Recurrent respiratory papillomatosis (RRP), also known as laryngeal papilloma, is the most common benign neoplasm of the larynx in children and the second most frequent cause of chronic childhood hoarseness.1 RRP is characterized by the proliferation of benign squamous papillomas within the aerodigestive tract, most commonly affecting the larynx. Although benign in histology, RRP carries the potential risk for airway compromise, anesthesia mishaps, malignant transformation, as well as a burden, both emotional and economic, to the patients and their families due to the need for repeated surgery, evaluation and adjunct treatments.
RRP is often difficult to treat because of its tendency to recur and spread throughout the aerodigestive tract. The delay from the time of onset of symptoms to definitive diagnosis averages about 1 year.1 In 75% of children with RRP, the diagnosis was made before the fifth birthday.2
Although the true incidence and prevalence of RRP are unclear, the estimated prevalence of the disease is 0.75–4/100,000 with as many as 1000 new pediatric cases being diagnosed each year in the United States. The mean number of procedures per child was found to be 19.7 with an average of 4.4 per year. This amounts to a need for as many as 10,000 surgical procedures and $100 million in healthcare costs per year.3
Transmission of the disease in children may be through exposure while traversing the birth canal of an infected mother, exposure to Human Papilloma Virus (HPV) in the amniotic fluid, iatrogenic infection in the operating room or child abuse. The risk of contracting the disease is 1/231–400 if the mother has active condylomata at birth.4 Patients with RRP are more likely to be first-born and vaginally delivered. However, prophylactic cesarean section is not recommended by American Congress of Obstetricians and Gynecologists given the high rate of subclinical maternal infection and the low rate of new cases of childhood RRP.5 Adult onset disease is thought to be secondary to either reactivation of pediatric disease or as a result of a sexually transmitted disease.
PATHOPHYSIOLOGY AND DISEASE COURSE
With the advent of the molecular probe in the 1990s, RRP was found to be caused by HPV. The most common types implicated in airway disease are HPV 6 and 11. The viral subtypes may be correlated with disease severity and clinical course.6 The histological result is multiple “fronds” or finger-like projections with a central fibrovascular core covered by stratified squamous epithelium.
The course of the disease is variable, with some patients experiencing spontaneous remission, whereas others may suffer from aggressive papillomatous growth and respiratory compromise, requiring multiple surgical procedures through many years. Onset in childhood is associated with a more aggressive form of the disease. Earlier diagnosis also portends disease progression as opposed to disease stability or regression. While disease tends to regress in late childhood, it may be exacerbated by pregnancy.
Extralaryngeal spread has been identified in approximately 30% of children and 16% of adults with RRP.2 The most frequent sites of extralaryngeal spread were the oral cavity, trachea and bronchi.2 The risk of malignant transformation, while small, has been documented in several case reports.7 Mortality occurs from RRP in 1–2% of cases and is attributed to airway obstruction, malignant degeneration, chronic lung disease or anesthesia complications.7
The most common presenting symptom of RRP is hoarseness followed by slowly progressive stridor.1 Less commonly, chronic cough, recurrent pneumonia, failure to thrive, dyspnea, dysphagia or acute life-threatening events may be the presenting symptoms. A maternal and/or paternal history of genital warts is significant. Examination of the child with suspected RRP should focus on the respiratory effort and voice quality, which can help the examiner localize the lesion.
The diagnosis is best made by visualization of the larynx. In the office setting, this can be done with flexible fiberoptic nasopharyngoscopy. This will give critical information with regard to the airway patency, vocal cord mobility and urgency of operative intervention. Examination can also be completed in the operating room, which allows the surgeon to accurately identify all sites of involvement, remove the offending tissue and use additional modalities of treatment to help ensure a safe airway.
The severity of RRP can be assessed using the Derkay–Coltrera grading system, which grades the extent of papillomatosis at defined subsites in the aerodigestive tract. This scale was developed to allow for tracking of the progression of a child’s disease, accurate communication between surgeons and treatment in a protocol format.8
Although there is no “cure” for RRP, surgical excision is the primary treatment modality. The goal of surgery is removal of as much of the papilloma as possible without damaging normal structures. This has been performed primarily with the CO2 laser which can vaporize the lesions with benefits of precision, minimal scarring and little bleeding. The risks, however, include laser injury to the patient, surgeon and others in the operating room; airway fire and potential for dissemination of disease to operating room personnel from exposure to active viral DNA contained in the laser plume. More recently, the endoscopic microdébrider has gained popularity as it can quickly debulk papilloma with improved voice quality, less OR time, decreased mucosal injury and a cost benefit.7
Anesthetic considerations are important for minimizing iatrogenic trauma and spread of papilloma. Spontaneous ventilation during surgery is ideal if the anesthesiologist is well-trained and the patient can tolerate it. Intermittent apnea-reintubation techniques will also provide the unobstructed surgical field, but at the expense of the potential need for multiple reintubations and risk of spreading the virus iatrogenically. Alternatively, the patient may be intubated with a “laser-safe” endotracheal tube. Of course, there is still a risk of airway fire and the tube can obstruct the surgeon’s view making this a less favorable option.
While surgery remains the first-line in management of RRP, up to 20% of patients require some form of adjunct therapy.7 Children who require more than 4 surgical procedures per year, have rapid regrowth of papilloma with airway compromise, or distal multisite spread of disease should be considered for adjunct medical therapy.7 Alpha-interferon was the first widely employed of these therapies and is now available as pegylated interferon.1 Cidofovir is an antiviral medication that is injected intralesionally and has become the most widely used adjunct therapy for RRP.4 It has shown very encouraging results in multiple studies8 but its use for RRP remains off-label. The recommended dosing is no more than 2 mL in children and 4 mL in adults of 2.5–7.5 mg/mL solution injected every 2–6 weeks for a trial of 5 treatments.9
Celecoxib, a selective COX-2 inhibitor, is currently being studied in a multicenter study. The efficacy of this drug appears to be due to the overexpression of the COX-2 enzyme in RRP, which stimulates the growth of papilloma. Bevacizumab (Avastin), best known as a chemotherapeutic agent, is a vascular endothelial growth factor inhibitor shown to be both safe and effective in both adults and children.10
While surgery and adjunct therapies for RRP are improving outcomes, the development of vaccines against HPV offers the potential to eradicate RRP in future generations. The quadrivalent HPV vaccine (Gardasil, Merck and Co., Inc., White House Station, NJ) was approved by the Food and Drug Administration in 2006. It is licensed and indicated for the prevention of cervical and anogenital cancers, precancerous lesions and genital warts associated with HPV types 6, 11, 16 and 18. The vaccine does not have a clear role in treatment of patients who already have RRP, but it can prevent infection with additional HPV serotypes in those patients and should be implemented for this purpose.11 While not its initial intent, the vaccine is expected to have benefits in reducing the incidence of HPV-related head and neck cancers and RRP.
RRP is a challenging disease to manage due to the potential for recurrence and severe complications. Patients with RRP often require frequent evaluation and intervention. The goal of surgery should be maintaining a safe airway while avoiding undue deterioration of the voice and excessive scarring. There is no single treatment modality shown to consistently or effectively eradicate RRP; however, many adjunct medical therapies are available to supplement surgical therapy. Children requiring surgery more than 4 times a year or those with evidence of distal spread of RRP outside the larynx should be considered for those options. In the future, vaccination may be able to help prevent transmission of this disease and its extensive consequences.
1. Derkay CS, Faust RAFlint PW, Haughey BH, Lund VJ. Recurrent respiratory papillomatosis, In: Otolaryngology: Head and Neck Surgery. 20105th ed. Philadelphia, PA Mosby Elsevier:2884–2895
2. Derkay CS. Task force on recurrent respiratory papillomas. A preliminary report. Arch Otolaryngol Head Neck Surg. 1995;121:1386–1391
3. 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;125:743–748
4. Shah KV, Stern WF, Shah FK, et al. Risk factors for juvenile onset recurrent respiratory papillomatosis. Pediatr Infect Dis J. 1998;17:372–376
5. Kosko JR, Derkay CS. Role of cesarean section in prevention of recurrent respiratory papillomatosis–is there one? Int J Pediatr Otorhinolaryngol. 1996;35:31–38
6. Wiatrak BJ, Wiatrak DW, Broker TR, et al. 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(11 pt 2 suppl 104):1–23
7. Schraff S, Derkay CS, Burke B, et al. American Society of Pediatric Otolaryngology members’ experience with recurrent respiratory papillomatosis and the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg. 2004;130:1039–1042
8. Derkay CS, Hester RP, Burke B, et al. Analysis of a staging assessment system for prediction of surgical interval in recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol. 2004;68:1493–1498
9. Derkay CS, Volsky PG, Rosen CA, et al. Current use of intralesional cidofovir for recurrent respiratory papillomatosis. Laryngoscope. 2013;123:705–712
10. Sidell DR, Nassar M, Cotton RT, et al. High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2014;123:214–221
11. Mudry P, Vavrina M, Mazanek P, et al. Recurrent laryngeal papillomatosis: successful treatment with human papillomavirus vaccination. Arch Dis Child. 2011;96:476–477