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Last updated: 6/8/2023
Years published: 1997, 1999, 2002, 2013, 2016, 2019, 2023
NORD gratefully acknowledges Craig Derkay, MD, FACS, FAAP, Fine Endowed Professor and Vice-Chairman, Department of Otolaryngology Head Neck Surgery, Eastern Virginia Medical School; Director, Pediatric Otolaryngology, Childrenโs Hospital of the Kingโs Daughters, for assistance in the preparation of this report.
Summary
Recurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the development of small, wart-like growths (papillomas) in the respiratory tract. The respiratory tract is the system of organs within the body that allows individuals to breathe. The respiratory tract includes the nose, mouth, throat (pharynx), voice box (larynx), windpipe (trachea), various airway passages (bronchi) and lungs. Papillomas can develop anywhere along the respiratory tract, but most often affect the larynx and the vocal cords (laryngeal papillomatosis). Less often, the disorder affects the area within the mouth (oral cavity), trachea and bronchi. Only in rare cases do these growths spread to affect the lungs. Papillomas are noncancerous (benign), but in extremely rare cases can undergo cancerous (malignant) transformation. Although benign, papillomas can cause severe, even life-threatening airway obstruction and respiratory complications. In RRP, papillomas tend to grow back after they have been removed. RRP can affect children, adolescents or adults and is caused by infection with human papillomavirus (HPV), although exposure to the virus alone may be insufficient to cause the disease.
Introduction
RRP is generally broken down into two subtypes โ the juvenile-onset form and the adult-onset form. Juvenile cases develop before the age of 12 and are generally more aggressive and recurring. Children tend to need surgical treatment more often than adults. The disorder tends to improve in late childhood. Although aggressive disease is more common in children, adults can still potentially develop an aggressive form of the disorder.
The specific symptoms, course of the disease, and severity of RRP can vary greatly from one person to another. In some people, the disease may resolve without treatment (spontaneous remissions) or it may remain stable requiring only periodic intervention (e.g. only a few surgeries during their lifetime). In other peoople, the disease may be aggressive requiring frequent medical intervention and potentially more than 100 surgeries during a personโs lifetime.
The most common presenting symptom of RRP is hoarseness. Hoarseness may become progressively worse, and the voice of an affected individual may be weak, raspy or sound low in pitch or strained. The severity of voice problems can vary from one person to another due, in part, to the size and specific locations of papillomas. Affected individuals may develop labored, noisy breathing (stridor) due to obstruction of the airway. Initially, stridor may occur when breathing in (inspiratory stridor), but eventually occurs both when breathing in and out (biphasic stridor). Some individuals may exhibit difficulty speaking (dysphonia) or lose their voice entirely (aphonia). Affected infants may also have a weak cry, episodes of choking and fail to grow and gain weight at the expected rate (failure to thrive).
Additional symptoms that can develop include a chronic cough, difficulty swallowing (dysphagia), shortness of breath or difficulty breathing (dyspnea), the sensation of a foreign body in the throat, and choking episodes.
Left untreated, papillomas can eventually compromise the airways, resulting in life-threatening breathing difficulties (acute respiratory distress). If RRP spreads to the lungs, affected individuals can potentially experience recurrent pneumonia, chronic lung disease (bronchiectasis) and, ultimately, progressive pulmonary failure. In extremely rare cases (i.e., less than 1% of cases), papillomas can become cancerous (malignant transformation) developing into squamous cell carcinoma.
Recurrent respiratory papillomatosis is caused by the human papillomavirus (HPV). This virus is common in human beings with some studies estimating that as many as 75%-80% of men and women will be affected by HPV at some point during their lives if they are not vaccinated against the virus. HPV is passed through genital contact, most often during sex. Most individuals who are infected with HPV never develop any symptoms. There are more than 150 different subtypes of HPV and approximately 40 of these subtypes can affect the genital tract. Two specific subtypes, HPV 6 and HPV 11, account for more than 90% of cases of RRP. These two subtypes are the same HPV subtypes most often identified in genital warts (anogenital condyloma). HPV subtypes 16 and 18 account for most of the remaining cases. Together, these four subtypes are responsible for about 70% of cases of cervical cancer.
In children, the most likely cause of the transmission of HPV is passage from an affected mother to the child during labor as the child passes through the birth canal. However, this may not account for all cases of juvenile onset RPP and other mechanisms for HPV infection may exist. Some cases appear to have developed before birth (in utero).
Most children born to women with HPV do not develop RRP. In addition, many individuals with HPV in the tissues of the respiratory tract never develop papillomas. This suggests that additional factors, such as immunologic or genetic ones, are necessary for the development of RRP in individuals with HPV. Other factors such as timing, length and volume of exposure to the HPV may play a role.
Certain risk factors have been identified for the development of RRP. Risk factors are variables that are associated with an increased risk of disease or infection. Three risk factors for juvenile-onset recurrent respiratory papillomatosis are being a firstborn child, having a vaginal delivery with a prolonged labor, and the mother being under 20 years of age. If the mother has active genital warts, the risk of passing on HPV is approximately 1 in 250-400. These risk factors do not apply to adult-onset recurrent respiratory papillomatosis.
In adults, the mode of transmission is less clear. Some cases may represent infection during infancy as described above, but that remains latent until being triggered for unknown reasons in adulthood. Some circumstantial evidence suggests that RRP can develop after HPV is transmitted through oral sexual contact.
Adult-onset recurrent respiratory papillomatosis may be worsened by tobacco exposure, gastroesophageal reflux, or radiation therapy.
The juvenile form of recurrent respiratory papillomatosis affects males and females in equal numbers. The adult form affects males slightly more often than females. In the United States, the incidence of RRP was previously estimated to be approximately 2 per 100,000 adults and 4 per 100,000 children with approximately 1,000 new pediatric cases in the United States each year. With the increased uptake of the HPV vaccine, these numbers are dropping precipitously. In children, JORRP is most often diagnosed between the ages of 2-4. In adults, the disorder occurs most often in the third or fourth decade though a second peak around age 60 has recently been noted.
Treatment
There is currently no โcureโ for RPP. Treatment is directed toward removing papillomas, decreasing the spread of disease, creating a safe and patent airway, preserving nearby anatomical structures, improving voice quality if necessary and increasing the time between surgical procedures. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, internists, ear-nose-throat specialists that focus on children (pediatric otorhinolaryngologists) or on airway abnormalities (laryngologists), anesthesiologists, speech pathologists and other healthcare professionals may need to systematically and comprehensively plan an RRP patientโs treatment.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as frequency of disease recurrences; specific location and spread of the disease; papilloma size; the presence or absence of certain symptoms; an individualโs age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference and other appropriate factors.
None of the various treatment options for RRP have proven consistently effective. Additionally, most treatment recommendations are based on case reports or small case series. Large scale clinical trials for treating RRP are required to determine the best therapeutic options, which ultimately may vary from one person to another.
The mainstay of treatment is surgical removal of papillomas. However, like warts on the hands and feet, these growths often return necessitating more surgery. The recurrence of papillomas is unpredictable. Some individuals may require surgery every few weeks while others may only require surgery twice a year or only a few times during their life. Surgical techniques used to treat individuals with RRP include โcoldโ excision, microdebridement, various pulsed dye lasers, or carbon dioxide lasers. Cold excision, sometimes referred to as โcold steel,โ is the use of sharp surgical equipment to remove papillomas. Cold excision may be beneficial for the initial removal (debulking) of papillomas and for papillomas located in certain areas. Microdebridement is an increasingly popular procedure for use in children with RRP in which suction is applied to affected tissue which is then cut away (debrided) by miniature shavers. Pulsed dye lasers use various light frequencies focused into a single beam to destroy the blood vessels that supply the papillomas. Laser ablation generates a laser beam by passing electricity through a mixture of several different gases including carbon dioxide (CO2). The CO2 laser is used to directly destroy papillomas in the voicebox and can also be used through a bronchoscope to effectively remove papillomas in the trachea (windpipe).
In severe cases where tumor growth is aggressive, an affected individual may need a tracheostomy to keep the breathing airways open. A tracheostomy involves surgically inserting a tube into the windpipe (trachea). A tracheostomy is used only as a method of last resort because the procedure may allow for spread of the disease further into the respiratory tract.
In the past, some individuals received certain medications designed to slow the regrowth of papillomas and increase the time between surgeries (adjuvant therapy). Medications that have been used include antivirals such as acyclovir, ribavirin or cidofovir (see below), interferon, and indole 3-carbinol (I3-C). Interferon is a drug that is a synthetic form of certain proteins produced by the immune system. I3-C is an anticancer compound that is found in cruciferous vegetables such as cabbage, cauliflower, and broccoli. Adjuvant therapy is usually recommended based upon specific indications: undergoing more than four surgeries in one year, rapid regrowth of papillomas causing airway compromise, or spread of the disease down the throat and into the lungs.
Some physicians recommend that affected individuals take medications for gastroesophageal reflux (GERD) as this condition has been known to worsen RRP.
One of the most common antiviral medications that have been used to treat individuals with recurrent respiratory papillomatosis is Cidofovir. This drug is an adjuvant therapy that is injected directly into the lesions (intralesional). Initial studies of cidofovir have demonstrated that the drug is active against RRP and led to a partial response in some patients or complete remission in others. In some cases, cidofovir increased the time between surgeries. However, cidofovir has been associated with several side effects including toxicity to the kidneys (nephrotoxicity) and a very small potential for malignant transformation of the papillomas. The exact role and specific cases where cidofovir will be most beneficial has not been established. More research is necessary to determine the long-term safety and effectiveness of cidofovir for the treatment of RRP.
Additional drugs are being studied as potential adjuvant therapies for individuals with RRP. The most promising of these is the monoclonal antibody bevacizumab (Avastin and its biosimilars). Monoclonal antibodies are manmade (synthetic) versions of an immune system protein. Bevacizumab can be injected into the papilloma growths and combined with the use of a pulse dye laser to prevent papillomas from growing new blood vessels, which are required to feed the tumor nutrients. Recently, it has been shown to be highly effective when administered intravenously (through an IV catheter in a vein) after surgical removal of papillomas. This form of treatment seems especially helpful in patients with rapidly recurring papillomas in the larynx,trachea and pulmonary tree. More research is necessary to determine the long-term safety and effectiveness of monoclonal antibody therapies for individuals with RRP with an eye towards initiation earlier in the course of the disease to minimize the deleterious effects of repeated surgeries on the larynx.
A nine-valent (effective in preventing 9 different strains) HPV vaccine (Gardasil-9) has been developed and approved by the Food and Drug Administration (FDA) to protect women from developing cervical cancer, men from developing penile cancer and both men and women from contracting genital warts, anal cancer and potentially certain cancers of the head and neck. Among the subtypes of HPV covered by the vaccine are HPV types 6, 11 (remember, RRP is caused by types 6 and 11). Researchers hope that the use of the Gardasil-9 vaccine in boys and girls before they are exposed to the virus will drastically lessen the spread of HPV in the general population. Near universal uptake of the vaccine in Australia through a school vaccination program has almost eliminated new cases of RRP on their continent. Unfortunately, this type of vaccine does not make existing infections go away so there is still work to do to treat those currently infected. The exact role of HPV vaccines in regard to RRP has not yet been established but a clinical study funded by the CDC has been undertaken to help sort out the effect of the vaccine on the incidence and prevalence of RRP in the United States.
Additional active investigational therapies include the use of check point inhibitors such as Pembrolizumab (Keytruda) and two HPV-DNA therapeutic vaccines (INO-3107 administered via electrocorpulation under study by Inovio and PRRGN-2012 a gorilla adenovirus vaccine under study by Precigen).
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in
Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Wiatrak BJ. Recurrent Respiratory Papillomatosis. In: Pediatric ENT, Graham JM, Scadding GK, Bull PD, eds. 2007;Springer-Verlag, Berlin, Germany. Pp. 255-265.
Derkay CS, Hester RP. Recurrent Respiratory Papillomatosis. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:676.
JOURNAL ARTICLES
Lee MY, Metenou S, Allen C. Preclinical study of a novel therapeutic vaccine for recurrent respiratory papillomatosis. NPJ vaccines.2021,6:86. https://www.nature.com/articles/s41541-021-00348-x
Derkay CS, Bluher AE. Update on Recurrent Respiratory Papillomatosis. Otolaryngol Clin North Am. 2019 Aug;52(4):669-679. https://www.ncbi.nlm.nih.gov/pubmed/31078306
Derkay CS, Bluher AE. Recurrent respiratory papillomatosis: update 2018. Current Opinion in Otolaryngology & Head and Neck Surgery. 2018 Dec;26(6):421-425. https://www.ncbi.nlm.nih.gov/pubmed/30300210
Best SR, Mohr M, Zur KB. Systemic bevacizumab for RRP: A national survey. Laryngoscope. 2017 Oct; 127(10): 2225โ2229. https://www.ncbi.nlm.nih.gov/pubmed/28657692
Derkay CS, Volsky PG, Rosen CA, et al. Current use of intralesional cidofovir for recurrent respiratory papillomatosis. Laryngoscope. 2013;123:705-712. https://www.ncbi.nlm.nih.gov/pubmed/23070868
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. https://www.ncbi.nlm.nih.gov/pubmed/23681032
Venkatesan NN, Pine HS, Underbrink MP. Recurrent respiratory papillomatosis. Otolaryngol Clin North Am. 2012;45:671. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682415/
Tjon Pian Gi RE, Dietz A, Djukic V, et al. Treatment of recurrent respiratory papillomatosis and adverse reactions following off-label use of cidofovir (Vistideยฎ). Eur Arch Otorhinolaryngol. 2012;269:361-362. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259328/
Katsenos S, Becker HD. Recurrent respiratory papillomatosis: a rare chronic disease, difficult to treat, with potential to lung cancer transformation: apropos of two cases and a brief literature review. Case Report Oncol. 2011;4:162-171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081647/
Maturo S, Hartnick CJ. Use of 532-nm pulsed potassium titanyl phosphate laser and adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children: initial experience. Arch Otolaryngol Head Neck Surg. 2010;136:561-565. https://www.ncbi.nlm.nih.gov/pubmed/20566906
Valera F, Maldonato L, Lima J, et al. Efficacy of cidofovir in recurrent juvenile respiratory papillomatosis. Braz J Otorhinolaryngol. 2010;76:713-717. https://www.ncbi.nlm.nih.gov/pubmed/21180938
Larson DA, Derkay CS. Epidemiology of recurrent respiratory papillomatosis. APMIS. 2010;118:450-454. https://www.ncbi.nlm.nih.gov/pubmed/20553527
Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope. 2008;118:1236-1247. https://www.ncbi.nlm.nih.gov/pubmed/18496162
Schraff S, Derkay CS, Burke B, Lawson L. American Society of Pediatric Otolaryngology membersโ experience with recurrent respiratory papillomatosis and the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg. 2004;130:1039-1042. https://www.ncbi.nlm.nih.gov/pubmed/15381589
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. https://www.ncbi.nlm.nih.gov/pubmed/15514560
INTERNET
Harman EM. Recurrent Respiratory Papillomatosis.Medscape. Updated: Dec 14, 2020. Available at: https://emedicine.medscape.com/article/302648-overviewAccessed May 15, 2023.
National Institute on Deafness and Other Communication Disorders. Recurrent Respiratory Papillomatosis or Laryngeal Papillomatosis. November 28, 2017. Available at: https://www.nidcd.nih.gov/health/voice/pages/laryngeal.aspx/
Accessed May 15, 2023.
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