. The association of neonatal dacryocystoceles and infantile of this procedure is witnessed by these publications, this dacryocystitis with nasolacrimal duct cysts (an American Ophthalmo- management strategy should be taken into consideration logical Society thesis). Trans Am Ophthalmol Soc 2012;110:74-93. in specific conditions, including stable patients, favourable 10 Calcaterra VE, Annino DJ, Carter BL, et al. Congenital nasolacri- nasal anatomy and an expert medical team. mal duct cysts with nasal obstruction. Otolaryngol Head Neck Surg The main limitations of the present study consist of its ret- 1995;113:481-4. https://doi.org/10.1016/s0194-5998(95)70090-0 11 Mansour AM, Cheng KP, Munna JV, et al. Congenital dacryocele. rospective nature and limited sample size. Considering the A collaborative review. Ophthalmology 1991;98:1744-51. https://doi. rarity of NLDC, a multicentre, prospective study would be org/10.1016/s0161-6420(91)32063-3 useful to better elucidate issues that are not reliably infer- 12 Righi PD, Hubbell RN, Lawlor PP Jr. Respiratory distress associated able on the basis of small case series. with bilateral nasolacrimal duct cysts. Int J Pediatr Otorhinolaryngol 1993;26:199-203. https://doi.org/10.1016/0165-5876(93)90028-2 13 Levin AV, Wygnanski-Jaffe T, Forte V, et al. Nasal endoscopy in Conclusions the treatment of congenital lacrimal sac mucoceles. Int J Pediatr Otorhinolaryngol 2003;67:255-61. https://doi.org/10.1016/s0165- NLDC is a rare disease to be included in the differential 5876(02)00379-8

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382 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:383-389; doi: 10.14639/0392-100X-N0670

OSAHS Behavioural disorders and parental stress in children suffering from obstructive sleep apnoea syndrome: a pre- and post-adenotonsillectomy confrontation Disordini comportamentali e indice di stress genitoriale nei bambini affetti da Sindrome dell’apnea ostruttiva nel sonno: confronto pre e post adenotonsillectomia Emanuela Sitzia1, Federica Pianesi2, Nadia Mirante3, Giulia Marini1, Mariella Micardi2, Maria Laura Panatta1, Alessandra Resca2, Pasquale Marsella2, Giovanni Carlo De Vincentiis1 1 UOC Otorinolarinogoiatria, Ospedale Pediatrico Bambino Gesù, Roma, Italy; 2 UOC Audiologia e Otochirurgia, Ospedale Pediatrico Bambino Gesù, Roma, Italy; 3 U.O.C. Pediatria Generale e Malattie Infettive, Ospedale Pediatrico Bambino Gesù, Roma, Italy

SUMMARY The primary goal of the present study was to compare breathing difficulties resulting from OSAS to possible cognitive-behavioural problems of the child linked to their parents’ emotional-relational aspects. There is strong evidence that sleep breathing disorders are associated with behavioural alterations, a tendency towards aggressiveness, weak school performance and a clear disorder in continuous and selective attention other than vigilance status. Not all patients suffering from OSA have cognitive and/or behavioural manifesta- tions; furthermore, the degree of dysfunction that the patient may present does not seem to be associated with the seriousness of sleep breathing disorder (SBD). It is therefore likely that genetic susceptibility associated with particular environmental factors has a role in Received: February 5, 2020 determining phenotypic manifestations which are unique for every single patient. Question- Accepted: May 15, 2020 naires were given to parents, one regarding executive functions and one regarding parental stress: Conners’ Rating Scale Revised; Parenting Stress Index. All parents of children who Correspondence suffer from moderate to severe OSA, with a McGill score of 3 to 4 and with no exclusion Maria Laura Panatta criteria are included in the study; behavioural and parental stress evaluation was made dur- U.O.C. Otorinolarinogoiatria, Ospedale Pediatrico ing hospitalisation and at 6 months after adenotonsillectomy. The results show that resolv- Bambino Gesù, Roma, Italy ing OSAS led to important improvements in the competence and behavioural attitudes of E-mail: [email protected] the patient, as well as in relational and management difficulties by parents. The identifica- tion of such indicators could represent a support to surgical programming, even in non- Funding None. severe SBD. Future research will have the goal of identifying standardised risk indicators that can provide further indications for surgical treatment in children up to 5 years of age. Conflict of interest KEY WORDS: obstructive sleep apnea syndrome (OSAS), parental stress, excessive daily The Authors declare no conflict of interest. drowsiness, Conner’s rating scale revised (CRS-R), parenting stress index, McGill score How to cite this article: Sitzia E, Pianesi F, RIASSUNTO Mirante N, et al. Behavioural disorders and Scopo del presente lavoro è valutare la relazione esistente tra le difficoltà respiratorie legate parental stress in children suffering from ob- all’OSAS ed i possibili disordini neurocomportamentali correlando questi ultimi al grado di structive sleep apnoea syndrome: a pre- and stress genitoriale. Non tutti i pazienti affetti da OSAS presentano questo tipo di problematiche post-adenotonsillectomy confrontation. Acta tuttavia i disturbi di comportamento non sembrano essere associati con la severità del SBD; Otorhinolaryngol Ital 2020;40:383-389. https:// è probabile che una suscettibilità genetica associata a particolari fattori ambientali abbia doi.org/10.14639/0392-100X-N0670 un ruolo determinante nello sviluppo fenotipico di queste manifestazioni. Sono stati utilizzati © Società Italiana di Otorinolaringoiatria due questionari: Conners’ Rating Scale Revised; Parenting Stress Index. Sono stati arruolati e Chirurgia Cervico-Facciale nello studio pazienti con OSAS di grado moderato-severo, con Mc Gill score 3 o 4 in cui non fossero presenti criteri di esclusione, la valutazione dei genitori è stata effettuata durante il ri- OPEN ACCESS covero e 6 mesi dopo l’intervento di adenotonsillectomia. I risultati ottenuti hanno dimostrato che risolvendo l’OSAS si ottengono miglioramenti nelle competenze e nel comportamento dei This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-Non- pazienti ed inoltre si riducono le difficoltà genitoriali. L’identificazione di tali indicatori può Commercial-NoDerivatives 4.0 International) license. The rappresentare un supporto all’indicazione chirurgica anche in casi di DRS non severo. article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and PAROLE CHIAVE: sindrome dell’apnea ostruttiva del sonno (OSAS), stress genitoriale, only in the original version. For further information: https:// eccessiva sonnolenza diurna, questionario di Conner’s rivisitato (CRS-R), punteggio di McGill creativecommons.org/licenses/by-nc-nd/4.0/deed.en

383 E. Sitzia et al.

Introduction Last, but not least, it is opportune to consider that not all patients suffering from OSA have cognitive and/or behav- In 1976, Guillelminault was the first to describe, in a sam- ioural manifestations; furthermore, the degree of dysfunc- ple of 8 patients, the association between sleep breathing tion that the patient may present does not seem to be asso- disorders and difficulty in learning, presence of school ciated with the severity of sleep breathing disorder (SBD). problems and the appearance of clear mood alterations that It is, therefore, likely that genetic susceptibility associated were somehow connected to a more or less accentuated with particular environmental factors has a role in deter- 1 daily drowsiness . mining phenotypic manifestations that are unique for every In the last 40 years, the literature has provided a concrete single patient 8. support to what was a mere observational evaluation. To- Recent studies have confirmed the importance that frag- day, we know that sleep breathing disorders are clinically mented sleep has on the genesis of attentive problems, expressed in a continuum which has its origins in primary whereas intermittent hypoxaemia, by acting mainly on a snoring and which its highest expression sees in obstructive state of inflammation of the vascular area, is responsible sleep apnoea syndrome (OSAS). Night ventilator dynamic for alterations in the hippocampus and pre-frontal region, in a patient suffering from obstructive sleep apnoea (OSA) mainly modifying executive functions 9. results in totally compromised hypopnoeic and apnoeic As there are no sufficient studies that deal with the child’s events, secondary to a partial or total obstruction of the res- behaviour and parental stress in the presence of paediatric piratory system, determining a de-structuring of sleep with OSAS, we carried out a study to evaluate both these aspects 2 significant alteration of normal patterns . in a group of patients treated in our paediatric hospital. It is now acknowledged that non-treated OSA can lead to It is now acknowledged in the literature that excessive dai- important consequences for the child’s health, starting from ly drowsiness in the paediatric population suffering from a normal postural and ponderal growth to the presence of SBD is present in 40-50% of cases. important cardiovascular alterations, which can lead to sys- Our purpose is to confirm these findings, evaluating per- temic arterial and pulmonary hypertension. Furthermore, formance of the child to the family context and trying to there is strong evidence that sleep breathing disorders are understand how this factor is influenced by the patient’s associated with behavioural alterations, a tendency towards health and how it represents a conditioning “environmental aggressiveness, weak school performance and a clear dis- factor”. order in continuous and selective attention other than vigi- lance status 3. Neuro-behavioural manifestations can be explained by intermittent hypoxic phenomena associated Materials and methods with the de-structuring of normal sleep stages, and ani- mal models provide the plausibility that OSA contributes Procedure to neuro-cognitive deficits; in fact, experiments on young All parents of children who suffer from moderate to severe mice subjected to intermittent hypoxia during sleep high- OSA, with a McGill score of 3 to 4 (McGill score is a pul- light similar difficulties in conditioned learning 4. sossimetric score which consent a diagnosis of OSAS with- MRI and spectroscopy scans have demonstrated that ap- out performing a regular polysomnography and indicate noeic patients suffer from an alteration of metabolites in priority for surgical intervention) and with no exclusion the left hippocampus and right frontal cortex 5; in the pre- criteria (association with other genetic syndromes, cog- fontal cortex, OSA-mediated hypoxic damage might play a nitive retardation, or diagnosed language disorders under role in the development of this cerebral area, with irrevers- treatment, certified ADHD, mild night breathing disorders, ible consequences even if apnoeic condition is resolved 6. previously ORL surgery) at our centre for Sleep Breath- Many questions are yet to be answered. It is known that – in ing Disorders of the ORL Operative Unite over a period its initial stage – fragmented sleep is less frequent in a pae- from September 2014 to February 2016 were invited to par- diatric age; in particular, the microstructure of sleep in ticipate in the study. Parents who took part in the research EEG tracings (A1 phase and A1 index of the CAP, Cycling signed an informed consent approved by the Institutional Alternating Pattern) is modified, thus suggesting the non- Review Board. restorative nature of non-REM sleep in these patients 7. Behavioural and parental stress evaluation was made dur- Oxidative stress can also play a role by increasing the loss ing hospitalisation and at 6 months after adenotonsillecto- of neuronal elements through direct damage as well as my, in line with the international literature 12-14 to verify the through activation of secondary inflammatory processes absence of rehabilitation and/or medical therapies (methyl- and reparative events 7. phenidate and psycho-stimulant generally).

384 OSAS and parental stress

Post-surgery questionnaires were filled-in during a routine Ethical approval check-up at 6 months after surgery. All procedures performed in studies involving human par- A psychologist handed out the questionnaires and explained ticipants were in accordance with the ethical standards of them to parents, who then filled them in autonomously in the institutional and/or national research committee (Os- the waiting room. The PSI questionnaire was completed by pedale Pediatrico Bambino Gesù Ethical Committee) and mothers and not fathers. with the 1964 Helsinki declaration and its later amend- In order to avoid missing data, the psychologist checked ments or comparable ethical standards. that all questionnaires were properly completed. The study was carried out in compliance with the Helsinki Results declaration. Overall, 50 children of age ranging from 28 months to 82 Observation questionnaires months were found eligible (68% boys) (average: 44; ± Questionnaires were given to parents, one regarding execu- SD:10.3). tive functions and one regarding parental stress. During the Abandonment rate was 0%. All children chosen, in fact, under- same evaluation meeting, children underwent non-struc- went evaluation before surgery and at 6 months after surgery. tured qualitative behavioural observation. Mothers who filled in the questionnaire were asked about Conners’ Rating Scale Revised: (CRS-R: C. Keith Con- their educational and economic level; 18% had secondary ners) 10: this is a structured questionnaire composed of 80 school diploma, a little over half had a high school diploma questions which investigated problematic or psycho-path- (52%), while the remaining 30% had a degree. Their socio- ological behaviours during developmental age, from 3 to economical level was similar to their educational level, i.e. 17. There are three versions of the questionnaire, one for 20% had a low level, a little more than half (54%) had me- dium level and about one-quarter of mothers had a high parents (CPRS-R), one for teachers (CTRS-R) and a self- social economic level (26%) (Tab. I). report for adolescents from 12 to 17 (YSR-R). As shown in Table II by Conners’ scales, the most signifi- There are 14 areas of investigation: 1) Oppositivity 2) cant items, with p < 0.01, were: oppositivity (p = 0.0008), Cognitive disorders 3) Hyperactivity-Impulsiveness 4) hyperactivity (p = 0.001), perfectionism (p = 0.003), rest- Anxiety-Shyness 5) Perfectionism 6) Social Issues 7) Psy- lessness/impulsiveness (p = 0.0003), emotional instability chosomatic traits 8) ADHD index 9) CGI – Restlessness/ (p = 0.0005) and general difficult behaviour (p = 0.0008). Impulsiveness 10) Emotional Instability 11) CGI – Total In particular, there was an increase in 24% of children 12) DSM IV – Lack of Attention 13) DSM IV – Hyperac- with standard oppositivity post-surgery, compared to pre- tivity/Impulsiveness 14) DSM IV-Total. surgery evaluation (from 62% of sample to 86%); in the The questionnaire includes 0-4 multiple choice. In our hyperactivity subscale, there was an increase in 20% of study, we used the parental version. Parenting Stress Index (Richard Abidin) 11: this is a mul- tiple choice questionnaire with a score between 0 and 4, Table I. Socio-demographic characteristics of sample (N = 50). composed of 36 questions, which investigates parental N (%) stress meant as discrepancy perceived by parents among Gender the resources available and the need to maintain a parental Male 34 (68) role. Pre-surgery chronological age, months Specifically, it investigates four areas: 1) Parental distress; (average, ± SD) 44 (± 10,3) 2) Dysfunctional child-parent interaction; 3) Difficult child; Post-surgery chronological age, months 4) Defensive response. [(average, ± DS) 50 (± 10,3) Education Statistical analysis of data Secondary School Diploma 9 (18) Categorical data are transcribed as numbers and percentage, while continuous data are transcribed as average and ± SD. High School Diploma 26 (52) As these are ordinal data, statistical analysis was elaborated Degree 15 (30) with Wilcoxon Test for paired data. A value of p < 0.05 Socio-economic level was considered significant, and a value of p < 0.01 as even Low 10 (20) more significant. Statistical elaboration was carried out Medium 27 (54) with STATA 14 statistical software. High 13 (26)

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Table II. Pre-post-surgery confrontation, results of Conners’ test (entire sample). Pre Post P value* N (%) N (%) Opposition Average 31 (62) 43 (86) 0.0008 Borderline 14 (28) 4 (8) Pathological 5 (10) 3 (6) Inattention/ Cognitive disorders Average 40 (80) 42 (84) 0.2674 Borderline 6 (12) 5 (10) Pathological 4 (8) 3 (6) Hyperactivity Average 32 (64) 42 (84) 0.0014 Borderline 9 (18) 7 (14) Pathological 9 (18) 1 (2) Anxiety/Shyness Average 42 (84) 43 (86) 0.40 Borderline 4 (8) 5 (10) Pathological 4 (8) 2 (4) Perfectionism Average 32 (64) 42 (84) 0.003 Borderline 10 (20) 6 (12) Pathological 8 (16) 2 (4) Social issues Average 48 (96) 50 (100) 0.16 Borderline 1 (2) 0 (-) Pathological 1 (2) 0 (-) Psycho-somatic disorders Average 37 (74) 44 (88) 0.02 Borderline 8 (16) 5 (10) Pathological 5 (10) 1 (2) ADHD Average 34 (68) 40 (80) 0.038 Borderline 10 (20) 6 (12) Pathological 6 (12) 4 (8) Restlesness/impulsiveness Average 29 (58) 40 (80) 0.0003 Borderline 11 (22) 9 (18) Pathological 10 (20) 1 (2) Emotional instability Average 33 (66) 45 (90) 0.0005 Borderline 12 (24) 2 (4) Pathological 5 (10) 3 (6) General behavioural issues Average 32 (64) 42 (84) 0.0008 Borderline 10 (20) 7 (14) Pathological 8 (16) 1 (2)

continues 

386 OSAS and parental stress

Table II. Pre-post-surgery confrontation, results of Conners’ test (entire sample) (follows). Pre Post P value* N (%) N (%) DSM-IV inattention Average 38 (76) 43 (86) 0.02 Borderline 8 (16) 4 (8) Pathological 4 (8) 3 (6) DSM-IV hyperactivity/impulsiveness Average 37 (74) 44 (88) 0.01 Borderline 9 (18) 6 (12) Pathological 4 (8) 0 (-) DSM-IV ADHD combined Average 37 (74) 42 (84) 0.05 Borderline 9 (18) 6 (12) Pathological 4 (8) 2 (4) * Wilcoxon test for paired data children in the standard (pre-post-surgery: 64% vs. 84%); Discussion during follow-up, children with problems of perfectionism For a long time, the scientific literature has given impor- were statistically decreased (pathological pre-post: 16% tance to the link between sleep disorders and behaviour, vs. 4%); almost all children with pathological restlessness/ focusing on the child’s functional abilities in terms of at- impulsivity went back to standard/borderline (from 20% to tention, restlessness, memory and learning ability 12,13,15,16. 2%). A similar outcome resulted in sub-scale “general dif- Parental stress related to child care for children suffering ficult behaviour” (from 16% to 2%); lastly, emotional insta- from SBD were not seen. bility also improved, ranging from 66% to 90% of children. The present study confirmed the previous literature data re- Sub-scales with p < 0.05 and p ≥ 0.01 were as follows: psycho- garding functional competence in children suffering from somatic problems (p = 0.02), ADHD, DSM-IV inattention SBD improve significantly after adenotonsillectomy. The in- (p = 0.02) and hyperactivity/impulsiveness (p = 0.01) (Tab. II). novative part of our study is having observed the emotional The DSM-IV ADHD combined parameter resulted in bor- behaviour by parents towards the problems of apnoeic pa- derline statistical significance (p = 0.05) (Tab. II). tients together with children’s executive functions. Breathing More specifically, children with psychosomatic problems disorders result in parental stress and preoccupation, so much decreased from 10% to 2%, with an increase of 12% in so that children negatively influence their sleep-wake rhythm, children with no ADHD (from 68% to 80% post-surgery). thus altering their parental competence. This parental dys- A similar increase was also seen for subscale DSM-IV in- functionality acts as environmental phenomenon which nega- attention, with a decrease of 10% at 6 months. Lastly, no tively influences already critical behavioural attitudes. pathological result was found for subscale DSM-IV hyper- Behavioural improvements mainly focus on three areas: activity/impulsiveness in post-surgery (8% of pathological Oppositivity, Hyperactivity, Perfectionism, Restlessness/ children at the beginning vs. 0% in post-surgery). impulsiveness, Emotional Instability and General Difficult Table III shows the results obtained with the PSI question- Behaviour. naire on parental stress, in this case related to mothers. The From the anamnesis of parents pre- and post-surgery, there area with p < 0.01 was on total stress, ranging from 62% of was evidence that children had a net improvement in op- parents to 78% in post-surgery. positive-provocatory behaviours, which in school age can Significant improvement was also seen in the parental lead to learning disorders. distress subscale (p = 0.1), with a 16% increase in moth- Qualitative analysis of results is also very interesting, as ers with normal values post-surgery compared to baseline parents report that their children are “easier to deal with (from 58% to 74%) (Tab. III). in shopping centres” (Item 13 CRS), less “perfectionist” Lastly, there are no significant differences between pre- and (Item 5 CRS), more “active“ and less “tired” or “they move post-surgery in the other subscales (Tab. III). as in slow motion” (Item 73 CRS).

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Table III. Pre-post PSI test confrontation. Pre Post P value* N (%) N (%) Parental distress Average 29 (58) 37 (74) 0.01 Borderline 17 (34) 10 (20) Pathological 4 (8) 3 (6) Parent/ disfunctional child interaction Average 38 (76) 40 (80) 0.542 Borderline 10 (20) 9 (18) Pathological 2 (4) 1 (2) Difficult child Average 25 (50) 29 (58) 0.122 Borderline 16 (32) 15 (30) Pathological 9 (18) 6 (12) Total stress Average 31 (62) 39 (78) 0.004 Borderline 12 (24) 7 (14) Pathological 7 (14) 4 (8) Defensive response Average 28 (56) 32 (64) 0.132 Borderline 17 (34) 14 (28) Pathological 5 (10) 4 (8) * Wilcoxon test for paired data

As for parental behaviour, the perception of their children cognitive-behavioural problems of the child linking them improved, especially the idea that their child was “more to their parents’ emotional-relational aspect. agitated”, and the fact that he/she had a tendency to cry The results obtained demonstrated that resolving OSAS more than other kids (Item 25 PSI) was dramatically de- brings about important improvements in the competence creased, and the same thing can be said with the feeling that and behavioural attitude of the patient, in addition to rela- their children woke up “in a bad mood” (Item 26 PSI), or tional and management difficulties by parents. that sleep and food rhythms were more difficult to manage The identification of such indicators could represent a sup- (Item 31 PSI). port to surgical programming, even in non-severe SBD. Food-wise, many parents referred that lack of appetite – a Future research needs to identify standardised risk indica- typical occurrence – changed into a suitable food behav- tors that can provide further indications on surgical treat- iour. ment in children up to 5 years of age. For what concerns criticalities, we observed that non-Ital- It would be interesting to monitor whether behavioural and ian parents had problems filling-in the questionnaire; fur- relational improvements are maintained in the family for thermore, during the first test, the lack of awareness of chil- periods longer than 6 months after surgery, and if the areas dren’s behaviours changed during post-surgery test, which that did not undergo changes in the first 6 months improve led to a clearer precision in filling-in the questionnaire. after a longer time span. An advantage was that evaluations were not “operator- mediated”, thus avoiding a possible influence in the test References result. 1 Guilleminault C, Tilkian AG, Dement WC. Sleep and respiration in the syndrome “apnea during sleep” in the child. Electroencephalogr Clin Neu- Conclusions rophysiol 1976;41:367-78. https://doi.org/10.1016/0013-4694(76)90099-7 2 Carroll JL. Sleep related upper airway obstruction WB in children The primary goal of the present study was to compare and adolescents. Child Adol Psyc Cl 1996;5:617-47. https://doi. breathing difficulties resulting from OSAS to possible org/10.1053/smrv.2001.0165

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3 Schechter MS. Section on Pediatric Pulmonology, Sub-commitee on 10 Conners CK, Sitarenios G, Parker JD, et al. The revised Conners’ Obstructive Sleep Apnea Syndrome. Technical report: diagnosis and Parent Rating Scale (CPRS-R): factor structure, reliability, and cri- management of childhood obstructive sleep apnea syndrome. Pediat- terion validity. J Abnorm Child Psychol 1998;26:257-68. https://doi. rics 2002;109:e69. org/10.1023/A:1022602400621 4 O’Brien LM, Mervis CB, Holbrook CR, et al. Neurobehavioral im- 11 Abidin RR. Parenting Stress Index (PSI) Third Edition. Odessa: Psy- plications of habitual snoring in children. Pediatrics 2004;114:44-9. cological Assesmnent Resources Inc; 1995 https://doi.org/10.1542/peds.114.1.44 12 Taylor HG, Bowen SR, Beebe DW, et al. Cognitive effects 5 Halbower AC, Degaonkar M, Barker PB, et al. Childhood obstructive of adenotonsillectomy for obstructive sleep apnea. Pediatrics sleep apnea associates with neuropsychological deficits and neuronal 2016;138:e20154458. https://doi.org/10.1542/peds.2015-4458 brain injury. PLoS Med 2006,3:e301. https://doi.org/10.1371/journal. 13 pmed.0030301 Garetz SL, Mitchell RB, Parker PD, et al. Quality of life and obstruc- tive sleep apnea symptoms after pediatric adenotonsillectomy. Pediat- 6 Beebe D, Gozal D. Obstructive sleep apnea and the prefrontal cor- rics 2015;135;e477. https://doi.org/10.1542/peds.2014-0620 tex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 14 Testa D, Carotenuto M, Precenzano F, et al. Evaluation of neurocogni- 2002;11:1-16. https://doi.org/10.1046/j.1365-2869.2002.00289.x tive abilities in children affected by obstructive sleep apnea syndrome 7 Keirandish-Gozal L, Miano S, Bruni O, et al. Reduced NREM before and after adenotonsillectomy. Acta Otorhinolaryngol Ital 2020; sleep instability in children with sleep disordered breathing, Sleep 40:122-32. https://doi.org/10.14639/0392-100X-N0267 2007;30:450-7. https://doi.org/10.1093/sleep/30.4.450 15 Esposito M, Antinolfi L, Gallai B,et al. Executive dysfunction in 8 Keirandish-Gozal L, Capdevila OS, Tauman R, et al. Plasma C-reac- children affected by obstructive sleep apnea syndrome: an observa- tive protein in nonobese children with obstructive sleep apnea before tional study Neuropsychiatr Dis Treat 2013;9:1087-94. https://doi. and after adenotonsillectomy. J Clin Sleep Med 2006;2:301-4. org/10.2147/NDT.S47287 9 Chervin RD, Ruzicka DL, Giordani BJ, et al. Sleep-disordered breath- 16 Konstantinopoulou S, Tapia IE. Neurocognitive and behavioral out- ing, behavior, and cognition in children before and after adenoton- comes following intervention for obstructive sleep apnea syndrome in sillectomy Pediatrics 2006;117:e769-78. https://doi.org/10.1542/ children. Paediatr Respir Rev 2016;20:51-4. https://doi.org/10.1016/j. peds.2005-1837 prrv.2016.05.004

389 ACTA OTORHINOLARYNGOLOGICA ITALICA 2020;40:390-395; doi: 10.14639/0392-100X-N0779

Otology Transmeatal microsurgery for intralabyrinthine and intrameatal schwannomas: a reappraisal Approccio transmeatale microchirurgico nei neurinomi intralabirintici e intrameatali: rivalutazione di una tecnica Antonio Mazzoni1*, Elisabetta Zanoletti1*, Diego Cazzador1,2, Leonardo Calvanese1, Domenico d’Avella3, Alessandro Martini1 1 Otolaryngology Section, Department of Neuroscience DNS, Padova University, Padova, Italy; 2 Section of Human Anatomy, Department of Neuroscience DNS, Padova University, Padova, Italy; 3 Academic Neurosurgery, Department of Neuroscience DNS, Padova University, Padova, Italy * A. Mazzoni and E. Zanoletti should be considered joint first authors.

SUMMARY Objective. The interest in surgical routes to the internal auditory canal (IAC) through the exter- nal auditory canal for vestibular schwannoma removal has been recently raised by the endoscop- ic approaches to the lateral skull base. The aim of the study was to reappraise the transmeatal microsurgical approach (TMMa) to the labyrinth and IAC, first described 50 years ago. Methods. A retrospective series of 8 consecutive patients treated for intralabyrinthine and intrameatal schwannomas through TMMa is presented. Main outcome measures consisted of surgical indications, postoperative complications, facial nerve status, bed mobilisation time, hospitalisation time and tumour recurrence rate. Results. Surgical indications for TMMa were tumour growth (62.5%) and disabling vertigo (37.5%) in the present series. Complete tumour removal with no complications and postoperative normal facial nerve function was obtained in all cases. Bed mobilisation occurred after a median Received: April 3, 2020 of 3 postoperative days (IQR 2.2-3.0) and discharge after a median of 5.6 days (IQR 4.7-7.0). Accepted: May 18, 2020 After a median follow-up of 13 months (IQR 7.5-27.5), no tumour recurrence was observed. Conclusions. TMMa indications are limited to schwannomas of the labyrinth and IAC, Correspondence which dropped out from observation protocols due to unmanageable symptoms or growth. Diego Cazzador Despite the narrow mini-invasive surgical corridor, the TMMa was a safe an effective mi- Otorhinolaryngology Unit, University of Padova, crosurgical technique in terms of tumour removal and postoperative course. via Giustiniani 2, 35128 Padova, Italy Tel. +39 049 821 8778. Fax +39 049 821 1994 KEY WORDS: microsurgery, vestibular schwannoma, endaural approach, transmeatal E-mail: [email protected] approach, internal auditory canal Funding RIASSUNTO None. Obiettivo. L’interesse per i corridoi chirurgici dal condotto uditivo esterno al condotto uditivo interno (CUI) nel trattamento del neurinoma è incrementato negli ultimi anni grazie alla divulga- Conflict of interest zione di approcci endoscopici al basecranio laterale. Lo studio si prefigge di rivalutare l’approccio The Authors declare no conflict of interest. microscopico transmeatale (TMMa) al labirinto e al CUI, descritto in origine circa 50 anni fa. Metodi. Otto pazienti sottoposti a TMMa per exeresi di neurinomi intralabirintici o intra- How to cite this article: Mazzoni A, Zano- meatali sono stati inclusi nello studio. Indicazione chirurgica a TMMa, complicanze posto- letti E, Cazzador D, et al. Transmeatal micro- peratorie, funzionalità del nervo facciale, tempo di mobilizzazione dal letto e di degenza, surgery for intralabyrinthine and intrameatal tasso di recidiva sono state le principali misure di outcome analizzate. schwannomas: a reappraisal. Acta Otorhi- Risultati. Crescita tumorale (62,5%) e vertigini incoercibili (37,5%) hanno rappresentato nolaryngol Ital 2020;40:390-395. https://doi. l’indicazione chirurgica più frequente. In tutti i pazienti il tumore è stato rimosso in toto, org/10.14639/0392-100X-N0779 in assenza di complicanze postoperatorie. La mobilizzazione dal letto è avvenuta dopo 3 giorni (IQR 2,2-3,0), la dimissione dopo 5,6 giorni (IQR 4,7-7,0). All’ultimo follow-up © Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale (mediana 13 mesi, IQR 7,5-27,5) non sono state registrate recidive. Conclusioni. L’indicazione al TMMa è limitata agli schwannomi intralabirintici e/o estesi OPEN ACCESS al CUI, che escono dal protocollo di osservazione a causa di sintomi invalidanti o cresci- ta. Nonostante l’accesso chirurgico mini-invasivo offra uno spazio limitato di manovra, il This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-Non- TMMa si è dimostrato una opzione di trattamento microchirurgico sicura ed efficace in Commercial-NoDerivatives 4.0 International) license. The termini di rimozione tumorale e decorso postoperatorio. article can be used by giving appropriate credit and mentio- ning the license, but only for non-commercial purposes and PAROLE CHIAVE: microchirurgia, schwannoma vestibolare, approccio endocanalare, only in the original version. For further information: https:// approccio transmeatale, condotto uditivo interno creativecommons.org/licenses/by-nc-nd/4.0/deed.en

390 Transmeatal microsurgery for vestibular schwannoma

Introduction thine in 59, middle cranial fossa in 26, retrosigmoid in 64, the two latter with hearing preservation intent. The TMM The straight line encompassing external auditory canal, technique was added to the treatment options since 2015, tympanum, labyrinth and internal auditory canal (IAC) is with the goal of assessing its potential in itself and in re- the anatomical premise for the transmeatal approach to the lation to the well documented endoscopic technique 14 -16 , above mentioned sites. The transmeatal route to the laby- as well as defining a mini-invasive surgical corridor to the rinth was used for draining suppurative labyrinthitis and for labyrinth and IAC. labyrinthectomy in vertigo 1-3, and was proposed in 1970 as a microsurgical technique for schwannomas of the IAC, sectioning the vestibular or cochlear nerve or exploration- Methods graft of facial nerve 4. In 1976, Bochenek 5 introduced a Ethical considerations modification in the approach. The few reports on the The procedures hereby described were in accordance with transmeatal approach to acoustic schwannoma are reported the ethical standards of the University and the Declaration in Table I 4,6-13. of Helsinki. Written informed consent was obtained from The endoscopic surgery of the middle ear recently evolved all patients prior to participation. into the transcanal endoscopic approach to labyrinth and IAC for schwannoma with good outcomes 14-16. Participants It is universally acknowledged that the endoscope al- From 2012 to 2019, 142 patients were diagnosed with in- lows excellent visualisation of structures and hidden sites tralabyrinthine schwannoma (ILS) or intrameatal vestibular “around the corner”. The endoscopic transcanal approach schwannoma. Ninety-seven patients were sent to observation, nevertheless has some drawbacks: 1) the need to create 45 were submitted to surgical excision. Twenty-one cases space at the expense of the tympanic bone for placing both (46.5%) were operated on with hearing preservation intent, instruments and endoscope; 2) the one-hand surgical tech- 16 (35.5%) with translabyrinthine approach, eight patients nique; 3) the 2D view. (18.0%) with ILS and/or intrameatal vestibular schwannoma The transmeatal microsurgical approach (TMMa) was reap- were operated on via TMMa. The present report focuses on praised as an effect of modern imaging and increase in early- this latter group composed of five ILSs, two intralabyrinthine- diagnosed small vestibular schwannomas. It underwent rapid intrameatal tumours and one pure intrameatal tumour. development given the promising experiences of the transca- nal endoscopic approaches and the expertise gained over the Preoperative assessment years with conventional microscopic approaches. Hearing was evaluated with pure tone and vocal audiometry Our small series of TMMa is part of a long-lasting ex- as pure tone average (PTA) at frequencies 500, 1000, 2000 perience in the microsurgical management of vestibular and 4000 Hz and word recognition score (WRS) classified ac- schwannoma. Between 1972 and 2019, 2048 cases were cording to the American Academy Otolaryngology-Head and 17 treated with different microsurgical approaches. Pure were Neck Surgery (AAO-HNS) classification . Diagnosis was obtained with contrast enhanced magnetic resonance imag- operated on with conventional approaches, translabyrin- ing (MRI) (Fig. 1). High resolution computed tomography

Table I. Literature on transmeatal microsurgical approach for schwannomas of the labyrinth and/or internal auditory canal. Author Year of publication Number of cases Alvarez De Cozar et al. 4 1970 1 Karlan et al. 6 1972 1 Wanamaker et al. 7 1972 1 Antoli Candela et al. 8 1975 5† Weimuller et al. 9 1975 1 DeLozier et al. 10 1979 6 Jiang et al. 11 2011 2 Zhu et al. 12 2012 1 Mazzoni et al. 13 2017 1‡ † The case reported in Alvarez de Cozar et al. 4 is included. Figure 1. Contrast enhanced T1-weighted MRI of an intrameatal tumour, left ‡ Included in the present series. side. The facial quadrant of the fundus is free from tumour.

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(HRCT) was indicated for surgical planning and immediate usually 2 mm but on the anterior wall, where it remains postoperative evaluation (Fig. 2d). Facial nerve status was intact. evaluated with the House-Brackmann (HB) grading system 18. 3. Vestibulo-cochleostomy. This is sufficient for intrameatal Indications to TMMa included ILS and intrameatal vestib- tumour, it is a step for the exposure of IAC. After foot- ular schwannomas, hearing class D according to the AAO- plate removal, the promontory is drilled between the oval HNS, unmanageable vertigo and/or tumour growth at serial and round window (Fig. 2a), and further anteriorly to open imaging. Hearing preservation or rehabilitation were not the cochlea basal and second turns, the access to vestibule considered. is enlarged. The medial wall shows the whitish dot of the saccular nerve entry. For ILSs, the vestibulocochleostomy Surgical technique is extended to the sites occupied by tumour itself. In tu- The patient is lying supine with the head turned to the op- mours of the vestibule only, it is not necessary to drill out posite side; surgery is performed with general endotracheal the cochlea. After carefully drilling the bone between the anaesthesia and continuous facial nerve monitoring. upper margin of the oval window and the Fallopius, and 1. After the endoaural incision, the tympano-malleo-meatal redirecting cranially the scope, the dot of the superior ves- flap is harvested with circumferential (from 10 to 2 o’clock) tibular nerve entry comes under view. The latter dot is the and longitudinal incisions. Malleus neck and tensor tym- landmark leading to the superior vestibular nerve to facial pani tendon are sectioned. The complex of skin-drum-mal- nerve and Fallopius entry (Fig. 2b). leus handle is raised against the anterior wall of the canal. 4. Exposure of IAC. The medial wall is thinned out with drill- If the anterior wall is to be drilled, the flap is raised further ing first around the saccule dot, thereon the utricular dot (Fig. up and placed against the cartilaginous wall. 2b), being here cautious as the facial nerve lies just deep to 2. Enlarging the ear canal. The outer ear canal is enlarged the superior vestibular nerve. The crista trasversalis, emerging by drilling of its bony walls as much as required by the in the drilled bed, is a landmark leading the bone removal to anatomy of the canal and by the access either to labyrinth completely open the fundus. Following the full exposure of or IAC, the latter requiring a larger access. The walls are the fundus, the facial nerve entering the labyrinthine portion not removed in full thickness, as they need to accommo- of the Fallopius can be appreciated (Fig. 2c). The canal can date the repositioned tympanomeatal flap at the end of the be exposed up to the porus by drilling first along the floor and procedure. The bony tympanic annulus is removed for thereon extending to the complete posterior wall. 5. Tumour removal. After opening the dura, displacing the tumour gives way to a moderate outflow of CSF. The main step here is to follow the interface between the tumour and the facial nerve at the fundus and Fallopius orifice, thereon proximally. The CSF pressure let the tumour herniate and favours grasping it with suction or instruments, allowing its piecemeal or en-bloc removal (Fig. 3). The cochlear nerve lies at the inferior-anterior wall of the canal. The flattened facial nerve is seen lying almost vertically at the anterior or antero- A B superior wall held by arachnoid at the porus and floating on, and pushed outward by the CSF (Fig. 4a, b). A piece of fat is placed to seal the IAC and labyrinth; the Eustachian tube is closed with muscle and fat obliterates the tympanum. The drum is repositioned, and the external auditory canal is packed. CSF leak was to be ruled out at day 5th, facial nerve func- tion was evaluated at day 1st and day 5th, then at one, 6 and 12 months after surgery. Vertigo, dizziness, imbalance, pain C D or other symptoms were recorded. Contrast enhanced MRI Figure 2. Transmeatal microsurgical approach, intraoperative pictures: was planned at one month, then 1-3-5-10 years. A) round window (arrow) and oval window (arrowhead) after removal of os- sicles; B) medial wall of vestibule with the whitish foramina of saccular (arrow) and utricular nerves (arrowhead); C) the tumour is visible in the internal audi- Results tory canal (arrow), the facial nerve exits from the Fallopius (arrowhead). D) Left side, postoperative coronal CT scan showing the surgical corridor from the Patient characteristics are summarised in Table II. At presen- external to the internal auditory canal. tation, severe to profound hearing loss was the most reported

392 Transmeatal microsurgery for vestibular schwannoma

Discussion The traditional approaches to the IAC and labyrinth, name- ly the microsurgical middle cranial fossa and translaby- rinthine with the extensions to the cochlea, are now faced by surgical corridors through the external auditory canal, i.e. the purely endoscopic transcanal and microsurgical transmeatal approaches. Although proposed in recent years with the exclusive use of the endoscope 14-16, a transcanal approach to the IAC was already described in 1970, when Alvarez De Cozar reported on the “… transvestibular ap- proach to the IAC, aiming at the surgery of the acoustic neuroma presents the following anatomical limits: anteri- Figure 3. Intraoperative specimen of a 10-mm intrameatal tumour. The orly, the carotid canal and Eustachian tube; posteriorly, the proximal end is the round surface on the right pole of the tumour. Irregular tumour borders are due to surgical manoeuvres. vertical Fallopius: inferiorly, the hypotympanum and the jugular bulb; superiorly, the tympanic portion of the facial nerve.” The authors added that “… The sacrifice of vesti- bule and cochlea provides a surgical field wide enough to remove an acoustic neuroma of one cm or less (…) and allows to drop the transtemporal approach as a route to ac- cess the IAC” 4. In 1975, the same group reported their ex- perience with the transvestibular approach to the IAC on 178 otoneurological cases, including 5 vestibular schwan- nomas 8. At those times, the diagnosis of millimetric tu- mours was still to come, literature studies were sparse and mostly involved single case reports on intrameatal schwan- A B nomas removed through a transmeatal-transvestibular ap- Figure 4. Intraoperative view at the end of the transmeatal microsurgical ap- proach (Tab. I). proach, after tumour removal. A) Endoscopic view with 0° endoscope; B) mi- Currently, intrameatal tumours are frequently diagnosed croscopic view. *: dura of the petrous posterior wall; arrow: entrance of the facial nerve into the Fallopius canal; arrowhead: facial nerve. and intralabyrinthine lesions are not an exceptional finding anymore. In our series of patients who underwent surgery via the TMMa for the treatment of intrameatal and intral- symptom (87.5%), followed by tinnitus (50.0%), vertigo abyrinthine schwannomas, the approach allowed direct ac- (25.0%) and auricular fullness (12.5%). Prior to surgical re- cess to the labyrinth and the IAC fundus with complete tu- moval, five patients had been enrolled in a wait and scan pol- mour removal in all cases. Surgical indications for TMMa icy for a median of 61 months (IQR 31.5-136.0). During ob- included ILS or/and intrameatal vestibular schwannomas servation, four of five patients (80%) showed tumour growth with AAO-HNS hearing class D, unmanageable vertigo, or at serial MRIs. The only patient with serviceable hearing at tumour growth at serial imaging. diagnosis went through progressive hearing loss to class D. The reappraisal of the TMMa at present might confer excel- Indications for surgical treatment were tumour growth lent outcomes with minimum surgical morbidity, as well as for five patients (62.5%) and disabling vertigo for three short hospital stay. TMMa allows to perform a straightfor- (37.5%). There were no postoperative complications. Post- ward surgical corridor to the IAC. The two-hands dissec- operative facial nerve status at day one and at last follow-up tion microsurgical technique involves improved ergonom- was grade I HB for all the patients. None required post- ics, which is a fundamental requisite for adequate handling operative ICU admission. One patient experienced vertigo of adherences tumour/facial nerve, as well as tumour/vas- for few days. Patient mobilisation was performed after a cular loops 20. There is no inherent morbidity of the surgical median time of 3 postoperative days (IQR 2.2-3.0). Patients access due to sacrifice of the external auditory canal. were discharged after a median time of 5.6 days (IQR 4.7- As such, the technical highlights of TMMa included endo- 7.0). At last follow-up (median 13 months; IQR 7.5-27.5 aural skin incision of the external auditory canal, tympa- months), no tumour recurrence was observed. All patients no-malleo-meatal flap that fully opened the lumen of the presented a well-healed tympanic membrane. canal to view and instruments, and limited removal of the

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Table II. Clinical characteristics of patients underwent transmeatal microsurgical approach for schwannomas of the labyrinth and internal auditory canal. Patients Age Sex Initial Extension§ IAC Decision for Complications Hospitalisation Follow-up observation involvement surgery (days) (months) 1 76 M Y IVC N Growth N 3 17 2 59 F Y IC N Growth N 4 35 3 37 F Y IV N Growth N 5 34 4 48 F Y TLAB Y Growth + symptoms N 7 21 5 44 M N IVC N Symptoms N 5 8 6 48 F Y IC N Symptoms Vertigo 9 9 7 38 M N TMOD Y Growth N 7 6 8 76 F N IAC Y Symptoms N 5 6 M: male; F: female; Y: yes; N: no; § according to the Modified Kennedy Classification19 ; IVC: intravestibulocochlear; IC: intracochlear; IV; intravestibular; TLAB: translabyrinthine; TMOD: transmodiolar; IAC: internal auditory canal. tympanic annulus and tympanic bone, that allowed reposi- vation. The goal is the removal of tumour with no surgical tioning of the tympanic membrane. Unfavourable size and morbidity, as it is postulated by the small benign lesion, as shape of the canal conditioned its enlargement, but did not well as by the results of the alternative, conventional op- require its suture. The next steps of the approach involved erations. Approaches through the external auditory canal the drill out of promontory, cochlea, vestibule medial wall are purported to having the advantage of a direct and quick with the familiar landmarks of the saccule and utricle dots route, which could appear to be progress over the conven- leading to the vestibular nerves at the fundus, and the poste- tional approaches. This theory seems to be supported by the rior-inferior wall of the IAC. If compared to the traditional initial experience and deserves further trial. Of the current lateral approach, the small outflow of CSF is characteristic endoscopic and microscopic approaches, the latter may be of the transcanal/transmeatal approaches and may be due to a step forward as effect of the microsurgical technique and the short time of dural opening, and possibly to the arach- safer handling of unexpected difficulties. noid folds in the IAC. As a consequence of CSF sparing, there are less brain collapse, less chances of pneumocepha- Acknowledgements lus and fast recovery. Further considerations on TMMa concern the possibility of The authors thank Frances Coburn for the English revision hearing rehabilitation with cochlear implant. This requires of the paper. preserving the cochlear nerve and cochlea, or the full laby- rinth 21 or carefully evaluating if the remains of the opened References 22 cochlea and spiral ganglion are suitable to implant . Wheth- 1 Schuknecht NF. Ablation therapy in the management of Ménière’s er an open cochlea would house a cochlear implant with suc- disease. Acta Otolaryngol Suppl 1957;132:1-42. cessful long-term outcomes is still a matter of debate. 2 Jongkees LBW. Chirurgie des Mastoids und der Pyramidenspitze sowie des intratemporalen Nervus facialis. In: Naumann HH, edi- Our conclusions on this preliminary experience with TM- tor. (Hrsg) Kopf und hals Chirurgie (Bd.1). Stuttgart: Thieme Verlag; Ma, despite the small number of the present series, rely up- 1976. p. 168. on our experience with over 2000 conventional approaches 3 Glasscock ME III, Shambaugh GE. Surgery of the ear. Philadelphia: and can be seen in the context of current management of Saunders; 1990. p. 492. small vestibular schwannomas 21. The applicability of the 4 Alvarez De Cozar F, Antoli Candela F. Chirurgie transvestibulaire. TMMa recognised for tumours of the labyrinth and/or in- Rev Laryngol Otol Rhinol 1970;91:927-35. 5 Bochenek Z, Kukwa A. Die Transtympanale Neurektomie des Nervus ternal auditory canal. The AICA looping inside the canal Vestibulo-cochlearis. HNO 1976;24:197-9. may represent a caveat in favour of a safe translabyrinthine 6 Karlan MS, Basek M, Potter GB. Intracochlear neurilemmoma. Arch approach. Otolaryngol 1972;96:573-5. 7 Wanamaker HH. Acoustic neuroma primary arising in the vestibule. Laryngoscope 1972;82-1040-4. https://doi.org/10.1288/00005537- Conclusions 197206000-00013 Transcanal or transmeatal approaches, either microsurgical 8 Antoli Candela F Jr, Alvarez de Cozar F, Antoli Cande- la F. Transvestibular approach to the internal auditory ca- or endoscopic, have rare indication for tumours of labyrinth nal. Ann Otol Rhinol Laryngol 1975;84:145-51. https://doi. and/or IAC, the majority of whom are submitted to obser- org/10.1177/000348947508400201

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9 Weimuller EA Jr. Unsuspected vestibular schwannoma. Arch Otolaryngol 16 Marchioni D, Soloperto D, Masotto D, et al. Transcanal transprom- 1975;101:630-2. https://doi.org/10.1001/archotol.1975.00780390044012 ontorial acoustic neuroma surgery. Results and facial nerve out- 10 DeLozier HL, Gacek RR, Dana ST. Intralabyrinthine schwan- comes. Otol Neurotol 2018;39:242-9. https://doi.org/10.1097/ noma. Ann Otol Rhinol Laryngol 1979;88:187-91. https://doi. MAO.0000000000001658 org/10.1177/000348947908800207 17 Committee on Hearing and Equilibrium guidelines for the evaluation 11 Jiang ZY, Kutz JW Jr, Roland PS, et al. Intracochlear schwannoma of hearing preservation in acoustic neuroma (vestibular schwanno- confined to the otic capsule. Otol Neurotol 2011;32:117-9. https://doi. ma). American Academy of Otolaryngology-Head and Neck Surgery org/10.1097/MAO.0b013e31822a20ea Foundation, INC Otolaryngol Head Neck Surg 1995;113:179-80. 12 Zhu AF, McKinnon BJ. Transcanal surgical excision of an intrac- https://doi.org/10.1016/S0194-5998(95)70101-X ochlear schwannoma. Am J Otolaryngol 2012;33:779-81. https://doi. 18 House JW, Brackmann DE. Facial nerve grading system. org/10.1016/j.amjoto.2012.07.007 Otolaryngol Head Neck Surg 1985;93:146-7. https://doi. 13 Mazzoni A, Zanoletti E, Faccioli C, et al. Acoustic schwannoma org/10.1177/019459988509300202 with intracochlear extension and primary intracochlear schwan- 19 Van Abel KM, Carlson ML, Link MJ, et al. Primary inner ear schwan- noma: removal through translabyrinthine approach with facial nomas: a case series and systematic review of the literature. Laryngo- bridge cochleostomy and transcanal approach. Eur Arch Otorhi- scope 2013;123:1957-66. https://doi.org/10.1002/lary.23928 nolaryngol 2017;274:2149-54. https://doi.org/10.1007/s00405- 20 017-4501-3 Mazzoni A, Hansen CC. Surgical anatomy of the arteries of the in- ternal auditory canal. Arch Otolaryngol 1970;91:128-35. https://doi. 14 Marchioni D, Alicandri-Ciufelli M, Rubini A, et al. Exclusive endo- org/10.1001/archotol.1970.00770040198005 scopic transcanal transpromontorial approach: a new perspective for internal auditory canal schwannoma. J Neurosurg 2017;126:98-105. 21 Zanoletti E, Mazzoni A, Martini A, et al. Surgery of the lateral skull base: https://doi.org/10.3171/2015.11.JNS15952 a 50-year endeavor. Acta Otorhinolaryngol Ital 2019;39(Suppl.1):S1- S146. https://doi.org/10.14639/0392-100X-suppl.1-39-2019 15 Marchioni D, Carner M, Soloperto D, et al. Expanded trans- canal transpromomtorial approach: a novel surgical technique 22 Choudhury B, Carlson M, Jethamanest D. Intralabyrinthine schwan- for cerebellopontine angle vestibular schwannoma remov- noma: disease presentation, tumor management, and hearing re- al. Otolaryngol Head Neck Surg 2018;158:710-5. https://doi. habilitation . J Neurolog Surg B 2019;80:196-202. https://doi. org/10.1177/0194599818756592 org/10.1055/s-0039-1678731

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Letter to the Editor Current evidence on confocal laser endomicroscopy for noninvasive head and neck cancer imaging Evidenze scientifiche attuali sulla endomicroscopia confocale laser nell’imaging del tumore non invasivo del distretto testa e collo Xi Yang1,2, Wei Liu2 1 Department of Oral and Maxillofacial-Head and Neck Oncology, Fengcheng Hospital of Fengxian District, Shanghai, China; 2 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

KEY WORDS: confocal laser endomicroscopy, head and neck squamous cell carcinoma, oral potentially malignant disorders, dysplasia, fluorescent molecular imaging PAROLE CHIAVE: endomicroscopia laser confocale, carcinoma spinocellulare testa e collo, lesioni orali potenzialmente maligne, displasia, imaging molecolare a fluorescenza

Dear Editor, Received: April 18, 2020 We read with interest the article entitled “Probe-based confocal laser en- Accepted: April 28, 2020 domicroscopy in detecting malignant lesions of vocal folds” recently pub- Correspondence 1 lished in Acta Otorhinolaryngologica Italica by Goncalves et al. . The Wei Liu authors determined the diagnostic value and inter-rater reliability of confo- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, cal laser endomicroscopy (CLE) by comparing 58 video sequences of 3 pa- Shanghai 200011, China tients with squamous cell carcinomas (SCC) and 4 patients with benign al- E-mail: [email protected] terations of the vocal folds 1. CLE imaging features of SCC compared with the benign alterations were well characterised 1, but the current evidence Funding This work was supported by Fengxian District on CLE imaging in noninvasive detection of HNSCC is making progress Clinical Diagnosis & Treatment Center of Oral and needs to be significantly expanded upon (Tab. I). This Letter aims to and Maxillofacial-Head and Neck Oncology provide the reader with an up-to-date review of the literature on CLE in the (fxlczlzx-a-201705) and Shanghai Municipal Health Committee (202040327). setting of HNSCC. We classify the research topics of current investigations into CLE head and neck imaging, and briefly discuss current practices and Conflict of interest challenges that implicate future directions. The Authors declare no conflict of interest. In studies before 2014, the main objective of preliminary studies was to investigate the CLE imaging characteristics of head and neck cancer tis- How to cite this article: Yang X, Liu W. Current sue compared to normal mucosa and surgical margins (reviewed in Abbaci evidence on confocal laser endomicroscopy for 2 noninvasive head and neck cancer imaging. Acta et al. ). Earlier studies have shown that by using CLE, micro-anatomical Otorhinolaryngol Ital 2020;40:396-398. https:// structures of normal mucosa/margins and cancerous lesions can be well doi.org/10.14639/0392-100X-N0801 identified, allowing for differentiation of malignant and benign mucosal. © Società Italiana di Otorinolaringoiatria However, these results should be interpreted prudently for several rea- e Chirurgia Cervico-Facciale sons: very small sample size, different measurement devices used, lack of diagnostic criteria based on micro-imaging of CLE. In addition, field OPEN ACCESS of view and depth penetration of this technology have not yet been well This is an open access article distributed in accordance with addressed 2. the CC-BY-NC-ND (Creative Commons Attribution-Non- Commercial-NoDerivatives 4.0 International) license. The Starting in 2014, the main objective of prior studies was to evaluate wheth- article can be used by giving appropriate credit and mentio- er CLE is useful in diagnosing HNSCC 3-8. According to preliminary da- ning the license, but only for non-commercial purposes and only in the original version. For further information: https:// ta 1,3,6-8, the sensitivity and specificity of diagnosing SCC was reported to creativecommons.org/licenses/by-nc-nd/4.0/deed.en

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be 85.0-95.3% and 72.0-100%, respectively. Addition- head and neck cancer imaging with EpCAM and EGFR ally, the interobserver accuracy and reliability of CLE antibodies conjugated to fluorescent labels 9,10. When com- for discrimination of head and neck lesions from normal bined with the molecular imaging capabilities of CLE at the mucosa has also been investigated 4-6. Intriguingly, the cellular level, these new fluorescent targets can contribute feasibility of automated analysis and classification of to the currently pursued topic of personalised medicine in cancerous tissue in CLE head and neck imaging using the field of head and neck cancer, by making it possible to deep learning has been demonstrated 7,8. Although the predict the cells’ response to the molecular imaging guided results are promising, they are limited to mainly small diagnosis and therapy. descriptive studies. The standardised diagnostic proto- In summary, the noninvasive point-of-care CLE for head cols as well as clinically relevant classification systems and neck imaging at the cellular level, as a new emerg- for head and neck diseases have not yet been described. ing science, is of great promise for research, especially in Moreover, the integration between pathologist and clini- molecular targeted chairside diagnosis and intraoperative cian/surgeon in the review process of CLE imaging has normal margins. Multi-institutional studies on the three not been elucidated. aforementioned research classifications are warranted to One of the greatest advantages of CLE with fluorescence is overcome the drawbacks and consolidate the value of CLE. its potential for multiplex analyses in which morphological The dynamic observation of early malignant changes at the information can be combined with molecular and/or func- cellular level is a crucial element in the understanding of tional markers. Alterations in molecular and/or functional patient-specific information and today, noninvasive CLE is properties of a cancerous tissue can be translated into sig- probably the most versatile technology to face this chal- nificant and optically measurable changes in fluorescent lenge. Nevertheless, substantial researches are still needed signals. In vivo molecular imaging of gastrointestinal can- in order to promote fluorescence molecular imaging tech- cer using CLE by targeting EGFR and VEGF has been niques to the status of routine use in clinical practice for demonstrated; this concept was recently applied to CLE HNSCC.

Table I. Summary of the English-language literature of confocal laser endomicroscopy for diagnostic assessment of head and neck squamous cell carcinoma (SCC). Year of First Country Manufacturer No. of subjects Subject setting Aim of study Sensitivity Specificity publication author and location % % 2019 Goncalves Germany CellVizio, France Vocal folds 4 benign vs. 3 Diagnostic assessment 91.4-96.6 100 et al. 1 SCC and interobserver agreement 2014 Nathan et USA CellVizio, France Oral 12 leukoplakia Diagnostic 85.7 100 al. 3 vs. 9 SCC assessment a 2016 Moore et USA CellVizio, France Oral 6 non-dysplasia Interobserver NA NA al. 4 vs. 7 dysplasia agreement vs. 11 SCC 2016 Linxweiler Germany CellVizio, France HN 50 normal vs. Interobserver NA NA et al. 5 135 SCC agreement b 2016 Oetter et Germany CellVizio, France Oral 45 normal Diagnostic assessment 95.3 88.9 al. 6 50 SCC and interobserver agreement 2016 Dittberner Germany CellVizio, France Oral, oropharynx, Self control of 12 Automated Diagnostic 85.0 72.0 et al. 7 others normal margins assessment and SCC 2017 Aubreville Germany CellVizio, France oral Self control of 12 Automated Diagnostic 86.6 90.0 et al. 8 normal margins assessment and SCC 2017 Englhard et Germany CellVizio, France HN 5 normal vs. 11 EGFR/EpCAM-targeted NA NA al. 9 SCC micro-imaging 2019 Watermann Germany Optiscan, NA Gingiva normal EGFR nanoparticles- NA NA et al. 10 Australia vs. Oropharynx targeted micro- SCC imaging HN: head and neck sites being not-specified; NA: not available.a SCC vs. non-dysplasia. b using formalin-fixed tissue specimens.

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References 6 Oetter N, Knipfer C, Rohde M, et al. Development and validation of a classification and scoring system for the diagnosis of oral squamous 1 Goncalves M, Aubreville M, Mueller SK, et al. Probe-based con- cell carcinomas through confocal laser endomicroscopy. J Transl Med focal laser endomicroscopy in detecting malignant lesions of vo- 2016;14:159. https://doi.org/10.1186/s12967-016-0919-4. cal folds. Acta Otorhinolaryngol Ital 2019;39:389-95. https://doi. 7 Dittberner A, Rodner E, Ortmann W, et al. Automated analysis of org/10.14639/0392-100X-2121. confocal laser endomicroscopy images to detect head and neck can- 2 Abbaci M, Breuskin I, Casiraghi O, et al. Confocal laser endomi- cer. Head Neck 2016;38(Suppl 1):E1419-26. https://doi.org/10.1002/ croscopy for non-invasive head and neck cancer imaging: a compre- hed.24253. hensive review. Oral Oncol 2014;50:711-6. https://doi.org/10.1016/j. 8 Aubreville M, Knipfer C, Oetter N, et al. Automatic classification of oraloncology.2014.05.002. cancerous tissue in laserendomicroscopy images of the oral cavity 3 Nathan CA, Kaskas NM, Ma X, et al. Confocal Laser Endomi- using deep learning. Sci Rep 2017;7:11979. https://doi.org/10.1038/ croscopy in the detection of head and neck precancerous le- s41598-017-12320-8 sions. Otolaryngol Head Neck Surg 2014;151:73-80. https://doi. 9 Englhard AS, Palaras A, Volgger V, et al. Confocal laser endomicros- org/10.1177/0194599814528660. copy in head and neck malignancies using FITC-labelled EpCAM- 4 Moore C, Mehta V, Ma X, et al. Interobserver agreement of confocal and EGF-R-antibodies in cell lines and tumor biopsies. J Biophoton- laser endomicroscopy for detection of head and neck neoplasia. La- ics 2017;10:1365-76. https://doi.org/10.1002/jbio.201600238 ryngoscope 2016;126:632-7. https://doi.org/10.1002/lary.25646 10 Watermann A, Gieringer R, Bauer AM, et al. Fluorescein- and EGFR- 5 Linxweiler M, Kadah BA, Bozzato A, et al. Noninvasive histological antibody conjugated silica nanoparticles for enhancement of real-time imaging of head and neck squamous cell carcinomas using confocal tumor border definition using confocal laser endomicroscopy in squa- laser endomicroscopy. Eur Arch Otorhinolaryngol 2016;273:4473-83. mous cell carcinoma of the head and neck. Nanomaterials (Basel) https://doi.org/10.1007/s00405-016-4145-8 2019;9:1378. https://doi.org/10.3390/nano9101378

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