10.14639/0392-100X-suppl.1-43-2023-14
Objectives. Recurrent respiratory papillomatosis (RRP) is a benign, rare disease caused by Human Papilloma Virus (HPV) that can be divided into juvenile and adult forms. The course of the disease is variable, but is usually more aggressive in the juvenile form. The standard surgical treatment is represented by CO2 laser resection, although photoangiolytic lasers represent a valid alternative. Adjuvant therapies have been proposed for disease control in case of frequent surgical resections or spreading into the lower airways. In recent years, the development of immunotherapy led to the use of bevacizumab either intratumorally or intravenously, but the most promising therapeutic development is represented by HPV vaccination. This paper aims to present a narrative review of the literature and the experience of three different University Centres in the treatment of RRP. Methods. A retrospective analysis of the clinical charts of all patients affected by laryngeal papillomatosis and treated in three different University Centres between 2002 and 2022 was performed. The following parameters were collected: sex, age at first evaluation, sites of larynx involved, HPV type, type of first surgical treatment, presence and number of recurrences, surgical treatment of recurrences, adjuvant therapies, side effects and status at last follow-up. Results. Seventy-eight patients were available for evaluation. Of these, 88% had adult onset RRP (Ao-RRP) and 12% juvenile onset RRP (Jo-RRP). The glottis was the most frequently involved subsite; all patients were submitted to surgical resection with CO2 laser under general anaesthesia. Recurrences appeared in 79% of the patients, the patients who did not recur were all adults. The mean number of recurrences was 9 (range 1-110). Recurrences were more frequent in children (M = 20; range 2-110) than adults (M = 5; range 1-21). Thirty-two (52%) of the 62 patients who recurred were re-treated with CO2 laser under general anaesthesia, while office-based treatment with a photoangiolytic laser was preferred in the remaining 30 (48%) patients. Adjuvant treatments were applied in 26 patients. The analysis of the course of the disease showed that in the 9 patients with Jo-RRP, 6 (67%) were free of lesions at the last follow-up, while the other 3 (33%) had papillomas. Of the 69 patients with Ao-RRP, 53 (77%) were alive and free of disease at the last visit, 14 (21%) were alive with disease, 1 (1%) was lost at follow-up and 1 (1%) died for other disease. Severe side effects were not observed except for 2 patients, who developed posterior glottic stenosis. Conclusions. Our results confirmed the literature review. RRP is a potentially aggressive disease, especially in juvenile onset. Surgical resection is still first-line treatment, but in case of multiple recurrences the use of adjuvant therapies must be taken into consideration.
text/xml
1827-675X
2616
en
Marco Benazzo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
HPV infection
Recurrent laryngeal papillomatosis: multimodal therapeutic strategies. Literature review and multicentre retrospective study
Text.Serial.Journal
https://www.actaitalica.it/
43
Annual congress report
2023-04-21
2023-04-21
2023-04-28
2023-04-28
S111-S122
1
Marco Benazzo
2023/04/21
10.14639/0392-100X-suppl.1-43-2023-14
S111
Department of Otolaryngology Head and Neck Surgery, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
1827-675X
HPV infection
S122
Recurrent laryngeal papillomatosis: multimodal therapeutic strategies. Literature review and multicentre retrospective study
https://www.actaitalica.it/article/download/2616/951
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43(SUPPL.1):S111-S122; doi: 10.14639/0392-100X-suppl.1-43-2023-14




Head and Neck section


Recurrent laryngeal papillomatosis:
multimodal therapeutic strategies.
Literature review and multicentre retrospective study
La papillomatosi laringea ricorrente: strategie terapeutiche multimodali.
Revisione della letteratura e analisi retrospettiva multicentrica
Giulia Bertino1, Fabio Pedretti1, Simone Mauramati1, Marta Filauro2, Alberto Vallin2,3, Francesco Mora2,3, Erika Crosetti4,
Giovanni Succo5,6, Giorgio Peretti2,3, Marco Benazzo1
1
 Department of Otolaryngology Head and Neck Surgery, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy;
2
 Unit of Otolaryngology Head and Neck Surgery, IRCCS Policlinico San Martino Hospital, Genoa, Italy; 3 DISC, University
of Genoa, Italy; 4 ENT Unit, Oncology Department, University of Turin, Orbassano (Turin), Italy; 5 ENT Department, San Giovanni
Bosco Hospital, Turin, Italy; 6 Oncology Department, University of Turin, Turin, Italy


SUMMARY
Objectives. Recurrent respiratory papillomatosis (RRP) is a benign, rare disease caused
by Human Papilloma Virus (HPV) that can be divided into juvenile and adult forms. The
course of the disease is variable, but is usually more aggressive in the juvenile form. The
standard surgical treatment is represented by CO2 laser resection, although photoangio-
lytic lasers represent a valid alternative. Adjuvant therapies have been proposed for dis-
ease control in case of frequent surgical resections or spreading into the lower airways.
In recent years, the development of immunotherapy led to the use of bevacizumab either
intratumorally or intravenously, but the most promising therapeutic development is rep-
                                                                                                Received: January 15, 2023
resented by HPV vaccination. This paper aims to present a narrative review of the lit-
                                                                                                Accepted: January 19, 2023
erature and the experience of three different University Centres in the treatment of RRP.
Methods. A retrospective analysis of the clinical charts of all patients affected by laryn-
                                                                                                Correspondence
geal papillomatosis and treated in three different University Centres between 2002 and          Giulia Bertino
2022 was performed. The following parameters were collected: sex, age at first evalu-           Department of Otolaryngology Head and Neck Sur-
ation, sites of larynx involved, HPV type, type of first surgical treatment, presence and       gery, University of Pavia, IRCCS Policlinico San
number of recurrences, surgical treatment of recurrences, adjuvant therapies, side effects      Matteo Foundation, piazzale Golgi 2, 27100 Pavia.
and status at last follow-up.                                                                   Tel. +39 0382503740. Fax +39 0328503667
Results. Seventy-eight patients were available for evaluation. Of these, 88% had adult          E-mail: g.bertino@smatteo.pv.it - prof.giulia.berti-
onset RRP (Ao-RRP) and 12% juvenile onset RRP (Jo-RRP). The glottis was the most                no@universitadipavia.it
frequently involved subsite; all patients were submitted to surgical resection with CO2
laser under general anaesthesia. Recurrences appeared in 79% of the patients, the pa-             How to cite this article: Bertino G, Pe-
tients who did not recur were all adults. The mean number of recurrences was 9 (range             dretti F, Mauramati S, et al. Recurrent la-
1-110). Recurrences were more frequent in children (M = 20; range 2-110) than adults              ryngeal papillomatosis: multimodal thera-
(M = 5; range 1-21). Thirty-two (52%) of the 62 patients who recurred were re-treated             peutic strategies. Literature review and
with CO2 laser under general anaesthesia, while office-based treatment with a photoan-            multicentre retrospective study. Acta Otorhi-
giolytic laser was preferred in the remaining 30 (48%) patients. Adjuvant treatments              nolaryngol Ital 2023;43(SUPPL.1):S111-S122.
                                                                                                  https://doi.org/10.14639/0392-100X-sup-
were applied in 26 patients. The analysis of the course of the disease showed that in the 9
                                                                                                  pl.1-43-2023-14
patients with Jo-RRP, 6 (67%) were free of lesions at the last follow-up, while the other
3 (33%) had papillomas. Of the 69 patients with Ao-RRP, 53 (77%) were alive and free
of disease at the last visit, 14 (21%) were alive with disease, 1 (1%) was lost at follow-      © Società Italiana di Otorinolaringoiatria
                                                                                                e Chirurgia Cervico-Facciale
up and 1 (1%) died for other disease. Severe side effects were not observed except for 2
patients, who developed posterior glottic stenosis.
                                                                                                               OPEN ACCESS
Conclusions. Our results confirmed the literature review. RRP is a potentially aggres-
sive disease, especially in juvenile onset. Surgical resection is still first-line treatment,   This is an open access article distributed in accordance with
                                                                                                the CC-BY-NC-ND (Creative Commons Attribution-Non-
but in case of multiple recurrences the use of adjuvant therapies must be taken into            Commercial-NoDerivatives 4.0 International) license. The
consideration.                                                                                  article can be used by giving appropriate credit and mentio-
                                                                                                ning the license, but only for non-commercial purposes and
KEY WORDS: recurrent respiratory papillomatosis, laser surgery, cidofovir, bevacizumab,         only in the original version. For further information: https://
vaccine, HPV infection                                                                          creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                      S111
G. Bertino et al.




RIASSUNTO
Obiettivi. La papillomatosi recidivante delle vie respiratorie è una rara patologia benigna causata dal Papilloma virus umano (HPV) e può es-
sere suddivisa in una forma giovanile ed una dell’adulto. Il decorso della malattia è variabile, di solito più aggressivo nella forma giovanile. Il
trattamento chirurgico standard è rappresentato dalla resezione con laser CO2, anche se i laser fotoangiolitici possono rappresentare una valida
alternativa. L’utilizzo di terapie adiuvanti è stato proposto per il controllo della malattia nei casi che richiedono trattamenti chirurgici frequenti o
che tendono a diffondere nelle vie respiratorie inferiore. L’alfa-interferon è stato uno dei primi farmaci ad essere utilizzati, seguito dal cidofovir.
Negli ultimi anni, lo sviluppo dell’immunoterapia ha condotto all’utilizzo del bevacizumab sia per somministrazione intralesionale o sistemica, ma
lo sviluppo terapeutico più promettente è rappresentato dalla vaccinazione anti HPV. Lo scopo di questo lavoro è di presentare una revisione della
letteratura e l’esperienza di tre differenti Centri Universitari nel trattamento della papillomatosi recidivante delle vie respiratorie.
Metodi. È stata condotta un’analisi retrospettiva sulle cartelle cliniche dei pazienti affetti da papillomatosi laringea e trattati in tre differenti
Centri Universitari tra il 2002 e il 2022. Sono stati analizzati i seguenti parametri: sesso, età alla prima visita, siti laringei coinvolti, sierotipi
di HPV, tipologia del primo trattamento chirurgico, presenza e numero di recidive, trattamento chirurgico delle recidive, terapie adiuvanti,
effetti collaterali e status all’ultimo follow-up.
Risultati. Settantotto pazienti sono stati selezionati per lo studio. Di questi, l’88% presentava papillomatosi dell’adulto (Ao-RRP) e il 12% una
forma giovanile (Jo-RRP). La glottide è risultata la sottosede più coinvolta; tutti i pazienti sono stati sottoposti a chirurgia con laser CO2 in
anestesia generale. Recidive sono state osservate nel 79% dei pazienti, i pazienti che non hanno mostrato recidive erano tutti adulti. Il numero
medio di recidive è stato di 9 (range 1-110). Le recidive sono risultate più frequenti nei bambini (M = 20; range 2-110); rispetto agli adulti
(M = 5; range 1-21). Il 52% dei 62 pazienti con recidiva è stato ritrattato con laser CO2 laser in anestesia generale, mentre nell’altro 48% dei
pazienti è stata scelta una procedura ambulatoriale con un laser fotoangiolitico. Terapie adiuvanti sono state impiegate in 26 pazienti. L’ana-
lisi del decorso della malattia ha rivelato che nei 9 pazienti con papillomatosi giovanile, 6 (67%) erano liberi da malattia all’ultimo follow-up,
mentre gli altri 3 (33%) avevano ancora papillomi. Dei 69 pazienti con papillomatosi dell’adulto, 53 (77%) erano liberi da malattia all’ultima
visita; 14 (21%) presentavano ancora papillomi; 1 (1%) è stato perso al follow-up e 1 (1%) è morto per altra malattia. Effetti collaterali severi
sono stati riscontrati solo in 2 pazienti che hanno sviluppato una stenosi glottica posteriore.
Conclusioni. I risultati hanno confermato quelli della revisione della letteratura. La papillomatosi respiratoria ricorrente è una malattia
potenzialmente aggressiva, specie nell’insorgenza giovanile. La resezione chirurgica è ancora il trattamento di prima linea, ma in caso di
multiple recidive è necessario prendere in considerazione l’uso di terapie adiuvanti.
PAROLE CHIAVE: papillomatosi respiratoria ricorrente, chirurgia laser, cidofovir, bevacizumab, vaccino, infezione da HPV



Introduction                                                                  Jo-RRP usually develops before the age of 12 years, with
                                                                              75% of cases diagnosed before the age of 5 and with no
Recurrent respiratory papillomatosis (RRP) is the term used                   difference in sex. It is more aggressive than the adult type
to describe infection of the upper aerodigestive tract by Hu-                 and is more active the earlier it appears in life. In this
man Papilloma Virus (HPV). HPV 6 and 11 are responsible                       case, the risk of obstructing and descending lesions in the
for more than 90% of RRP cases 1. HPV 16 and 18 are high-                     lower respiratory tract is very high. It is estimated that
risk subtypes, with the potential for malignant transforma-                   the appearance before the age of 3 is associated with a
tion, which occurs in less than 1% of juvenile RRP cases 2.                   3.6-fold higher risk of more than 4 surgical procedures
Although papillomas can arise anywhere in the tract, the                      and to 2-fold higher risk of multiple anatomic sites being
larynx is the most affected organ. A bimodal age of dis-                      affected 5.
tribution is characteristic, with young adults or young                       Ao-RRP occurs after the age of 12; the peak of incidence
children affected. Juvenile RPP (Jo-RRP) has a more ag-                       is between 20-40 years, with males being more affected.
gressive and recurring course with a high risk of extension                   The disease is less active, and the anterior part of the glottis
to the lower respiratory tract. The adult RRP (Ao-RRP) is                     is the most frequently involved site 5. It has been reported
mostly located at the glottic level with the occurrence of                    that the average number of surgeries in the first five years
dysphonia as the main symptom. Because of this unpredict-                     of diagnosis is 5.1 per year, decreasing to 0.1 per year after
able course, knowledge and management of RRP is essen-                        15 years 6,7.
tial to any otolaryngologist 3.
                                                                              Human papilloma virus
Epidemiology
                                                                              In 1923, Ullman first confirmed the presence of an infec-
The incidence and prevalence of RRP are not well defined.                     tious agent in laryngeal papillomas, but it was only in the
It is estimated that Jo-RRP is present in 4.3 per 100,000                     1980s that RRP was confirmed to contain HPV-DNA 3.
children and 1.8 per 100,000 adults in the United States 4.                   HPV 6 and 11 account for most cases of RRP and type 11
The prevalence of the disease is variable depending on the                    is responsible for the most aggressive clinical course, fol-
age of presentation, country and socioeconomic status 3.                      lowed by type 6. Types 16, 18, 31, and 33 have also been



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rarely detected, and their presence is linked to a major risk      HPV in Ao-RRP is sexually transmitted, and patients
of malignant transformation 3,5.                                   with Ao-RRP have significantly more lifetime sex part-
It is widely accepted that HPV infection is limited to the ba-     ners and a higher frequency of oral sex than nonaffected
sal cells of the stratified epithelium. In the cervix uteri, the   adult controls 10.
squamous columnar junction is the most common site for
development of condylomas. The larynx also has a similar           Clinical findings
junction, namely the squamous ciliary junction (lSCJ) be-
tween the stratified squamous epithelium and pseudostrati-         Juvenile and adult RRP differ in terms of clinical presen-
fied ciliated columnar epithelium. Laryngeal papillomas            tation, progression, and severity of the disease. Despite
often develop at sites with lSCJ and are characterised by a        being infected before or during birth, most children do not
fibrovascular core of connective tissue covered by stratified      manifest any symptoms of RRP immediately 3. Because
squamous epithelium 4. However, the laryngeal papilloma            the larynx is the most common site of infection, hoarse-
often appears on any site of the laryngeal mucosa that is not      ness is the first symptom in most paediatric patients. How-
covered by genuine stratified epithelium, especially in the        ever, this finding is frequently associated with asthma, al-
juvenile onset form. This is because both stratified squa-         lergy, laryngitis and nodules of the vocal cords, so that it
mous epithelium and pseudostratified respiratory epithe-           is only when stridor appears that laryngeal papillomatosis
lium express p63 and integrin-a6, proteins which are nec-          is considered. Usually, the mean time between the first
essary for infection and replication of HPV 8. Furthermore,        clinical findings and the diagnosis is about 1 year 3,5. Jo-
it is known that repeated surgical procedures to eliminate         RRP is mostly diagnosed between 2 and 4 years of age
papillomas, inducing a squamous metaplasia of the ciliated         even if 75% of the juvenile patients with RRP are diag-
epithelium, and increasing the number of subsites exposed          nosed by age 5 years 3,11.
to viral infection 8.                                              Thirty percent of the affected children present extralaryn-
It remains unclear why only a small fraction of HPV-ex-            geal spread of disease; the oral cavity is the most common
posed individuals develop RRP and why still fewer develop          site, followed by trachea, bronchi, and oesophagus. Rarely,
a severe course of the disease 3.                                  the larynx is not affected despite the presence of lower res-
Different studies have demonstrated that patients with RRP         piratory tract disease 3,11.
are unable to produce an effective HPV-specific T-cell im-         Dysphonia is the first symptom in adults because of the
mune response, present abnormal expression of IL-10 and            predominant involvement of the glottis. Dyspnea is rarely
IFN-g and a downregulation of the transporter associated           observed when treatments are available 5.
with antigen presentation (TAP-1) 3,9. These alterations are
more severe in Jo-RRP because of the immaturity of the             Clinical course
immune-system and could explain the more severe course
of the disease in children 9.                                      The clinical course of RRP can vary. Some patients show
The main reservoir of HPV 6 and 11 is the anogenital tract         an aggressive disease which requires frequent surgery to
and HPV is the most common sexually transmitted disease.           prevent airway obstruction; others show a progressive and
The prevalence of HPV is increasing in the female popula-          spontaneous remission, but in many cases the course re-
tion, in women aged 14 to 59 years is 26.8% and in women           mains unpredictable 3.
between 20-24 years is nearly 45%. These percentages in-           There is no unanimous and rigorous definition of the sever-
crease when factors such as education, poverty index and           ity of the RRP. This depends on the degree of dysphonia,
number of sexual partners are taken into consideration 3,5.        the consequences at the level of communication, social and
Vertical mother-to-child transmission during passage               professional integration, and the frequency of surgical pro-
through the birth canal is the main way of infection for           cedures necessary for disease control 5. Recurrent dyspho-
Jo-RRP. The risk is increased in young primipara mothers           nia, especially that related to the surgical treatments, can
because of a higher viral load and prolonged labour. There-        have a negative impact on the personal, social, and profes-
fore, not all children born from HPV-positive mothers with         sional life of patients.
genital condylomata develop respiratory papillomatosis.            A severity scale, the Derkay Staging System, is used in
Other factors seem to be important: patient immunity, tim-         the literature to quantify the severity of the RPP and is
ing, length and volume of virus exposure, local traumas            based on the laryngeal structures involved (Fig. 1) 12. Der-
(intubation, extra-oesophageal reflux). Moreover, neonates         kay’s score is composed of a for-site score and a clinical
may become infected before birth through transplacental            score. The for-site score takes into account the amount of
transmission 3,5.                                                  disease (0: none; 1: surface; 2: raised; 3: bulky) in the dif-



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G. Bertino et al.




Figure 1. The Derkay Staging System 12.


ferent laryngeal and extra-laryngeal subsites. The clinical   Diagnosis
score takes into consideration voice quality, presence of
stridor, urgency of intervention and presence of respira-     Fibreoptic examination of the larynx with normal white
tory distress 12.                                             light is the first-line endoscopy in the diagnosis of larynge-
The risk of spreading into the subglottis or the trachea is   al diseases. Nevertheless, in many cases, this examination
rare but tremendously increased by a tracheotomy or pro-      does not allow to precisely recognise the peculiar findings
longed intubation. Pulmonary involvement is the most ag-      and satellite foci of RRP, so the ultimate diagnosis must be
gressive course of the disease and can lead to complete       verified by histology 13.
pulmonary failure by destruction of the lung parenchyma       For this reason, in recent years new endoscopic techniques
with a higher risk of malignant transformation 3. This rare   such as Narrow Band Imaging (NBI), iScan, autofluores-
presentation accounts for less than 1% of RRP and is usu-     cence, contact endoscopy and optical coherence tomogra-
ally associated with HPV-11 infection 3.                      phy have been developed to give deeper insight into the



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biological properties of lesions, ensuring both a high rate        duction of office-based treatment of RRP, it has been pos-
of true positive biopsies and a reduction in unnecessary bi-       sible to treat bulky lesions involving the entire glottis under
opsies 13.                                                         general anaesthesia, leaving small residual commissural or
In particular, NBI allows for better distinction between be-       para-commissural ones and treat them, after the complete
nign and malignant lesions because it allows us to study           healing process, in office under local anaesthesia.
the laryngeal mucosal and submucosal vascular patterns             In patients with very aggressive disease, an additional
and to detect any vascular changes or neoangiogenesis 14.          goal is to prevent distal spreading to the lower respiratory
In 2010, Ni et al. proposed a classification of laryngeal le-      tract. Tracheotomy must be reserved only for very severe
sions based on changes in intraepithelial papillary capillary      cases at risk of airway obstruction, providing an addition-
loops (IPCL) patterns: benign lesions have type I-III pat-         al risk for colonisation and distal spread of RRP 19. The
terns, are pre-cancerous and suspected malignant type IV           advent of new ventilation technique with small catheters,
and malignant type Va, b, c 15. In the literature, the sensitiv-   such as the Tritube of Evone system by Ventinova, allows,
ity, specificity, and accuracy of NBI in detecting malignant       even in cases of lesions obstructing the airways, safe in-
lesions are > 95% 14; however, this diagnostic tool has one        tubation thu avoiding tracheotomy and trachea-bronchial
main limitation: laryngeal papillomatosis. In fact, laryngeal      viral spreading 20.
papillomatosis shows the same IPCL type V pattern of la-           Different surgical techniques have evolved in the manage-
ryngeal cancer 16. In 2015, the European Laryngological            ment of RRP, moving from cold instruments and microde-
Society (ELS) published another classification of laryn-           briders to different types of lasers 1,19.
geal vascular changes to better distinguish the difference
between laryngeal papillomatosis and cancer 17. According          Lasers
to this classification, lesions with longitudinal vessels are      There are two different categories of lasers: ablative/cut-
benign, while lesions with IPCL can be typical for both            ting lasers such as CO2 and thulium lasers, which target wa-
papillomatosis and laryngeal cancer. The difference be-            ter, and photoangiolytic lasers, such as pulsed-dye (PDL),
tween them is the angle of the turning point of the vessel:        potassium-titanyl-phosphate (KTP) lasers and True-Blue
laryngeal papillomatosis usually has wide-angled turning           laser, which target haemoglobin 2,19.
points, whereas cancer lesions have narrow-angled turn-            The CO2 laser quickly gained popularity to treat RRP since
ing points 17. However, these features are not easily visible,     the 1960s because of its fine cutting and coagulating ability,
so that high expertise of the otolaryngologist and practice
                                                                   but repeated surgical sessions may result in fibrosis, scar
with high-quality equipment are mandatory 18. In experi-
                                                                   formation, loss of the elastic properties of the mucosa of
enced hands, NBI is extremely useful in the diagnosis of
                                                                   the vocal cords and voice impairment 21.
untreated lesions in the pre-operatory and intra-operative
                                                                   Conversely, photoangiolytic lasers precisely target haemo-
setting, and even during follow-up, improving the detection
                                                                   globin in highly vascularised papillomas and may have a
of multifocal foci of disease that are otherwise not visible
                                                                   better haemostatic effect than the CO2 laser 19,21. In particu-
under white light 13.
                                                                   lar, KTP laser wavelength is more strongly absorbed by
                                                                   haemoglobin, resulting in greater coagulation and less tis-
Treatment modalities                                               sue damage 19. It has been demonstrated that the application
The standard care for the management of RRP is surgical            of KTP laser in laryngeal microsurgery seems to guarantee
resection. The surgery must be aimed to provide an ade-            better accuracy and precision surgery, less tissue damage,
quate vocal outcome, preserving as much as possible the            shorter hospital stays and lower rate of recurrences than the
integrity of the underlying anatomical structures and main-        CO2 laser; nevertheless, there is still a major limitation on
taining airway patency 1,19, while avoiding any iatrogenic         its widespread use because KTP laser equipment is more
complications. Aggressive resection must not be the goal,          expensive than CO2 lasers 21.
as injury to the surrounding mucosal surface can increase
expression of HPV dormant in nearby cells 19. Moreover,            Microdebrider
wide resection in single-stage is absolutely contraindi-           Microdebriders have gained popularity due to the speed
cated for laryngeal lesions located in the anterior or pos-        they provide in removing bulky papillomas and the absence
terior commissure; in these sites, double-stage procedures         of thermal effects. They are often used in combination with
or subtotal resections are required to avoid webbing and           a laser: the microdebrider removes the bulk of the papil-
scarring that can determine permanent dysphonia or airway          loma while lasers provide the haemostatic effect and treat
obstruction 19. As an alternative, thanks to the recent intro-     the sessile lesions 19.



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In-office lasers procedures                                        Pegylated interferon alpha2a is the novel counterpart. It has
In-office lasers procedures, usually performed with KTP or         improved half-life and pharmacokinetics; side effects are
PDL lasers, and the newly introduced true-blue laser 2,20,22,      less severe, but still present during long-term treatment, so
have offered an alternative to the traditional management          that it is rarely used due to emergence of other drugs with
under general anaesthesia. The glass fibre laser is inserted       fewer local and systemic side effects, such as cidofovir and
into the working channel of the video endoscope, thereby re-       bevacizumab 19.
ducing costs and hospital stays, while giving the possibility
to treat even small lesions that are not suitable for treatment    Antiviral agents and cidofovir
under general anaesthesia 2,21,23. This allows patients to main-   Antiviral drugs used in the treatment of RRP include acy-
tain a better voice-related quality of life, moving the treat-     clovir, ribavirin and cidofovir 11.
ment goal from airway patency to a better and permanent            The efficacy of acyclovir and ribavirin was tested in the
quality of voice.                                                  1990s in a few case series and seemed to be linked to the
In general, the procedures are safe and well tolerated in          presence of viral co-infections (herpes simplex, cytomeg-
adult patients who have received adequate local anaesthesia        alovirus, or Epstein-Barr virus). These clinical studies
(5% lidocaine or 5% neobucaine). However, they are not             are insufficient to conclude for a beneficial effect of these
an option for every patient; patients with bulky or extended       drugs 5,11.
lesions or with inadequate tolerance to the videoendoscope         The introduction of cidofovir for the management of the
are poor candidates. Awake procedures are also not suitable        RRP since the late 1990s resulted in a great improvement
in children19.                                                     in the control of the disease 5. Cidofovir is a cytosine nu-
In general, adult patients with a new diagnosis of laryngeal       cleotide analogue. Once converted in the active form, it is
papillomatosis should first be treated under general anaes-        incorporated into DNA and exerts its toxicity in the Herpes
thesia to allow for disease evaluation, biopsies and removal       Virus and Papilloma virus families. Its systemic use is ap-
of bulky and disseminated lesions. Subsequent procedures           proved for treatment of CMV retinitis in HIV patients, Her-
can be performed in the office according to the extent of          pes Simplex, Herpes Zoster and Epstein-Barr infections in
disease, patient tolerance and surgeon skills 19.                  immune-compromised patients. Systemic treatment is as-
In addition, there is evidence for the possibility to perform      sociated with neutropenia and nephrotoxicity 26. The intral-
in-office intralesional administration of cidofovir or beva-       esional off-label use has been adopted for the treatment of
cizumab after laser procedures 24,25.                              genital HPV or RRP. The antiviral effect is dose-dependent,
                                                                   but there are no clear protocols for dose, concentration, and
                                                                   frequency of administration 27.
Adjuvant therapies
                                                                   Even if many studies have reported significant response
Although surgery is the main treatment modality for RRP,           rates with almost no side effects (Tab. I) 28-36, in 2012 a
it has been estimated that 20% of patients require some            Cochrane review of clinical trials comparing intralesional
form of adjuvant therapy to control the disease 19. Although       use of cidofovir vs placebo after surgical debulking found
there is no specific indication for the use of adjuvant treat-     that there was no significant difference in disease control in
ment, it is widely considered when the need for surgical           the two groups after 12 months of follow-up and concluded
debridement is frequent (more than 4 to 6 procedures/year)         that there was insufficient evidence to support the efficacy
or if the lesions begin spreading beyond the larynx 26.            of antiviral agents as adjuvant therapy in the management
                                                                   of RRP 37.
Interferon                                                         Moreover, in January 2011, a communication provided by
Alpha-interferon was one of the first adjuvant treatments          the manufacturer of cidofovir addressed very serious side ef-
adopted at the beginning of the 1980s. It is a cytokine that       fects concerning its off-label use. The warning included re-
binds to specific cell receptors and modifies the immune re-       ports on nephrotoxicity, neutropenia, oncogenicity and even
sponse with an anti-proliferative and anti-viral effect. It has    some fatalities. The manufacturer did not specify the severity
been used in either intralesional or intramuscular routes of       of the reported complications, the off-label indication of the
administration. The efficacy of intramuscular use is dose-         drug, or its way of administration or concentration dosage;
dependent, suspension of the treatment is associated with          nonehteless, it decided to withdraw the drug from all non-
rebound effects, and the sustained response is inadequate11.       USA countries 38.
Moreover, side effects, especially hepatotoxicity and toxic-       As this was a general warning, it was inconclusive whether
ity on the nervous system, were severe in some cases. For          this would account for its use in RRP 38. For this reason, the
these reasons, its use was progressively abandoned 26.             European Laryngological Society initiated a research project



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Table I. Summary of cidofovir in reviewed clinical trials.
 Study          Year    Number     Median Pre-treat        Pre-treat    Post-treat    Post-treat      HPV        Mean                    Results and conclusions
                           of        age   mean            surgical       mean       surgical rate    type    concentration
                        patients   (years) Derkay            rate        Derkay      (surgery per               (mg/ml)
                                            score          (surgery       score          year)
                                                           per year)
 Ablanedo-      2022     4, 1 Jo      17        23.5          3.4           0.5           0                        5           Decrease in the Derkay severity score with IL
 Terrazas et                                                                                                                                    cidofovir
 al. 28
                          3 Ao
 Jackowska      2019       42         30                  8 (mean of                 2.5 (mean of                                  Treatment with intraepithelial cidofovir
 et al. 29                                                procedures                  procedures                               injections and CO2 laser debulking can lead to
                                                            before                       after                                a nearly normal voice. 22 complete remissions.
                                                           cidofovir)                  cidofovir)                                           20 partial remissions
                          3 Jo
                         39 Ao
 McMurray       2008       19         32        13.2                        2.7                                   0.3-5        Cidofovir demonstrate a reduction in severity
 et al. 30                                                                                                                                    index score
                          3 Jo
                         16 Ao
 Naiman         2006       17          4      7.67 (CR)                   0 (CR)                                  5-7.5        12 complete remissions. 5 partial remissions
 et al. 31
                         17 Jo                9.75 (PR)                  4.25 (PR)
 Chung et       2006       11          7        13.7          7.4           2.6          6.9                       5           The effectiveness of cidofovir as an adjuvant
 al. 32                                                                                                                          treatment for RRP remains unproven, but
                                                                                                                                the possibility of some therapeutic effect is
                                                                                                                              modestly suggested. 5 complete remissions. 6
                                                                                                                                              partial remissions
                         11 Jo
 Peyton         2004       11          2        11.9                                                 HPV 11       5-7.5         Cidofovir is a useful tool adjunctive therapy
 Shirley et                                                                                                                      in RRP. Significant response 27%, partial
 al. 33                                                                                                                              response 18%, no response 55%
                         11 Jo                                                                       HPV 6
 Chhetri et     2003       5                     9.2                         1                       HPV 11        5           A scheduled protocol for the treatment of Jo-
 al. 34                                                                                                                         RRP with cidofovir, with increasing interval
                                                                                                                               between treatments, is effective in controlling
                                                                                                                                               this disease
                          5 Jo                                                                       HPV 6
 Bielamowicz 2002          13         48         10          2.15            0            0          HPV 11    4.17-6.25      Intralesional injection of cidofovir is an excellent
 et al. 35                                                                                                                    treatment option with limited local and systemic
                                                                                                                                   toxicities. The long-term remission rates
                                                                                                                                  for patients with respiratory papilloma are
                                                                                                                                                     unknown
                         13 Ao                                                                       HPV 6
 Pransky et     2000       10          7        19.6      19 (mean of      12.7      2.2 (mean of    HPV 11                   Cidofovir therapy is an effective and beneficial
 al. 36                                                   procedures                  procedures                                                 treatment
                                                            before                       after
                                                           cidofovir)                  cidofovir)
                          10 Jo                                                                      HPV 6
Jo: Juvenile onset; Ao: Adult onset; CR: Complete Response; PR: Partial Response.


on the side effects of off-label use of cidofovir in RRP pa-                              function before and after cidofovir. There was no significant
tients 39. A newsletter and editorial were written to recruit                             difference in upper airway and tracheal malignancies be-
otorhinolaryngologists who treated RRP patients with in-                                  tween the cidofovir and non-cidofovir groups. No clinical
tralesional cidofovir. All participating centers received a                               evidence was found for long-term nephrotoxicity, neutro-
questionnaire and a retrospective case file report. Sixteen                               penia, or laryngeal malignancies after the administration of
hospitals from 11 countries worldwide submitted 635 RRP                                   intralesional cidofovir in RRP patients 38. Nevertheless, drug
patients, of whom 275 were treated with cidofovir. There                                  import is now allowed only for authorised use for clinical
were no significant differences in neutropenia or renal dys-                              trials.



                                                                                                                                                                          S117
G. Bertino et al.




Table II. Summary of bevacizumab in reviewed clinical trials.
 Study      Year Number Median Pre-treat Pre-treat              Post-treat   Post-treat    HPV       Dose of         Results and conclusions
                     of       age        mean        surgical     mean        surgical     type    bevacizumab
                 patients (years) Derkay                rate     Derkay         rate                   (mg)
                                         score       (surgery     score       (surgery
                                                    per year)                per year)
 Albanedo      2022         6            20      9     1           1.5           0                  25 mg/ml     Decrease of Derkay scores but no
 Terrazas                                                                                                             statistical significance
 et al. 28
                          2 Jo
                          4 Ao
 Rogers et 2013            10            8       19    8           13            4        HPV 11    2.5 mg/ml    Bevacizumab may indeed limit the
 al. 45                                                                                              (0.5 ml)      number of surgical procedures
                                                                                                                 required per year and increase the
                                                                                                                  duration between procedures in
                                                                                                                 patients with aggressive RRP, while
                                                                                                                   simultaneously improving voice
                                                                                                                              outcomes
                          7 Jo                                                            HPV 6
                          3 Ao
 Best et       2012        43            48                                                                      Higher doses of bevacizumab are
 al. 46                                                                                                           relatively safe in adult patients
                         43 Ao
 Zeitels et 2011          20            Range                                                      7.5-12.5 mg    3 complete responses, 16 partial
 al. 24                                (18-60)                                                                      responses with less disease
                                                                                                                    in treated vocal fold, 1 more
                                                                                                                     disease in the treated vocal
                                                                                                                   fold. Treating RRP by coupling
                                                                                                                     the antiangiogenetic agent
                                                                                                                    bevacizumab with KTP laser
                                                                                                                    photoangiolysis is synergistic
Jo: Juvenile onset; Ao: Adult onset.



Bevacizumab                                                                  The approved dose is 5-15 mg/kg every 2-3 weeks in adults
Bevacizumab is a recombinant monoclonal humanised an-                        and 5-10 mg/kg every 2-4 weeks in children 42,43.
tibody that blocks angiogenesis by inhibiting human vas-                     Intralesional use is indicated for recurrent laryngeal mani-
cular endothelial growth factor A (VEGF-A) and by pre-                       festations of the disease. The approved dose is 7.5-12.5 mg
venting the activation of its receptor (VEGF-R) 19. Rahbar                   at 25 mg/ml 44.
et al. conducted a retrospective study to determine the role                 Table II summarises the results of bevacizumab in clinical
of VEGF-A in the pathogenesis of RRP patients 40. Strong                     trials 24,28,45,46.
expression of VEGF-A mRNA was noted in the squamous
epithelium of RRP patients, and strong expression of VEG-                    Other adjuvant treatments
FR-1 and VEGFR-2 were noted in the endothelial cells of                      Other compounds have been proposed in small case series
the papilloma blood vessels 40. These observations provid-                   for the management of RRP, such as celecoxib, indole-
ed the rationale to evaluate the use of bevacizumab in RRP.                  3-carbinol, anti-reflux drugs, PD-1 inhibitors, and gefitinib.
The predominant effect of bevacizumab in RRP is modula-                      Unfortunately, no clinical trials are yet available to assess
tion of vasculature and not the induction of apoptosis, and                  the actual efficacy of these adjuvant treatments.
stronger effects are seen coupling the use of this drug with
photoangiolytic lasers, especially KTP 40.                                   Vaccines
Bevacizumab can be administered both intravenously and                       The most promising development in the treatment of RRP
intralesionally. Intravenous use is indicated for patients with              is HPV vaccination. The quadrivalent HPV vaccine (Gar-
non-accessible bronchial lesions, lung parenchyma involve-                   dasil) is active against HPV type 6, 11, 16 and 18, and
ment, papillomas of the paranasal sinuses, or for patients at                has been used in different adult and juvenile case series to
high risk for voice mutilation by interventional therapies 41.               manage RRP with promising results in terms of increased



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interval between surgeries or decreased recurrence 47,48.           of HPV were present only in 11 cases and HPV 6 was the
Moreover, quadrivalent vaccination in RRP patients with             most frequent subtype detected.
HPV DNA positivity and zero or low anti-HPV antibodies              The following parameters were collected: sex, age at first
increases both anti-HPV 6 and anti-HPV 11 antibodies 49.            evaluation, sites of the larynx involved, HPV types, type of
Therefore, the greatest hope lies in prophylactic vaccina-          the first surgical treatment, presence and number of recur-
tion of pre-adolescent boys and girls. It is expected that          rences, surgical treatment of recurrences, adjuvant thera-
widespread vaccination of pre-adolescents will decrease             pies, side effects and status at last follow-up.
HPV genital wart acquisition and, as a secondary effect,            The high number of variables related to the patient and dis-
will reduce the incidence of laryngeal infections to new-           ease as well as the heterogeneity of the cohort does not
borns via vertical HPV transmission and, in turn, reduce            permit statistical analysis.
the incidence of juvenile and overall RRP 50.
                                                                    Results
Personal series                                                     The glottis was the most often involved subsite (76% as
                                                                    a unique localisation); spreading to supraglottis, subglot-
                                                                    tis or trachea was observed in 13 patients. In 2 cases,
Methods                                                             the lesion affected only the supraglottis and in 1 case the
We conducted a retrospective analysis of the clinical charts of     trachea.
all the patients affected by laryngeal papillomatosis and treated   All patients were submitted to surgery under general an-
in three different University Centres between 2002 and 2022.        aesthesia with CO2 laser combined with microdebrider
Demographic results are reported in Table III. Seventy-             in case of bulky and obstructing lesions at first diagnosis
eight patients (54 males and 24 females) were available for         (Tab. IV). Recurrences appeared in 79% of patients, and the
evaluation. The mean age was 43 years (range 0-82); of              16 patients (21%) who did not recur were all adults. Over-
these, 88% had adult onset RRP (Ao-RRP) and 12% ju-                 all, the mean number of recurrences was 9 (range 1-110).
venile onset RRP (Jo-RRP). Data regarding the subtypes              Recurrences were more frequent in children (M = 20;
                                                                    range 2-110) than adults (M = 5; range 1-21).
Table III. Demographic characteristics (n = 78).                    Thirty-two (52%) of the 62 patients who recurred were
 Sex                           M                     54 (69%)       re-treated with CO2 laser under general anaesthesia, while
                               F                     24 (31%)       office-based treatment with a photoangiolytic laser was
 Age                          Mean                   43 years       preferred in the other 30 (48%) patients.
                             Range                  0-82 years      Adjuvant treatments were applied in 26 patients (Tab. IV).
                           < 12 years                 9 (12%)       Intralesional alfa-interferon was administered in 8% of
                           > 12 years                69 (88%)       cases; these patients were all adults and were treated be-
 Site                        Glottis                 59 (76%)       tween 2003 and 2013. Bevacizumab was the preferred
                          Supraglottis                 5 (6%)       compound administered since 2005, both intralesional or
                     Glottis + supraglottis            5 (6%)       systemic, alone or in combination with quadrivalent vac-
              Glottis + supraglottis + subglottis      3 (4%)
                                                                    cine (Tab. IV).
                      Glottis + subglottis             2 (3%)
                                                                    The analysis of the course of the disease showed that in
                                                                    the 9 patients with Jo-RRP, 6 (67%) were free of lesions at
                       Larynx +trachea                 3 (4%)
                                                                    the last follow-up, while the other 3 (33%) had papillomas.
                            Trachea                    1 (1%)
                                                                    These were the most severe cases with 8, 34 and 110 recur-
 HPV                      Determined                 11 (14%)
                                                                    rences, respectively. Of the 69 patients with Ao-RRP, 53
                             HPV 6                        4
                                                                    (77%) were alive and free of disease at the last visit (16
                             HPV 16                       2
                                                                    with no recurrences and 37 with recurrences), 14 (21%)
                             HPV 18                       1
                                                                    were alive with disease; 1 (1%) was lost at follow-up and 1
                             HPV 31                       1
                                                                    (1%) died for other disease.
                             HPV 44                       1
                                                                    Severe side effects were not observed except for 2 patients,
                             HPV 45                       1
                                                                    with 110 and 7 recurrences respectively, who developed
                             HPV 51                       1         posterior glottic stenosis. Only 1 patient underwent malig-
                             HPV 50                       1         nant transformation of the lesions. Some degree of dyspho-
                        Undetermined                 67 (86%)       nia was observed in 9 patients.



                                                                                                                               S119
G. Bertino et al.




Table IV. Treatment data.
 First surgical treatment                                      CO2 laser                                         78 (100%)
 Recurrences                                                      Yes                              62 (79%)                      9 < 12 yrs
                                                                                                                                 53 > 12 yrs

                                                                  No                               16 (21%)                        all adults

                                                    Overall mean n. of recurrences                    9
                                                             Overall range                          1-110

                                                    Mean n. of recurrences < 12 yrs                  20
                                                           Range < 12 yrs                           2-110

                                                    Mean n. of recurrences >12 yrs                     5
                                                           Range > 12 yrs                            1-21
 Surgical treatment for                                        CO2 laser                           32 (52%)
 recurrences
                                                         Office based blu laser                    30 (48%)
 Adjuvant treatments for                                         IL-IFN                             5 (8%)                         5 adults
 recurrences
                                                            Sy Bevacizumab                         10 (16%)                  8 adults + 2 children
                                                                Vaccine                            6 (10%)                   4 adults + 2 children
                                                       Sy Bevacizumab + Vaccine                     4 (6%)                   3 adults + 1 children
                                                    IL + Sy Bevacizumab + Vaccine                   1 (2%)                          1 child
                                                                 None                              36 (58%)
IL: Intralesional; IFN: Interferon; Sy: Systemic.



Conclusions                                                                           the lesions in one treatment session and extensive resec-
                                                                                      tions of the anterior and posterior commissures must be
RRP is a chronic disease that is difficult to treat because of
                                                                                      avoided because of the risk of glottic stenosis. Even in case
the unpredictability of its recurrences and aggressiveness.
                                                                                      of compromised patency of the airway, tracheotomy should
HPV infection drives local immune dysfunction, but it is
                                                                                      be postponed as long as possible to avoid the spread of the
still unclear why some patients experience a more severe
                                                                                      disease to the trachea; in case of tracheotomy cannulation,
disease than others, especially in the juvenile onset form 19.
                                                                                      the time must be as short as possible 11.
Currently, primary management of RRP is surgical resec-
tion of lesions by cold instrumentation such as the micro-                            When surgical treatment requires more than 4 procedures
debrider, or photoangiolytic and CO2 lasers. The choice be-                           per year, or in case of extensive or aggressive disease with
tween the treatment under general anaesthesia and in-office                           airway compromise, adjuvant pharmacological therapies
procedures is based on the lesion’s size and localisation and                         must be considered. IFN-alfa was the first compound used
the patient’s compliance. In case of frequent recurrences,                            to increase the immune response in RRP patients with good
treatments under local anaesthesia are better tolerated by                            results, also confirmed in our experience, but its system-
the patient, thus improving adherence to the follow-up pro-                           ic side effects limited its use and research moved toward
tocol.                                                                                intralesional or systemic cidofovir and recently to intral-
The principles of surgical therapy in RRP have been well                              esional or systemic bevacizumab.
stated by Bergler et al. 11. According to these authors, sur-                         However, additional studies on the interaction between the
gery must be considered as relief of symptoms, and rarely                             low-risk types of HPV and the immune system are nec-
a definitive cure.                                                                    essary to develop novel immunomodulatory molecules to
Surgical trauma may induce new papilloma growth and                                   better manage RRP patients 11.
consequentially any damage to healthy mucosa must be                                  HPV vaccination has shown therapeutic benefit, but, due
avoided whenever possible. There is no need to treat all                              to the low incidence of RRP, multicentre clinical trials are



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still required to assess the efficacy of the HPV vaccines in                     6
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reducing the recurrence rate of the disease. Routine pro-                             Neck Surg 2004;130:711-716. https://doi.org/10.1001/archotol.130.6.711
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pected to decrease the HPV genital warts and, as a second-                            nile-onset recurrent respiratory papillomatosis. Arch Otolaryngol Head
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the vertical transmission of HPV to newborns.                                    8
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                                                                                      geal papillomatosis based on laryngeal epithelial characteristics. La-
Recently, emerging office-based procedures represent a                                ryngoscope Investig Otolaryngol 2019;7:89-94. https://doi.org/10.1002/
valid adjunctive therapeutic option to carefully follow these                         lio2.242
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anaesthesia. Moreover, the routine utilisation of bioendo-                       10
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scopic techniques in the pre- and intra-operative settings                            onset and adult-onset recurrent respiratory papillomatosis. Laryngoscope
allows better and earlier detection of recurrences, thereby                           1992;102:9-13. https://doi.org/10.1288/00005537-199201000-00002
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ited resection.                                                                       cal management of juvenile-onset recurrent respiratory papillomatosis.
                                                                                      Eur Arch Otorhinolaryngol 2000;257:263-269. https://doi.org/10.1007/
                                                                                      s004050050236
Conflict of interest statement                                                   12
                                                                                      Derkay CS, Malis DJ, Zalzai G, et al. A staging system for assess-
The authors declare no conflict of interest.                                          ing severity of disease and response to therapy in recurrent respira-
                                                                                      tory papillomatosis. Laryngoscope 1998;108:935-937. https://doi.
                                                                                      org/10.1097/00005537-199806000-00026
Funding                                                                          13
                                                                                      Dippold S, Becker C, Nusseck M, et al. Narrow band imaging: a
This research did not receive any specific grant from fund-                           tool for endoscopic examination of patients with laryngeal papillo-
ing agencies in the public, commercial, or not-for-profit                             matosis. Ann Otol Rhinol Laryngol 2015;124:886-892. https://doi.
sectors.                                                                              org/10.1177/0003489415590656
                                                                                 14
                                                                                      Saraniti C, Gallina S, Verro B. NBI and laryngeal papillomatosis: a di-
                                                                                      agnostic challenge: a systematic review. Int J Environ Res Public Health
Author contributions                                                                  2022;19:8716. https://doi.org/10.3390/ijerph19148716
GB: designed the study, performed literature search, ana-                        15
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lysed the data and wrote the paper; FP collected the data,                            and precancerous lesions by narrow band imaging. J. Laryngol Otol
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                                                                                 16
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                                                                                      magnifying endoscopy in the prehistologic diagnosis of laryngeal papil-
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                                                                                 17
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