• Users Online: 193
  • Print this page
  • Email this page

Table of Contents
Year : 2020  |  Volume : 17  |  Issue : 4  |  Page : 259-263

Recurrent respiratory papillomatosis: A challenging clinical entity

1 Department of Otorhinolaryngology, IMS and SUM Hospital, Siksha “O” Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India
2 Department of Anesthesiology, Apollo Hospital, Bhubaneswar, Odisha, India
3 Directorate of Medical Research, IMS and SUM Hospital, Siksha “O” Anusandhan (Deemed to be University), Bhubaneswar, Odisha, India

Date of Submission13-May-2020
Date of Decision01-Sep-2020
Date of Acceptance05-Oct-2020
Date of Web Publication03-Dec-2020

Correspondence Address:
Santosh Kumar Swain
Department of Otorhinolaryngology, IMS and SUM Hospital, Siksha “O” Anusandhan (Deemed to be University), Bhubaneswar, Odisha
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_45_18

Rights and Permissions

Recurrent respiratory papillomatosis (RRP) is a benign lesion seen in the respiratory airway caused by human papillomatosis virus (HPV).RRP can affects children to young adults. Most of the childhood RRP occur at birth which contaminated from birth canals of the mother. In adult ages, the infections transmitted via sexual route. The lesions are often seen as exophytic nodules, mostly in the larynx and occasionally at the nasopharynx, tracheobronchial trees and lung parenchyma. This disease is often unpredictable and varies from spontaneous remission to aggressive persistent or recurrence in nature.RRP has chance for malignant transformation to squamous cell carcinoma although it is a rare happening. The diagnosis is confirmed by histopathological study. Presently there is no definite treatment for RRP available. Surgery is the treatment of choice along with several adjuvant therapies available. The aim of this review article is to describe the detail etiology, epidemiology, clinical presentations, investigations and treatment of RRP.

Keywords: Human papillomavirus, larynx, laser, recurrent respiratory papillomatosis

How to cite this article:
Swain SK, Mohanty S, Nahak B, Sahu MC. Recurrent respiratory papillomatosis: A challenging clinical entity. Apollo Med 2020;17:259-63

How to cite this URL:
Swain SK, Mohanty S, Nahak B, Sahu MC. Recurrent respiratory papillomatosis: A challenging clinical entity. Apollo Med [serial online] 2020 [cited 2021 Jan 25];17:259-63. Available from: https://www.apollomedicine.org/text.asp?2020/17/4/259/302212

  Introduction Top

Recurrent respiratory papilloma (RRP) is a benign and self-limiting disease caused by the human papillomavirus (HPV) where the lesions seen in the aerodigestive tract.[1] The bimodal age distribution is associated with RRP where characteristic young children and young adults are often affected.[1] This disease is often seen in children and the virus is transmitted by contact with infected secretions from the birth canal. The histopathological presentations are benign squamous epithelium stratification.[2] These lesions are typically confined to the larynx but sometimes seen at the nasopharynx, tracheobronchial area, and very uncommonly the lungs parenchyma.[3] The prognosis of RRP vary from spontaneous remission to aggressive progression and spreading to the lungs. The diagnosis of RRP is based on medical records, clinical presentations, and imaging. The final diagnosis of RRP is always based on histopathological examination where samples are taken from the lesions of the larynx and trachea. Laryngeal papillomatosis is a benign neoplasm, described as exophytic proliferative lesions of connective tissue covered by epithelial tissue. It often begins at the commissure and anterior part of the vocal cords and later on involves all the parts of the larynx and even lower airway such as the trachea, bronchi, and lung parenchyma in some patients. The lesions of the laryngeal papillomatosis are usually multiple in numbers and less frequently solitary.[4] There are two forms of RRP: Juvenile RRP and adult-onset RRP. If the age of the patient is <12 years in RRP is called Juvenile RRP and often seen in 2–5 years.

  Epidemiology Top

The incidence of RRP is around 4 per 1 lakh in children and 2 per 1 lakh in adults.[5] The incidence of RRP varies according to different factors such as age and socioeconomic status.[5] These are higher among low socioeconomic status and low educational backgrounds.[6] However, the severity of the diseases is not associated with socioeconomic status.[5] The prevalence of HPV infections is more among female sex. The prevalence of the disease among females is 26.8% in 14–59 years of age and 45% in 20–24 years of age.[6] RRP has bimodal distribution and affects both children and young adults.[6] The juvenile type is seen in the patients <20 years of age.[2] The juvenile type has aggressive presentations with multiple papillomatosis lesions and has high recurrence rate.[2] The adult form of RRP seen after 20 years and more commonly seen in male. In adult RRP, the papillomatosis lesions are often solitary with a high degree of inflammatory reactivity and do not spread and have less chance of recurrence, and less common than the juvenile type.[2] HPV infection mostly occurs during birth as the birth canal acts as a source of infection. Sometimes transmission of infection occurs before birth through the placenta in approximately 12% of cases.[6] Anogenital warts of the mother act as risk factors for the juvenile type of RRP. The presence of maternal anogenital papillomatous lesions during pregnancy period or during birth of baby enhances the risk of RRP by around 231 times in comparison to the absence of such lesions at the time of birth.[7] In adult patients, HPV is transmitted sexually through oral contact with infected genitalia. Sexual activity with several partners increases the risk for HPV infections in adults.[8]

  Etiopathology Top

RRP is caused by a virus called human papillomatosis (HPV), mostly by subtypes 6 and 11 which are also seen in the genital condylomas.[9] The subtypes of HPV 16 and 18 are also involved in laryngeal papillomatosis and in uterine cervical carcinoma.[10] HPV is a DNA virus which parasitizes the epithelial cells nuclei. RRP can be seen in any places of the aerodigestive tract. It has a predilection for the sites where there is a junction of squamous and ciliary columnar epithelium. The common sites of the RRP lesions are the limen vestibule, the nasopharyngeal surface of the soft palate, mid-zone of the laryngeal surface of the epiglottis, upper and lower margins of the laryngeal ventricle, underthe surface of the vocal cords, carina, and bronchial spurs.[11] HPV usually infects the basal epithelial layer of the mucous layer via minor excoriation. Then, it stimulates the epidermal growth factor receptor pathway and inhibits different tumor-suppressing proteins, culminating in cellular proliferation, and epithelial differentiation. These mechanisms lead to cauliflower-like exophytic mass lesions, typical of RRP.[12] This growth often seen in the transitional areas between the squamous epithelium and the ciliated columnar epithelium.[12] The nodular growth of RRP often seen in the larynx [Figure 1], but quite often involves the vocal folds, ventricles, subglottis, and laryngeal surface of the epiglottis. However, the RRP can affect any part of the aerodigestive tract and extend to the tracheobronchial tree and lung parenchyma.[8] RRP affects the distal airway in only 2–5% of the patients with papilloma of the larynx, whereas the pulmonary parenchyma is affected in only 1% of cases.[8]
Figure 1: Polypoidal/nodular papillomatosis at the vocal cord

Click here to view

  Clinical Presentations Top

Juvenile RRP patients present with multiple lesions and a high chance of recurrence. However, in adult RRP, the papilloma can be aggressive and less prone to recurrent. The common clinical presentations are progressive hoarseness of voice, stridor, and respiratory distress. Less frequently seen symptoms are cough, failure to thrive, and dysphagia.[13] In pediatric patients, the clinical presentations include triad of progressive hoarseness of voice, stridor, and breathing difficulty. In adult patients, the most common clinical presentation is hoarseness of voice.[14] On examination, patients present with wheezing, tachypnea, stridor, and accessory muscle retraction during respiration.[15] In severe cases of RRP, patients often present with airway obstruction and respiratory distress.[15] Due to several non-specific clinical presentations, RRP may mimic to common laryngeal diseases such as laryngitis, bronchial asthma, bronchitis, and croup.[16] Peripheral dissemination of the lesions may cause recurrent pneumonia, atelectasis, and malignant degeneration with presentations of dyspnea, hemoptysis, fever, and cough.[17] RRP is often confused with pulmonary tuberculosis.[17] Sometimes the clinicians classify the RRP into aggressive and nonaggressive on the basis of the severity of the symptoms and signs. Aggressive RRP is characterized by requirement of ten or more surgical procedures with three or more surgery being done within 1 year duration or by when the disease spread distally toward the subglottic airway. Nonaggressive RRP is characterized by the requirement of fewer than ten surgical procedures with lesser than three surgeries are being performed within the 1 year period or no distal spread of the disease reaching to the subglottic area.[18] In comparison to adult RRP, juvenile RRP needs more surgical procedures because of recurrences more in juvenile variety and a larger area of involvement occurs in children. Juvenile RRP has similar involvement in the airway between males and females.[19] The first symptoms in children appear between the ages of 2 and 4 years and the most common symptom is dysphonia. The progressive and extensive growth [Figure 2] in the airway leads to dyspnea and stridor. Less common symptoms are chronic cough and dysphagia in the juvenile variety. Children diagnosed as RRP before the age of the 3 years are 3.6 times more likely require >four surgeries per year and show more than one diseased anatomical locations.[18]
Figure 2: Extensive laryngeal papillomatosis obstructing the airway

Click here to view

  Investigations Top

There are several investigations modalities available for the diagnosis of RRP. The diagnosis of the RRP is less commonly done by imaging like X-ray. In case of pulmonary involvement, the chest X-ray may show solid or cavitated nodules in the lungs. Nodular lesions or pedunculated mass are seen less frequently in the trachea and main bronchi.[20] Helical computed tomography scan is the ideal modality of imaging for the assessment of RRP. It has a high degree of accuracy for the identification of the lesions in tracheobronchial pulmonary lesions.[21] The CT scan pictures are focal or diffuse airway narrowing due to nodular lesions occurring at the mucosal surface of the tracheobronchial lumen. CT scan picture of lungs in RRP are single or multiple multilobulated well-delineated solid nodular or polypoidal lesions of different sizes with a centrilobular distribution, scattered throughout the lungs [Figure 3]. The nodules increase its size and become large air-filled cysts, may lead to a large cavity with irregular internal borders. Lesions are often multiples seen at the basal and posterior part of the lungs. The cavity may show fluid level if associated with superimposed infections. Other findings in CT scan are atelectasis, consolidations, air trapping, and bronchiectasis. Pleural effusion and lymph node enlargement are rarely seen except in case of malignant transformation of RRP. Regular check-up should be done with CT scan to rule out the malignant transformation. Virtual bronchoscopy is sometimes an alternative method for CT scan for assessing the tracheobronchial tree. It reveals the three-dimensional images after processing with the use of specific imaging protocols. It is a non-invasive method which avoids the complications of the conventional bronchoscopy. Airway stenosis is not a limiting factor for avoiding the virtual bronchoscopy.MRI can show the airway structures such as larynx, trachea, bronchi, and lungs but its role in the diagnosis of RRP is not well evaluated. The lesions in the RRP may show uptake on18F-fluorodeoxyglucose positron emission tomography/CT due to elevated cellular proliferation.[22] However, it is not helpful for early detection of malignancy in RRP. The diagnosis of RRP is done by flexible nasopharyngolaryngoscopy, rigid laryngoscopy, and confirmation is done through histopathological testing. Macroscopically, the laryngeal papillomas appear pedunculated, uneven, and nodular with varying in sizes. In histopathological examination, the papillomas are highly vascularized, often keratinized neoplasms made up of connective tissue lined by stratified squamous epithelium and project outwardly in finger-like fronds.[23]
Figure 3: Computed tomography scan picture of the lungs in recurrent respiratory papillomatosis showing multiple multilobulated well-delineated solid nodular or polypoidal lesions scattered throughout the lungs

Click here to view

  Treatment Top

The treatment of RRP consists of resection of papillomas for maintaining airway patency, improve voice quality, and prevent complications. Surgery is the treatment of choice in RRP. Cold microsurgery, laser, or surgery with microdebrider or coblation is used which helps to spare healthy tissue. Surgery can not prevent recurrence of the disease, so different adjuvant therapies are often given to the patients. The complete removal of the lesions may lead to recurrences in many patients due to latent virus. In pediatric patients, approximately five surgeries a year needed to prevent recurrences.[19] The type of surgery often decides the surgical outcome. Nowadays, the recent surgical options in RRP are conventional tweezers, CO2 laser, coblation, and microdebrider. Neodymium-yttrium-aluminum-garnet laser and pulsed light are sometimes used in Juvenile RRP.[24] In case of extensive disease with a serious risk for laryngeal airway compromise, especially when several surgical interventions failed for getting patent airway, tracheostomy is needed.[25] Comparing with HPV-6 infection, HPV-11 infection appears to be more likely to result in tracheostomy.[25] When tracheostomy is must, decannulation is done as soon as the airway is stable and disease is controlled, as it may lead to rapid viral colonization and cause distal spread of the disease.[5] Unfortunately, around 50% of the patients those undergoes tracheotomy develops tracheal papillomas.[6] Approximately 20% of the patients suffering from RRP require adjuvant medical treatment in addition to surgery for controlling the disease.[26] The present criteria for adjuvant therapy are >four surgical procedures per year; recurrence of papillomas with compromised airway and distal multiple sites spread of the disease.[26] The majority of the medical treatment act in immunomodulation and inhibition of HPV replication and proliferation of the virus. The medications used are interferon, retinoid, antiviral (such as acyclovir, ribavirin, and cidofovir), and inhibitors of the oxygenase-2 cycle).[26] There are different adjuvants treatments are given in case of RRP care. These adjuvant therapies have been documented in the literatures but none appear to helpful for the cure of the disease. The palliative care has been given in the form of photodynamic therapy, interferon-alpha, indole-3-carbino, cis-retinoic acid, cidofovir, acyclovir, ribavirin, bevacizumab, and tetravalent HPV vaccines.[27] Interferon is one of the adjuvant medication in RRP which give positive results in terms of disease evolution by causing reduction of the lesion growth.[7] The limitation of the interferon when given in the intravenous route leads to systemic toxicity with a reversible rise in serum transaminase level and possibility for thrombocytopenia and leukopenia.[1] Common side effects of interferon are fatigue, transient fever, nausea, arthralgia, headache, and spastic diplegia in infants. At present, topical application of interferon alpha is tried, but it needs further studies in patients with RRP.[1] Cidofovir is a cytosine nucleotide analog which selectively inhibits viral DNA polymerase during replication of virus. In RRP, it can be administrated intravenously or through nebulization or by intralesional injection. Adjuvant intralesional cidofovir is helpful for partial or total regression of the lesions and reduces the frequency of surgical treatment.[28] Intralesional injection has advantage for maintaining a low plasma level so that toxicity will be minimized without any side effects.[28] The development of vaccines against HPV provides the potential for the future eradication of the diseases by decreasing the incidence and so that prevent transmission of the virus. The quadrivalent vaccine is often given for the prevention of cervical and anogenital malignancies and precarcinogenetic lesions due to HPV subtypes 6, 11, 16, and 18.[29] Currently, HPV vaccines are not approved for use in neonates, so it needs further research.[6] Cidofovir (an analog of cytosine) is the most commonly used medical adjuvant in the treatment of RRP.[28] It can be administrated by intravenous route or nebulization or intralesional injection. Intralesional administration of cidofovir cause partial to total regression of the lesions and decrease the frequency of surgical procedures in RRP.[28] Intralesional injection of the cidofovir has almost minimal side effects.[28] The long-term risks in intralesional injections are not well known whereas the theoretical risk for malignant transformation can not be ruled out.[28]

  Conclusion Top

RRP is a benign lesion characterized by papillomatous appearance seen anywhere in the aero-digestive tract. It may cause significant morbidity and in few cases mortality due to recurrence and obstructing the airway. The disease often restricted to the larynx and sometimes spread to the whole airway including bronchioles. The diagnosis is confirmed by histopathological examination. Clinician should have knowledge about the etiology, clinical presentations, laryngoscopic picture, and imaging aspects of the disease for the early management of the disease. Unfortunately, there is no curative treatment for RRP available presently and surgery is the mainstay of the treatment now.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Carifi M, Napolitano D, Morandi M, Dall’Olio D. Recurrent respiratory papillomatosis: Current and future perspectives. Ther Clin Risk Manag 2015;11:731-8.  Back to cited text no. 1
Marchiori E, Araujo Neto CD, Meirelles GS, Irion KL, Zanetti G, Missrie I, et al. Laryngotracheobronchial papillomatosis: Findings on computed tomography scans of the chest. J Bras Pneumol 2008;34:1084-9.  Back to cited text no. 2
Ağgünlü L, Erbaş G. Recurrent respiratory papillomatosis with lung involvement. Diagn Interv Radiol 2009;15:93-5.  Back to cited text no. 3
Soldatski IL, Onufrieva EK, Steklov AM, Schepin NV. Tracheal, bronchial, and pulmonary papillomatosis in children. Laryngoscope 2005;115:1848-54.  Back to cited text no. 4
Fortes HR, von Ranke FM, Escuissato DL, Araujo Neto CA, Zanetti G, Hochhegger B, et al. Recurrent respiratory papillomatosis: A state-of-the-art review. Respir Med 2017;126:116-21.  Back to cited text no. 5
Venkatesan NN, Pine HS, Underbrink M. Recurrent respiratory papillomatosis. Otolaryngologic Clin N Am2012;45:671-94.  Back to cited text no. 6
Lee JH, Smith RJ. Recurrent respiratory papillomatosis: Pathogenesis to treatment. Curr Opin Otolaryngol Head Neck Surg 2005;13:354-9.  Back to cited text no. 7
Taliercio S, Cespedes M, Born H, Ruiz R, Roof S, Amin MR, et al. Adult-onset recurrent respiratory papillomatosis: A review of disease pathogenesis and implications for patient counseling. JAMA Otolaryngol Head Neck Surg 2015;141:78-83.  Back to cited text no. 8
Quick CA, Watts SL, Krzyzek RA, Faras AJ. Relationship between condylomata and laryngeal papillomata. Clinical and molecular virological evidence. Ann Otol Rhinol Laryngol 1980;89:467-71.  Back to cited text no. 9
Niv A, Sion-Vardi N, Gatot A, Nash M, Fliss DM. Identification and typing of human papillomavirus (HPV) in squamous cell carcinoma of the oral cavity and oropharynx. J Laryngol Otol 2000;114:41-6.  Back to cited text no. 10
Kashima H, Mounts P, Leventhal B, Hruban RH. Sites of predilection in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 1993;102:580-3.  Back to cited text no. 11
Fusconi M, Grasso M, Greco A, Gallo A, Campo F, Remacle M, et al. Recurrent respiratory papillomatosis by HPV: Review of the literature and update on the use of cidofovir. Acta Otorhinolaryngol Ital 2014;34:375-81.  Back to cited text no. 12
Derkay CS. Recurrent respiratory papillomatosis. Laryngoscope 2001;111:57-69.  Back to cited text no. 13
Silverman DA, Pitman MJ. Current diagnostic and management trends for recurrent respiratory papillomatosis. Curr Opin Otolaryngol Head Neck Surg 2004;12:532-7.  Back to cited text no. 14
Xiao Y, Wang J, Han D, Ma L. A case of the intrapulmonary spread of recurrent respiratory papillomatosis with malignant transformation. Am J Med Sci 2015;350:55-7.  Back to cited text no. 15
Boston M, Derkay CS. Recurrent respiratory papillomatosis. Clin Pulmonary Med 2003;10:10-6.  Back to cited text no. 16
Marchiori E, Pozes AS, Souza Junior AS, Escuissato DL, Irion KL, Araujo Neto CD, et al. Diffuse abnormalities of the trachea: Computed tomography findings. J Bras Pneumol 2008;34:47-54.  Back to cited text no. 17
Doyle DJ, Gianoli GJ, Espinola T, Miller RH. Recurrent respiratory papillomatosis: Juvenile versus adult forms. Laryngoscope 1994;104:523-7.  Back to cited text no. 18
Reeves WC, Ruparelia SS, Swanson KI, Derkay CS, Marcus A, Unger ER. National registry for juvenile-onset recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg 2003;129:976-82.  Back to cited text no. 19
Marchiori E, Zanetti G, Mauro Mano C. Tracheobronchial papillomatosis with diffuse cavitary lung lesions. Pediatr Radiol 2010;40:1301-2.  Back to cited text no. 20
Shiau EL, Li MF, Hsu JH, Wu MT. Recurrent respiratory papillomatosis with lung involvement and malignant transformation. Thorax 2014;69:302-3.  Back to cited text no. 21
Derkay CS, Darrow DH. Seminar series recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 2006 ;115:1-11.  Back to cited text no. 22
Bailey BJ, Calhoun KH, Derkay CS, Friedman N, Gluckman J, Healy GB, et al., editors. Recurrent respiratory papillomatosis. In: Head and Neck Surgery Otolaryngology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 659-65.  Back to cited text no. 23
Hartnick CJ, Boseley ME, Franco RA, Cunningham MJ, Pransky S. Eft cacy of treating children with anterior comissure and true vocal fold respiratory papilloma with the 585-nm pulsed-dye laser. Arch Otolaryngol Head Neck Surg 2007;133:127-30.  Back to cited text no. 24
Donne AJ, Hampson L, Homer JJ, Hampson IN. The role of HPV type in recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol 2010;74:7-14.  Back to cited text no. 25
Katsenos S, Becker H. Recurrent respiratory papillomatosis: A rare chronic disease, difficult to treat, with potential to lung cancer transformation: A propos of two cases and a brief literature review. Case Rep Oncol 2011;4:162-71.  Back to cited text no. 26
Mudry P, Vavrina M, Mazanek P, Machalova M, Litzman J, Sterba J. Recurrent laryngeal papillomatosis: Successful treatment with human papillomavirus vaccination. Arch Dis Child 2011;96:476-7.  Back to cited text no. 27
Tasca RA, Clarke RW. Recurrent respiratory papillomatosis. Arch Dis Child 2006;91:689-91.  Back to cited text no. 28
Wilcox LJ, Hull BP, Baldassari CM, Derkay CS. Diagnosis and management of recurrent respiratory papillomatosis. Pediatr Infect Dis J 2014;33:1283-4.  Back to cited text no. 29


  [Figure 1], [Figure 2], [Figure 3]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Clinical Present...
Article Figures

 Article Access Statistics
    PDF Downloaded22    
    Comments [Add]    

Recommend this journal