AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Recurrent respiratory papillomatosis (RRP) is a disease caused by the human papillomavirus (HPV). See Human Papillomavirus and Medscape’s HPV and Cervical Cancer Resource Center for more information on HPV. Warty growths in the upper airway may cause significant airway obstruction or voice change. RRP has a bimodal age distribution and manifests most commonly in children younger than 5 years (juvenile-onset RRP [JORRP]) or in persons in the fourth decade of life (adult-onset RRP [AORRP]).

JORRP is more common and more severe than AORRP. JORRP is caused by exposure to HPV during the peripartum period. Researchers do not know with certainty the manner in which adult patients acquire the virus that causes AORRP, but sexual transmission is likely.

Treatment usually involves repeated debulking of the warty growths by angiolytic laser or microdebridement coupled with intralesional cidofovir therapy in patients with moderate or severe disease. Interferon treatment appears to slow the rate of growth without curing the disease. Although some antiviral agents (eg, cidofovir) also may slow the rate of regrowth of lesions, they are not curative. Eventually, some patients may enter remission. In 3-5% of patients, respiratory papillomas may undergo malignant degeneration to squamous cell carcinoma, and the prognosis for patients with these cancers is quite poor. See Squamous Cell Carcinoma for more information on this topic.

A few related Medscape CME courses are as follows:

• Recurrent Respiratory Papillomatosis: High-Risk Consequences of Low-Risk HPV Infection
• Introduction: HPV Vaccine Overview
• Preventing STD-Related Cancers: An Update on Vaccination Strategies

Pathophysiology

HPV, the virus associated with cutaneous warts, genital condyloma, and cervical cancer, causes RRP. While more than 20 types of HPV can cause genital warts, only 2 of these, HPV-6 and HPV-11, cause the vast majority of cases of RRP. The disease associated with HPV-11 is more severe; thus, in children with HPV-11–associated disease, as many as 70% may require tracheostomy, compared with less than 20% of children infected with HPV-6 (see Human Papillomavirus).

The cause of JORRP is peripartum transmission of the virus from an infected mother. Vaginal delivery is a risk factor, but cesarean delivery is not completely protective.¹ The classic triad for increased risk of JORRP includes being firstborn, vaginal delivery, and having a mother younger than 20 years.² Suspect sexual abuse in children older than 5 years who acquire RRP. The mode of transmission of the virus in adults with RRP is unknown, but sexual transmission is probable.

Papillomas may develop anywhere in the respiratory tract, from the nose to the lung; however, 95% of cases involve the larynx. The sites of respiratory system involvement have been described more completely for JORRP; 52% of children have only laryngeal involvement. The trachea is the next most commonly involved site. However, 31.8% of children had papillomas in areas outside of the trachea and larynx (eg, oropharynx, nasopharynx, mouth, bronchi, lung parenchyma).

Frequency

United States

In 1993, survey results estimated 5977 new cases of RRP occur each year in the United States—2354 new pediatric cases and 3623 new adult cases. The estimated incidence in children aged 14 years or younger is 4.3 cases per 100,000 population. In adolescents older than 15 years, the incidence is 1.8 cases per 100,000 population.³

International

Researchers in Denmark have studied the incidence of JORRP and concluded that the incidence in Denmark is the same as that in the United States.

Mortality/Morbidity

• Because the disease is uncommon and requires direct laryngoscopy for diagnosis, children usually have symptoms for a year before a physician makes the diagnosis. The morbidity of this disease has been studied more completely for JORRP, in which the average number of surgical procedures required is 4.4 per child per year and the average number of procedures per child's lifetime is more than 20.⁴ This exacts a tremendous financial cost and severely affects quality of life, including the ability to attend school and work. Ten to 15% of children with JORRP ultimately require tracheostomy, usually when younger than 2 years. Many eventually tolerate decannulation.
• The need for tracheostomy in adults appears to be less common than in children, but repeated surgical procedures are the rule, and procedures may be required as often as every few weeks.
• Malignant degeneration of papillomatous lesions to squamous cell carcinoma occurs in 3-5% of patients with RRP.

Race

Initial results from the National Registry for Juvenile-Onset Recurrent Respiratory Papillomatosis,³ a study encompassing 399 children from 20 tertiary care pediatric otolaryngology centers, indicate that 62.7% of the children were white, 28.3% were black, and 2.3% were Asian or Native American.

Sex

JORRP affects males and females in equal numbers, whereas AORRP is more common in males.

Age

The mean age at diagnosis of JORRP is 3.8 years. The adult form usually manifests in the third or fourth decade of life but may rarely manifest in patients older than 60 years.

CLINICAL

Section 3 of 11  

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History

RRP is a rare disease, and adult patients may have symptoms for months or longer before the disease is recognized. Because the larynx is the most frequently affected site for both JORRP and AORRP, symptoms of upper airway obstruction predominate. Upper airway obstruction may be life threatening and may be the presenting symptom. Hoarseness is the most common presenting symptom. Other symptoms include the following:

• Voice change
• Choking episodes
• Foreign body sensation in the throat
• Cough
• Dyspnea
• Inspiratory wheeze
• Stridor

Physical

Physical findings often are nonspecific. Voice change may be noted. Inspiratory wheezing, stridor, or both may develop over the trachea or the upper thorax.

Patients with JORRP commonly present with a weak cry, episodes of choking, hoarseness, or failure to thrive. Patients with AORRP present with hoarseness, choking spells, voice change, dyspnea, or a foreign body sensation in the throat.

Causes

HPV causes RRP. HPV-6 and HPV-11 are the most common types associated with RRP, but, rarely, affected tissues contain HPV-16 and HPV-18. HPV is the most common sexually transmitted disease in the United States; as many as 75% of women have genital HPV at some time in their lives. Thirty to 60% of mothers of children affected with JORRP have genital HPV, compared with 5% of mothers of unaffected children. A study using questionnaires of affected children or their parents (identified through the RRP Foundation) verified that the 3 risk factors for JORRP are (1) firstborn child, (2) vaginal delivery, and (3) mother younger than 20 years. The risk factors for JORRP do not apply to adult-onset cases. This suggests that adult disease does not represent reactivation of latent disease. The mode of transmission of HPV in AORRP is not known. Child-to-parent transmission by cough has never been documented. Sexual transmission is likely.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Squamous cell lung cancer
Benign laryngeal or tracheal tumors
Malignant laryngeal or tracheal tumors
Laryngeal infection
Vocal cord dysfunction
Reflux
Relapsing polychondritis
Tracheomalacia
Subglottic stenosis
Vocal cord paralysis

WORKUP

Section 5 of 11  

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Lab Studies

Once the physician diagnoses RRP via laryngoscopy or bronchoscopy, typing of the virus may be helpful for determining prognosis. This may be accomplished by polymerase chain reaction on fresh tissue. As noted, HPV-11 is associated with more severe disease and, possibly, with a greater risk of malignant transformation.

Imaging Studies

Chest radiographs rarely may reveal an intratracheal density. This may be observed best on the lateral view. In the uncommon instance of distal bronchial involvement, chest radiographs may reveal segmental or lobar atelectasis or postobstructive pneumonia. Nodules or cystic lesions on chest radiographs provide evidence of pulmonary parenchymal involvement.

CT scans of the upper airway may be helpful in revealing the tumorlike papillomatous growths on the larynx or in the trachea.

Other Tests

Pulmonary function studies may be helpful in suggesting the presence of upper airway obstruction. The flow-volume loop may show the characteristic flattening of the inspiratory limb, suggesting variable extrathoracic upper airway obstruction or flattening of both the inspiratory and expiratory limbs if the upper airway obstruction is fixed.

Procedures

Laryngoscopy or bronchoscopy findings provide confirmation of the diagnosis of RRP. Confirmation in patients presenting with hoarseness or voice change requires visualization of the vocal cords. Because laryngeal involvement occurs in more than 95% of patients, direct laryngoscopy reveals the characteristic warty growths. Rarely, the trachea is involved without laryngeal lesions, and bronchoscopy may be required for diagnosis. These procedures reveal the characteristic cauliflowerlike warty growths.

Obtaining a biopsy specimen of visualized lesions is essential for histologic confirmation of respiratory papillomatosis. Biopsy is necessary both for viral typing and for histologic examination to rule out malignant transformation. Atypical histologic features often are noted, sometimes making the diagnosis of malignant transformation difficult.

Histologic Findings

Under low power, the lesion has a papillary appearance. This results from the exophytic growth of keratinized squamous epithelium overlying a fibrovascular core. Koilocytes, vacuolated cells with clear cytoplasmic inclusions, are noted and are indicative of viral infection. Metaplasia and dysplasia occur in varying degrees.

TREATMENT

Section 6 of 11  

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Medical Care

The goals of therapy are to relieve airway obstruction, improve voice quality, and facilitate remission. The primary treatment involves repeated surgical debulking, usually by means of microdebridement, angiolytic laser, cryotherapy, or carbon dioxide laser. This may be followed by an injection of cidofovir into the resection site in patients with moderate-to-severe disease. Compared with microdebridement and laser procedures, surgical resection may be associated with a higher risk of complications (eg, tracheal stenosis). Tracheostomy may be needed if significant airway obstruction occurs.

Because the disease is rare, large-scale trials of medical therapies have not been possible; however, several agents are available that appear to increase the intervals between need for resection. These include intralesional cidofovir,^{5, 6, 7, 8} oral indole-3-carbinol,^{9, 10} interferon,^{11, 12} and photodynamic therapy.¹³ Agents that demonstrate variable effect include acyclovir¹⁴ and retinoic acid.¹⁵ Agents that have shown some benefit in case series and are undergoing further study include cimetidine, zinc, intralesional mumps vaccine, and cyclooxygenase-2 inhibitors. With the increased use of intralesional cidofovir, interferon therapy is now infrequently used.

A vaccine for prevention of genital HPV infection in young women was approved in 2006. This vaccine protects against HPV types 6, 11, 16, and 18 and therefore has promise for decreasing the incidence of RRP.¹⁶ Vaccine therapy for those already affected with HPV is under study.

Surgical Care

Multiple resections are typical. Microdebridement of laryngeal lesions is often preferred to laser therapy. With anesthesia induction, take extreme care to maintain the already-compromised airway. The surgical team should be prepared for the possibility that emergency tracheostomy may be required. A survey of anesthesiologists regarding anesthesia techniques for patients undergoing laser procedures for RRP indicated the following preferences:

• Laser-safe endotracheal tube (46%)
• Jet ventilation (26%)
• Apneic technique (16%)
• Spontaneous ventilation (12%)
• Preferred anesthetic agents - Halothane and propofol

Physicians may combine surgery with an injection of the surgical bed with medication that may slow regrowth. Cidofovir is effective in a significant proportion of patients and has replaced intralesional interferon.

The carbon dioxide laser previously was the preferred method for resection of papillomas because it affords good hemostasis and minimizes potential thermal injury of surrounding healthy tissues. The use of microdebridement using angled oscillating blades that incorporate suction and irrigation or the use of pulsed dye laser is now the preferred resection method at many centers. These offer the advantage of shorter operative times, potential for outpatient surgery, decreased risk to personnel, and avoidance of the risk of airway burns. These methods may also decrease recurrence rates. Repeat evaluation of the airway in newly diagnosed RRP may be required as frequently as every 2-4 weeks.

Photodynamic therapy, in small trials, has been shown to slow the rate of papilloma growth. Hematoporphyrins are taken up selectively by neoplastic cells and are used as photosensitizing agents for subsequent laser therapy. Dihematoporphyrin ether (DHE) usually is administered 2-3 days before surgery. Delivery of argon laser light to the affected area via laryngoscope or bronchoscope activates the drug.

The virus may be aerosolized during surgical procedures; therefore, staff should take particular care to wear goggles and a particulate barrier facemask or shield during procedures.

Consultations

Consider participation in ongoing clinical trials of various therapies.

Diet

Animal studies and observational studies in patients with RRP indicate that a diet high in cruciferous vegetables (eg, cabbage, cauliflower, broccoli, Brussels sprouts) may have a favorable effect.⁹ Researchers hypothesize that indole-3-carbinol is the active agent in these vegetables. Treatment with indole-3-carbinol is beneficial for persons with RRP.

MEDICATION

Section 7 of 11  

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No drug can cure RRP. Several drugs appear to slow the growth of papillomas and increase the interval between necessary surgical debulking procedures. Intralesional cidofovir is frequently effective; however, because optimal dosing and long-term effects are not known, it should probably be reserved for persons with moderate-to-severe disease. Dietary supplementation with oral indole-3-carbinol is often effective. Because of its adverse effects, treatment with interferon is now used infrequently as second-line therapy for patients with refractory severe disease. Control of gastroesophageal reflux is beneficial in children with RRP.

Drug Category: Dietary supplements

Certain types of vegetable extracts appear to improve symptoms.

Drug Category: Antiviral agents

Nucleoside analogs are phosphorylated initially by viral thymidine kinase to eventually form a nucleoside triphosphate and inhibit viral replication.

Drug Category: Interferons

Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa, beta, and gamma interferons may be administered topically, systemically, and intralesionally.

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

RRP is devastating to individuals and families. Children with JORRP may require repeated surgery and may be ill for a long time. The RRP Foundation may provide group support for individuals and families.

In/Out Patient Meds

The primary treatment involves surgery and intralesional therapy at the time of surgery. Six months of subcutaneous interferon therapy frequently is beneficial.

Transfer

Because RRP is a rare disease, consider transfer to a center with personnel experienced in its management. Patients may receive the best care in a tertiary center.

Deterrence/Prevention

In 2006, a vaccine was released that protects against HPV types 6, 11 (associated with venereal warts), 16, and 18 (associated with cervical cancer). Administration to girls before they become sexually active is expected to be highly effective in preventing HPV infection and resultant venereal warts and would be expected to lead to a future reduction in JORRP incidence.¹⁶

The role of cesarean delivery in the prevention of JORRP is controversial because the disease is quite uncommon, despite the frequency of genital HPV infection. Consider cesarean delivery in a young woman with visible condylomata who is giving birth to her first child.¹

Complications

Complications of this disease include airway obstruction and malignant transformation.

With regard to tracheostomy, older literature suggests that in RRP patients, it may promote distal airway spread (ie, distal to the larynx) of papillomas. A more recent review suggests that patients who require tracheostomy tend to present at a younger age with more severe disease that already involves the more distal airway. Distal spread after a tracheostomy most commonly involves the tracheostomy site. After laser and antiviral treatment over a period of years, the tracheostomy often can be removed successfully; therefore, tracheostomy is a reasonable option if required due to significant airway obstruction.¹⁷ The need for tracheostomy probably is a marker of more severe disease rather than an independent cause of distal spread.

Malignant degeneration of papillomatous lesions to squamous cell carcinoma occurs in 3-5% of patients with RRP. Distal airway spread of papillomas often is a forewarning of malignant degeneration. The site of malignancy in JORRP usually is the bronchial or pulmonary parenchyma, whereas the larynx is the usual site in AORRP. Malignant degeneration is more common with disease caused by HPV-11 and HPV-16. Cigarette smoking, bleomycin therapy, and radiation treatment of involved areas also increase the risk of malignant degeneration in RRP.

Prognosis

Children with RRP frequently experience remission after several years, which may be related to puberty. By this time, the patient may have undergone more than 20 surgical procedures. Disease in adults tends to be milder.

As noted previously, 3-5% of patients develop squamous cell carcinoma. The prognosis for squamous cell carcinoma in the context of RRP is grave. Cure is uncommon.

Patient Education

RRP usually is a pediatric disease. The main problem is recurrent airway obstruction. Teach parents to recognize potential warning signs, including a weak cry, hoarseness, stridor, wheezing, cyanosis, and decreased exercise tolerance. Airway obstruction may recur as soon as 2-4 weeks after laser procedures, and recognizing its development before critical, life-threatening obstruction develops is important.

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to make the diagnosis: In JORRP, patients characteristically are symptomatic for 1 year prior to diagnosis, and this author's experience with adult patients is similar.
• Failure to consider airway obstruction in patients with hoarseness, voice change, and wheezing: This may have dire consequences, including life-threatening airway obstruction.
• Failure to consider direct laryngoscopy in adults and children with hoarseness
• Failure to consider transfer to a tertiary center that has staff with experience in management of the disease

Special Concerns

Pregnancy in patients with RRP appears to increase the rate of growth of papillomas and may result in disease recurrence after a period of remission.

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  A 48-year-old woman presents with inspiratory stridor, dyspnea, and hoarseness. On direct laryngoscopy, extensive respiratory papillomatosis were diagnosed as the cause of her symptoms. Courtesy of Sat Sharma, MD, and L. Garber, MD.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Mar 6, 2008