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Contents lists available at ScienceDirect

Auris Nasus Larynx

journal homepage: www.elsevier.com/locate/anl

Trends in the management of recurrent respiratory papillomatosis

in Japan
Shigeyuki Murono *, Yosuke Nakanishi, Akira Tsuji, Kazuhira Endo, Satoru Kondo,
Naohiro Wakisaka, Hiroshi Yoshida, Tomokazu Yoshizaki
Department of Otolaryngology, Head and Neck Surgery, Kanazawa University, Kanazawa 920-8640, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Recurrent respiratory papillomatosis (RRP) has historically been and still continues to be a
Received 7 July 2014 difficult disease to treat. The present study aimed to characterize current practices in the treatment of
Accepted 10 October 2014 RRP in Japan.
Available online xxx
Methods: A questionnaire was posted to the Department of Otolaryngology of all 80 central university
hospitals in Japan.
Keywords: Results: A total of 56 universities responded to the survey. Regarding the use of surgical instruments, a
Respiratory papillomatosis
trend toward a preference for lasers (50 hospitals) rather than a microdebrider (16 hospitals) or cold
Therapy
Survey
instruments (20 hospitals) was observed. Among the 50 hospitals frequently performing laser surgery, a
Japan carbon dioxide (CO2) laser was most commonly used, followed by a potassium-titanyl-phosphate (KTP)
Cidofovir laser. The most favored adjuvant therapy was traditional Chinese medicine. Eight of the 56 university
hospitals had an experience of using cidofovir, involving a total of 28 patients.
Conclusion: The present study demonstrated the current trends in the management of RRP based on a
questionnaire survey in a geographical area other than the US and UK for the first time. Treatment trends
were generally similar in all three areas except for the least popular use of cidofovir in Japan.
ß 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction RRP [4]. Although almost all surveyed board-certified otolaryngol-

ogists in the US preferred carbon dioxide (CO2) laser use in the
Recurrent respiratory papillomatosis (RRP), caused by human initial report by Derkay, various surgical instruments are currently
papillomavirus infection and most commonly by subtypes 6 and available [5]. In addition to surgical management, adjuvant
11, is characterized by exophytic, benign, papillary lesions of the pharmacotherapy for the treatment of RRP continues to be an
upper aerodigestive tract [1]. Although it is a benign disease that area of exploratory interest [6]. Therefore, characterization of the
usually involves the larynx, RRP has an unpredictable clinical current surgical and medical management of RRP is required.
course, and tends to recur and spread throughout the aerodigestive From this perspective, the American Society of Pediatric
tract [2]. Many treatments, both medical and surgical, have been Otolaryngology (ASPO) and British Association of Paediatric
applied; however, there is no ‘‘cure’’ at present [2]. Otorhinolaryngology (BAPO) individually reported results of
The current standard of care is surgical therapy with the goal of surveys of their members [7,8]. However, no surveys have been
completely removing the papillomas and preserving the normal reported to date from geographical areas other than these two. The
structures [2]. However, repeated surgeries put a heavy emotional present study aimed to investigate the current trend in the
burden on patients and families [3]. According to a report by the management of RRP in Japan using a postal survey.
RRP Task Force in the United States (US), the mean number of
surgical procedures per child was 4.4 per year for juvenile-onset
2. Methods

In order to evaluate the nationwide trends, a questionnaire was

* Corresponding author at: Department of Otolaryngology, Head and Neck
Surgery, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8640, Japan.
posted to the Department of Otolaryngology of all 80 central
Tel.: +81 76 265 2413; fax: +81 76 234 4265. university hospitals in Japan at the beginning of December
E-mail address: [email protected] (S. Murono). 2013. The questionnaire asked about the number of RRP patients

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0385-8146/ß 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Murono S, et al. Trends in the management of recurrent respiratory papillomatosis in Japan. Auris
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2 S. Murono et al. / Auris Nasus Larynx xxx (2014) xxx–xxx

during the last 1 year, preferred surgical procedures and

instruments, preferred adjuvant pharmacotherapies, and experi-
ence of using cidofovir. Multiple answers were allowed in response
to questions on surgical procedures, instruments, and adjuvant
pharmacotherapies. The survey responses submitted by the
representative doctor in each university hospital were collected
and the results were analyzed.

3. Results

A total of 56 (70.0%) universities responded to the survey. The

total number of RRP patients during the last 1 year was 196,
including 12 pediatric patients. The mean and median numbers of Fig. 2. Surgical instruments used for the treatment of recurrent respiratory
RRP patients were 3.5 and 2, respectively, ranging from 0 to papillomatosis.
19. While 46 (82.1%) of the 56 university hospitals had
encountered at least one RRP patient during the last 1 year, most
of the hospitals, namely 39 (84.8%) of 46, had encountered 5 or
fewer RRP patients, as shown in Fig. 1. followed by the diode laser in 3 (6.0%), Nd:YAG laser in 3 (6.0%),
Regarding surgical instruments, a trend toward a preference and Ho:YAG laser in 3 (6.0%), although multiple answers were
for lasers rather than a microdebrider or cold instruments was allowed. Among three hospitals sometimes performing laser
observed (Table 1 and Fig. 2). Laser surgery was frequently and surgery, one hospital used the CO2 laser, and remaining two
sometimes chosen for the treatment of RRP in 50 (89.3%) and 3 hospitals used the KTP laser.
(5.4%) of the 56 university hospitals, respectively. On the Adjuvant medical therapy was considered frequently in 16
other hand, a microdebrider was frequently and sometimes used (28.6%) and sparingly in 6 (10.7%) of the 56 university hospitals. All
in 16 (28.6%) and 10 (17.9%) of the 56 university hospitals, adjuvant therapies other than cidofovir were traditional Chinese
respectively. Cold instruments were frequently and sometimes medicine except for indole 3 carbinol (I3C) in two university
used in 20 (35.7%) and 7 (12.5%) of the 56 university hospitals, hospitals. Interferon was used in only one case. There were no
respectively. responses for antireflux medication.
Different types of laser were the preferred means of surgery Eight (14.3%) of the 56 university hospitals had an experience
for RRP. Among 50 hospitals frequently performing laser of using cidofovir for selected patients. The total number of
surgery, the CO2 laser was used in 27 (54.0%). The potassium- patients receiving cidofovir was 28, including 1 patient each in
titanyl-phosphate (KTP) laser was used in 16 (32.0%) hospitals, 5 hospitals, 3 patients in 1 hospital, 9 patients in 1 hospital, and
11 patients in 1 hospital. Intralesional injection of the agent was
performed in all cases.

4. Discussion

This survey aimed to determine the current treatment

strategies for RRP in Japan. This study clearly had limitations
because the questionnaire was sent to only central university
hospitals. There are many prefectural hospitals where RRP patients
are treated. Therefore, the number of patients in this study is just a
small percentage of the total population. Despite these circum-
stances, it is important to note that, even in highly advanced
central university hospitals, there seemed to be a trend toward the
bipolarization of care for RRP patients in Japan.
Only a few reports have documented questionnaire-based
surveys in the US and United Kingdom (UK) [5,7,8]. In 1994, the
CO2 laser was the most favored treatment modality by 92% of
Fig. 1. Distribution of recurrent respiratory papillomatosis patients during the last
the respondents in the US [5]. Then, Schraff et al. reported that
1 year in central university hospitals in Japan.
the microdebrider replaced the laser as the most preferred
instrument, with 53% of ASPO members using it as the main
modality, followed by the CO2 laser (42%), in 2004 [7]. On the
Table 1
Surgical instruments frequently used for treatment of RRP.a
other hand, Tasca et al. reported that the CO2 laser was the most
preferred instrument, accounting for 46.1% of BAPO members,
Surgical instrument Number of hospitals followed by the microdebrider (38.5%), in 2006 [8]. Interestingly,
Laser 50 the KTP laser was used by 19.2% in the BAPO survey, whereas
CO2 laser 27 there was no report of its usage in the ASPO survey [7,8].
KTP laser 16
In the present study, the most preferred instrument was the
Diode laser 3
Nd:YAG laser 3 CO2 laser, being consistent with previous reports. The micro-
Ho:YAG laser 3 debrider was also preferably used. However, preference for it was
Microdebrider 16 much or relatively less when compared with the 53% usage by the
Cold instrument 20 ASPO members or 38.5% usage by the BAPO members, respectively.
a
Recurrent respiratory papillomatosis. The microdebrider is frequently used in endoscopic sinus surgery

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S. Murono et al. / Auris Nasus Larynx xxx (2014) xxx–xxx 3

in Japan. However, blades for laryngeal surgery may be unfamiliar 5. Conclusions

with Japanese otolaryngologists in some central university
hospitals because they take care of fewer RRP patients as shown The present study demonstrated current trends in the manage-
in Fig. 1. Therefore, Japanese otolaryngologists may use micro- ment of RRP based on a questionnaire survey in an area other than
debrider less frequently compared with pediatric otolaryngolo- the US and UK for the first time. Treatment trends were generally
gists in the US and UK. On the other hand, the KTP laser and similar to those areas except for the least popular use of cidofovir in
especially cold instruments were much more preferably used than Japan. Because treatment for RRP continues to be difficult, we have
in BAPO and ASPO surveys. to make efforts to search for better therapies. For this purpose, the
The subject of surveys in the US and UK was juvenile-onset RRP, establishment of a centralized national base as well as further
whereas the present study mainly involved adult-onset RRP. From research and international cooperation will be required.
this perspective, it may be difficult to compare the results of the
present study with previous reports. However, the commonly
Conflict of interest
observed preference for the CO2 laser and microdebrider in both
juvenile- and adult-onset RRP may be due to the ease of handling
The authors declare that they have no conflict of interest.
and precision of those instruments. The KTP laser tends to be
invasive compared with the CO2 laser. Therefore, it may be
Acknowledgements
preferred for adult-onset RRP.
The handling of cold instruments may be difficult in the small
The authors sincerely thank to all the survey respondents for
operative field for RRP. Therefore, the instruments may be
providing the data.
preferred for adult-onset RRP. Indeed, a mutiauthor review that
arose from a panel discussion at the American Academy of
Otolaryngology-Head and Neck Surgery meeting in 2000 suggests References
that the preferred treatment technique for adult glottic RRP is cold
[1] Duggan MA, Lim M, Gill MJ, Inoue M. HPV DNA typing of adult-onset respira-
steel excision using phonomicrosurgical equipment and techni- tory papillomatosis. Laryngoscope 1990;100:639–42.
ques [9]. This strategy is based on the fact that RRP is an epithelial [2] Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryn-
disease, and that it is crucial to preserve the underlying superficial goscope 2008;118:1236–47.
[3] Lindman JP, Lewis LS, Accortt N, Wiatrak BJ. Use of the pediatric quality of life
lamina propria. inventory to assess the health-related quality of life in children with recurrent
Adjuvant therapy using traditional Chinese medicine is a respiratory papillomatosis. Ann Otol Rhinol Laryngol 2005;114:499–503.
unique feature in the present study. Although no evidence has [4] Armstrong LR, Derkay CS, Reeves WC, the RRP Task Force. Initial results from
the national registry for juvenile-onset recurrent respiratory papillomatosis.
been established, a Japanese group reported its effectiveness Arch Otolaryngol Head Neck Surg 1999;125:743–8.
based on a small retrospective study, which may support its [5] Derkay CS. Task force on recurrent respiratory papillomas. A preliminary
relatively frequent use in Japan [10]. Twelve patients with report. Arch Otolaryngol Head Neck Surg 1995;121:1386–91.
[6] Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomato-
aggressive laryngeal papillomatosis were administered individ-
sis. Otolaryngol Clin North Am 2012;45:671–94.
ual oral formulations of a traditional Chinese medicine after [7] Schraff S, Derkay CS, Burke B, Lawson L. American Society of Pediatric Otolar-
surgery. These patients served as their own controls and after yngology members’ experience with recurrent respiratory papillomatosis and
taking Chinese herbal medicine they often required fewer the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg 2004;130:
1039–1042.
surgeries and achieved lower Derkay’s score [10]. These observa- [8] Tasca RA, McCormick M, Clarke RW. British Association of Paediatric Otorhi-
tions lend support to the current practice of using traditional nolaryngology members experience with recurrent respiratory papillomato-
Chinese medicine for RRP in Japan. There is a trend toward using sis. Int J Pediatr Otorhinolaryngol 2006;70:1183–7.
[9] Zeitels SM, Casiano RR, Gardner GM, Hogikyan ND, Koufman JA, Rosen CA.
Kampo products, such as Hochu-ekki-to (TJ-41), instead of Management of common voice problems: committee report. Otolaryngol Head
individually formulated crude drug products. Although TJ-41’s Neck Surg 2002;126:333–48.
precise mechanism of action is unknown, it is speculated to [10] Okubo K, Saito K, Fukuda H, Watanabe K, Ogawa K, Shiotani A. Traditional
Chinese medicine for treatment of laryngeal papillomatosis. J Altern Comple-
enhance natural killer cell activity [11]. ment Med 2010;16:427–33.
The intralesional use of cidofovir has been one of the mainstays [11] Cho JM, Sato N, Kikuchi K. Prophylactic anti-tumor effect of Hochu-ekki-to
of adjuvant therapy for patients with RRP since 1998 [12,13]. In (TJ41) by enhancing natural killer cell activity. In Vivo 1991;5:389–91.
[12] Snoeck R, Wellens W, Desloovere C, Van Ranst M, Naesens L, De Clercq E, et al.
accordance with this, the most common adjuvant medical therapy Treatment of severe laryngeal papillomatosis with intralesional injections of
was cidofovir in the ASPO and BAPO surveys. However, the present cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine]. J Med
study demonstrated that the treatment was not popular in Japan Virol 1998;54:219–25.
[13] Chadha NK, James AL. Antiviral agents for the treatment of recurrent respira-
compared with the US and UK [7,8,14]. Currently, the treatment is
tory papillomatosis: a systematic review of the English-language literature.
considered off-label. Therefore, the RRP Task Force approved Otolaryngol Head Neck Surg 2007;136:836–9.
18 statements to define the indications, administration, adverse [14] Manickavasagam J, Wu K, Bateman ND. Treatment of paediatric laryngeal
events, and informed consent associated with this treatment papillomatosis: web survey of British Association of Paediatric Otolaryngol-
ogists. J Laryngol Otol 2013;127:917–21.
[15]. Considering these circumstances, the use of this agent should [15] Derkay CS, Volsky PG, Rosen CA, Pransky SM, McMurray JS, Chadha NK, et al.
be extensively discussed in Japan. Laryngoscope 2013;123:705–12.

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