Malignant Transformation and Distal Airway Complications



Recurrent respiratory papillomatosis (RRP) are benign neoplasms of the larynx caused by low-risk human papillomavirus (HPV) viral subtypes, predominantly 6 and 11. Extension beyond the larynx and transformation to dysplasia and invasive carcinoma have been described but the incidence is rare. Overall, juvenile-onset RRP tends to be more aggressive than the adult form, and a higher proportion of children will experience these life-threatening complications. Children are more likely to require a tracheotomy, develop distal spread of RRP, and experience pulmonary complications such as abscess, pneumatocele, and respiratory failure. Patients diagnosed as adults are more likely to develop laryngeal dysplasia but have a far smaller chance of developing pulmonary complications. Treatment strategies for benign papilloma continue to hinge on surgical removal, with considerations for adjuvant therapy when airway obstruction is imminent, frequency of surgery is intolerable, or distal spread is diagnosed. The most common adjuvant therapies have been interferon and cidofovir. The most recent treatments to show promise include HPV vaccination and bevacizumab, a monoclonal antibody that targets angiogenesis by binding to vascular endothelial growth factor. The development of pulmonary papillomatosis and malignant transformation portends a far more dire prognosis.


  1. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Armstrong LR, Derkay CS, Reeves WC. Initial results from the national registry for juvenile-onset recurrent respiratory papillomatosis. RRP Task Force Arch Otolaryngol Head Neck Surg. 1999;125:743–8.CrossRefPubMedGoogle Scholar
  3. Bartlett JG, Gorbach SL. Treatment of aspiration pneumonia and primary lung abscesses. JAMA. 1975;234:935–7.CrossRefPubMedGoogle Scholar
  4. Blackledge FA, Anand VK. Tracheobronchial extension of recurrent respiratory Papillomatosis. AnnOtol Rhinol Laryngol. 2000;109:812–8.CrossRefGoogle Scholar
  5. Boston M, Riter M, Myer C, Cotton R. Airway reconstruction in children with recurrent respiratory papillomatosis. Intl J Pediatr Otorhinolaryngol. 2006;70:1097–101.CrossRefGoogle Scholar
  6. Byrne JC, Tsao MS, Fraser RS, et al. Human papillomavirus-11 DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous-cell carcinoma of the lung. N Engl J Med. 1987;317:873–8.CrossRefPubMedGoogle Scholar
  7. Cole RR, Myer CM, Cotton RT. Tracheotomy in children with recurrent respiratory papillomatosis. Head Neck. 1989;11:226–30.CrossRefPubMedGoogle Scholar
  8. Cook JR, Hill A, Humphrey PA, Pfeifer JD, El-Mofty SK. Squamous cell carcinoma arising in recurrent respiratory papillomatosis with pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association. Mod Pathol. 2000;13:914–8.CrossRefPubMedGoogle Scholar
  9. Derkay C. Task force on recurrent respiratory Papillomas. A preliminary report. Arch Otolaryngol Head Neck Surg. 1995;121:1386–91.CrossRefPubMedGoogle Scholar
  10. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope. 2008;118:1236–47.CrossRefPubMedGoogle Scholar
  11. DiLorenzo TP, Tamsen A, Abramson AL, Steinberg BM. Human papillomavirus type 6a DNA in lung carcinoma of a patient with recurrent laryngeal papillomatosis is characterized by partial duplication. J Gen Virol. 1992;73:423–8.CrossRefPubMedGoogle Scholar
  12. Dines DE. Diagnostic significance of pneumatocele of the lung. JAMA. 1968;204:1169–72.CrossRefPubMedGoogle Scholar
  13. Doorbar J, Quint W, Banks L, et al. The biology and life cycle of human papillomaviruses. Vaccine. 2012;30(Suppl 5):F55–70.CrossRefPubMedGoogle Scholar
  14. El-Bitar MA, Zalzal GH. Powered instrumentation in the treatment of recurrent respiratory papillomatosis: an alternative to the CO2 laser. Arch Otolaryngol Head Neck Surg. 2002;128:425–8.CrossRefPubMedGoogle Scholar
  15. Fleskens SA, Bergshoeff VE, Voogd AC, et al. Interobserver variability of laryngeal mucosal premalignant lesions: a histopathological evaluation. Mod Pathol. 2011;24:892–8.CrossRefPubMedGoogle Scholar
  16. Gerein V, Schmandt S, Babkina N, et al. Human papilloma virus (HPV)-associated gynecological alteration in mothers of children with recurrent respiratory papillomatosis during long-term observation. Cancer Detect Prev. 2007;31:276–81.CrossRefPubMedGoogle Scholar
  17. Hallmo P, Naess O. Laryngeal papillomatosis with human papillomavirus DNA contracted by a laser surgeon. Eur Arch Otolarynolaryngol. 1991;248:425–7.CrossRefGoogle Scholar
  18. Inglis AF Jr. Cidofovir and the black box warning. Ann Otol Rhinol Laryngol. 2005;114:834–5.CrossRefPubMedGoogle Scholar
  19. Karatayli-Ozgursoy S, Bishop JA, Hillel A, Akst L, Best S. Risk factors for dysplasia in recurrent respiratory Papillomatosis in an adult and pediatric population. Ann Otol Rhinol Laryngol. 2016;125:235–41.CrossRefPubMedGoogle Scholar
  20. Kashima HK, Kessis T, Mounts P, Shah K. Polymerase chain reaction identification of human papillomavirus DNA in CO2 laser plume from recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg. 1991;104:191–5.CrossRefPubMedGoogle Scholar
  21. Kashima H, Mounts P, Leventhal B, Hruban R. Sites of predilection in recurrent respiratory Papillomatosis. Ann Otol Rhil Laryngol. 1993;102:580–3.CrossRefGoogle Scholar
  22. Kitasato H, Delius H, zur Hausen H, Sorger K, Rosl F, de Villiers EM. Sequence rearrangements in the upstream regulatory region of human papillomavirus type 6: are those involved in malignant transition? J Gen Virol. 1994;75:1157–62.CrossRefPubMedGoogle Scholar
  23. Kramer SS, Wehunt WD, Stocker JT, Kashima H. Pulmonary manifestations of juvenile laryngotracheal papillomatosis. AJR. 1985;144:687–94.CrossRefPubMedGoogle Scholar
  24. Lee JH, Smith RJ. Recurrent respiratory papillomatosis: pathogenesis to treatment. Curr Opin Otolarngol Head Neck Surg. 2005;13:354–9.CrossRefGoogle Scholar
  25. Lee LA, Cheng AJ, Fang TJ, et al. High incidence of malignant transformation of laryngeal papilloma in Taiwan. Laryngoscope. 2008;118:50–5.CrossRefPubMedGoogle Scholar
  26. Lele SM, Pou AM, Ventura K, Gatalica Z, Payne D. Molecular events in the progression of recurrent respiratory papillomatosis to carcinoma. Arch Pathol Lab Med. 2002;126:1184–8.PubMedGoogle Scholar
  27. McMurray JS, Connor N, Ford C. Cidofovir efficacy in recurrent respiratory papillomatosis: a prospective blinded placebo-controlled study. Ann Otol Rhinol Laryngol. 2008;117:477–83.CrossRefPubMedGoogle Scholar
  28. Mirghani H, Amen F, Moreau F, et al. Human papilloma virus testing in oropharyngeal squamous cell carcinoma: what the clinician should know. Oral Oncol. 2014;50(1):1–9.CrossRefPubMedGoogle Scholar
  29. Mohr M, Schliemann C, Biermann C, et al. Rapid response to systemic Bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett. 2014;8:1912–8.PubMedPubMedCentralGoogle Scholar
  30. Mounts P, Kashima H. Association of human papillomavirus subtype and clinical course in recurrent respiratory papillomatosis. Laryngoscope. 1984;94:28–33.CrossRefPubMedGoogle Scholar
  31. Pasquale K, Wiatrak B, Woolley A, Lewis L. Microdebrider versus CO2 laser removal of recurrent respiratory papillomas: a prospective analysis. Laryngoscope. 2003;113:139–43.CrossRefPubMedGoogle Scholar
  32. Patel N, Rowe M, Tunkel D. Treatment of recurrent respiratory papillomatosis in children with the microdebrider. Ann Otol Rhinol Laryngol. 2003;112:7–10.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. Rimell F, Maisel R, Dayton V. In situ hybridization and laryngeal papillomas. Ann Otol Rhinol Laryngol. 1992;101:119–26.CrossRefPubMedGoogle Scholar
  35. Rimell F, Shoemaker DL, Pou AM, Jordan JA, Post PC, Ehrlich GD. Pediatric respiratory papillomatosis: prognostic role of viral typing and cofactors. Laryngoscope. 1997;107:915–8.CrossRefPubMedGoogle Scholar
  36. Rogers DJ, Ojha S, Maurer R, Hartnick CJ. Use of adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children. JAMA Otolaryngol Head Neck Surg. 2013;139:496–501.CrossRefPubMedGoogle Scholar
  37. Ruparelia S, Unger ER, Nisenbaum R, et al. Predictors of remission in juvenile-onset recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg. 2003;129:1275–8.CrossRefPubMedGoogle Scholar
  38. Sajan JA, Kerschner JE, Merati AL, et al. Prevalence of dysplasia in juvenile-onset recurrent respiratory papillomatosis. JAMA Otolaryngol Head Neck Surg. 2010;136:7–11.Google Scholar
  39. Sanchez GI, Jaramillo R, Cuello G, et al. Human papillomavirus genotype detection in recurrent respiratory papillomatosis (RRP) in Colombia. Head Neck. 2013;35:229–34.CrossRefPubMedGoogle Scholar
  40. Sawchuk WS, Weber PJ, Lowy DR, Dzubow LM. Infectious papillomavirus in the vapor of warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J Am Acad Dermatol. 1989;21:41–9.CrossRefPubMedGoogle Scholar
  41. Schraff S, Derkay CS, Burke B, Lawson L. American Society of Pediatric Otolaryngology members’ experience with recurrent respiratory papillomatosis and the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg. 2004;130:1039–42.CrossRefPubMedGoogle Scholar
  42. Shapiro AM, Rimmell FL, Shoemaker D, Pou A, Stool SE. Tracheotomy in children with juvenile-onset recurrent respiratory papillomatosis: the Children’s Hospital of Pittsburgh experience. Ann Otol Rhinol Laryngol. 1996;105:1–5.CrossRefPubMedGoogle Scholar
  43. Soldatski IL, Onufrieva EK, Steklov AM, et al. Tracheal, bronchial, and pulmonary papillomatosis in children. Laryngoscope. 2005;115:1848–54.CrossRefPubMedGoogle Scholar
  44. Steinberg BM, DiLorenzo TP. A possible role for human papillomaviruses in head and neck cancer. Cancer Metastasis Rev. 1996;15:91–112.CrossRefPubMedGoogle Scholar
  45. Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomatosis. Otolaryng Clin N Am. 2012;45:671–94.CrossRefGoogle Scholar
  46. Weiss MD, Kashima HK. Tracheal involvement in laryngeal papillomatosis. Laryngoscope. 1983;93:45–8.CrossRefPubMedGoogle Scholar
  47. Wemer RD, Lee JH, Hoffman HT, et al. Case of progressive dysplasia concomitant with intralesional cidofovir administration for recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2005;114:836–9.CrossRefPubMedGoogle Scholar
  48. Wiatrak BJ, Wiatrak DW, Broker TR, Lewis L. Recurrent respiratory papillomatosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a large pediatric population. Laryngoscope. 2004;114:1–23.CrossRefPubMedGoogle Scholar
  49. Zur K, Fox E. Bevacizumab chemotherapy for management of pulmonary and laryngotracheal papillomatosis in a child. Laryngoscope. 2016;127:1538–2. doi: 10.1002/lary.26450.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of OtolaryngologyChildren’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations