eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Laryngology

Recurrent Respiratory Papillomatosis

John E McClay, MD, Assistant Professor, Department of Otolaryngology, Division of Pediatric Otolaryngology, Children's Medical Center, University of Texas Southwestern Medical School

Updated: Oct 29, 2008

Introduction

Recurrent respiratory papillomatosis (RRP) is a benign lesion of the larynx and trachea. Recurrent respiratory papillomatosis (RRP) is caused by the human papillomavirus (HPV), which similarly causes warts often visible on the skin, especially on the hands.

Recurrent respiratory papillomatosis (RRP) is most commonly observed in children, but it can occur in adults. Although lesions histologically and pathologically seem similar in children and adults, clinically they behave much differently. Children often require multiple surgical procedures, and their disease often becomes quiescent in adolescence. Adults with recurrent respiratory papillomatosis (RRP) usually require only a few surgical excisions for cure. Recurrent respiratory papillomatosis (RRP) can be a devastating disease for a child, occasionally necessitating up to 150 surgeries over the child's lifetime. Recurrent respiratory papillomatosis (RRP) is one of the most common causes of hoarseness and airway obstruction in children.

History of the Procedure

Historically, recurrent respiratory papillomatosis (RRP) was believed to be a surgical disease only. However, because of its significant recurrence rate, various medications have been attempted over the last 2 decades with varying degrees of success. In 1990, human papillomavirus (HPV) was discovered as the etiologic agent responsible for papilloma in the larynx and trachea. Since this discovery, the disease mechanism has been extensively investigated, and new antivirals have been tested. International meetings devoted solely to HPV have been organized.

In 1995, the Centers for Disease Control and Prevention (CDC) created a recurrent respiratory papillomatosis (RRP) task force to learn more about the disease. Because recurrent respiratory papillomatosis (RRP) in children is rare and its clinical course hard to predict, the task force combined data from 20 institutions and children's hospitals around the country. The initial goal of the recurrent respiratory papillomatosis (RRP) task force was to diagnose the true incidence and prevalence of the disease because most medical centers have only 15-40 patients with recurrent respiratory papillomatosis (RRP), even in large metropolitan areas.

Once the epidemiology of the disease is established, then prospective medical and surgical therapy trials can be evaluated more thoroughly in large groups of patients. Today, despite these efforts, human papillomavirus (HPV) is still misdiagnosed as asthma, croup, or chronic bronchitis because they all display symptoms of airway obstruction. However, as the disease becomes better known, recurrent respiratory papillomatosis (RRP) diagnosis will be made more often.

Problem

Recurrent respiratory papillomatosis (RRP) is a wart on the laryngeal, tracheal, bronchial, or other respiratory mucosa.

Frequency

Based on a survey of otolaryngologists, 1500-2500 new cases of childhood-onset recurrent respiratory papillomatosis (RRP) are estimated to occur each year in the United States. Incidence among children in the United States is estimated at 4.3 cases per 100,000 persons. Adult incidence is estimated at 1.8 cases per 100,000 persons.

The distribution of cases of recurrent respiratory papillomatosis (RRP) is bimodal, with an initial peak in the childhood years and a second peak in the adult years in people aged 20-40 years.

In children, the male-to-female ratio is approximately equal. For adults, the male-to-female ratio may be 4:1. Childhood onset for recurrent respiratory papillomatosis (RRP) is more common and more aggressive than in adults. Most children with recurrent respiratory papillomatosis (RRP) appear to be the first born of young mothers and come from families with low economic status.

Roughly 15,000 surgical procedures are performed each year at an estimated cost of $100 million.

Etiology

Human papillomavirus (HPV) causes recurrent respiratory papillomatosis (RRP). Seventy types of human papillomaviruses (HPVs) have been identified. Human papillomavirus (HPV) types 6 and 11 cause benign papilloma in the airway and are responsible for genital warts. Human papillomavirus (HPV) types 16 and 18 have most often been associated with cancer in the genital area and upper aerodigestive tract in both children and adults.

In patients with laryngeal papilloma, normal mucosa has human papillomavirus (HPV) in 20% of cases. In otherwise normal airways, human papillomavirus (HPV) deoxyribonucleic acid (DNA) has been retrieved from laryngeal and tracheal mucosa in 4% of cases.

Pathophysiology

Childhood-Onset Recurrent Respiratory Papillomatosis

The precise mode of human papillomavirus (HPV) transmission is unclear. Most studies indicate that childhood-onset recurrent respiratory papillomatosis (CORRP) occurs during exposure of a child's upper aerodigestive tract to the cervix and vagina of a mother with genital human papillomavirus (HPV) infection during normal abdominal delivery. Why CORRP develops in only a few percent of children who are born abdominally to mothers with active genital condyloma is not well understood.

Statistics

• In 1998, Shah et al reported the risk of an abdominally delivered child contracting RRP from a mother who has active condylomatous lesions at approximately 1 in 400.¹
• Fifty percent of mothers of affected children had active or previous condylomata.
• Human papillomavirus (HPV) was recovered on nasopharyngeal swab from a third of infants born to mothers with active uterine human papillomavirus (HPV).
• In the United States, 1 million cases of genital papilloma per year manifested as condyloma acuminatum involving the cervix, vulva, penis, or other anogenital sites.
• Clinically apparent human papillomavirus (HPV) infection has been noted in 1.5-5% of pregnant women in the United States. Human papillomavirus (HPV) has been recovered in up to 20% of disease-free mucosa in the anogenital area of pregnant women.

Factors possibly contributing to development of HPV

• Status of the child's immune system
• Length of time in the birth canal
• Volume of virus in the birth canal
• Abdominal delivery: One case reports a child born by cesarean delivery (with no premature ruptured membrane) who developed recurrent respiratory papillomatosis (RRP), casting doubt on the birth canal theory.
• Presence of local trauma

Adult-Onset Recurrent Respiratory Papillomatosis

For adult-onset recurrent respiratory papillomatosis (AORRP), oroanal or orogenital contact is considered a possible mode of virus transmission versus a latent virus becoming active. Ten percent of sexually active men and women with no clinical evidence of disease have human papillomavirus (HPV) identified in the penis or cervix by Southern blot hybridization analysis, suggesting presence of latent infection.

Virus mechanisms

• Once transmitted to the airway, human papillomavirus (HPV) establishes itself in the basal layer of the mucosa, where viral DNA enters the cell and produces ribonucleic acid (RNA) to produce viral proteins, similar to the replication mechanism of other viruses. This action incites the transformation of the mucosa to papilloma formation.
• In 1993, Kashima et al reported an increased risk of papilloma in the airway at sites of squamous epithelium or squamous metaplasia.²

Presentation

Childhood-Onset Recurrent Respiratory Papillomatosis

Children with CORRP usually present when aged 2-3 years with hoarseness, stridor, or airway obstruction. Papilloma has been reported to manifest as early as the first day of life or as late as the octogenarian years.

Symptoms and signs

• Stridor usually begins as an inspiratory noise consistent with glottic or supraglottic disease but then becomes biphasic with progression of disease.
• As the papilloma grows, the airway obstructive features worsen. Other clinical presentations include cough, pneumonias, and dysphagia. Children are often misdiagnosed with asthma, croup, allergies, vocal nodules, or bronchitis. Recurrent respiratory papillomatosis (RRP) is misdiagnosed because of its rarity and the slowly progressive nature of the disease. Hoarseness without airway obstruction may indicate the small lesion.
• Aphonia or breathy voice suggests a larger glottic lesion.
• A low-pitched, coarse, fluttering voice suggests a subglottic lesion.
• Children with papillomas of the larynx do not usually become symptomatic before age 6 months.
• Document the quality of the voice on physical examination.
• Signs of severe airway obstruction include tachypnea, stridor, retractions (suprasternal, substernal, intracostal), flaring of the nasal ala, and use of accessory neck or chest muscles.
• Increasing air hunger may cause the child to sit with the neck hyperextended in an attempt to improve airflow.
• All children with any of the signs of stable airway obstruction or voice disturbances must have a flexible fiberoptic nasopharyngoscopy in clinic.

Indications

Indications for surgery in recurrent respiratory papillomatosis (RRP) are based on the presence or absence of a lesion that causes symptoms. Laryngeal lesions, if present, usually cause symptoms and must be removed or treated. In a patient undergoing multiple surgeries a year, a lesion may only need to be removed because it is symptomatic and not necessarily every lesion needs to be removed in every surgical procedure. Surgical excision is the current standard of care in the treatment of recurrent respiratory papillomatosis (RRP). Adjuvant medical therapy has been investigated over the past 2 decades and continues to this day.

If the child or adult has only hoarseness, surgery can be scheduled as an elective procedure. If the child or adult has airway obstruction, immediately treat it as an emergency procedure.

Relevant Anatomy

During surgical removal, use caution to spare all vital structures and to prevent iatrogenic scarring of the larynx or trachea.

Up to 30% of patients who have had surgical excision of papilloma in the anterior commissure of the larynx have developed anterior glottic scarring and web formation. Unless the surgeon can be assured that iatrogenic injury will not result from their technique, papilloma should be left in the anterior commissure in children requiring several surgeries a year.

A small percentage of patients have developed subglottic stenosis from repeated surgical excisions at the anterior commissure of the larynx.

Avoid tracheotomy at almost all cost. Frequent surgical excision (ie, as often as once per 2 wk) is preferable to tracheotomy for children or adults who have recurrent aggressive disease. Tracheotomy is believed to induce spread of the papilloma down the trachea and into the bronchi and lungs.

Contraindications

No contraindications to surgical removal of recurrent respiratory papillomatosis (RRP) exist.

Workup

Laboratory Studies

• Laboratory studies for recurrent respiratory papillomatosis (RRP) do not exist, although biopsies of the papillomas themselves can be tested to determine the type of human papillomavirus (HPV) present. Some reports indicate that human papillomavirus (HPV) type 11 may be more aggressive than human papillomavirus (HPV) type 6; however, that is debatable.
• Currently, no clinical reason exists to type human papillomavirus (HPV). Routinely or occasionally, however, obtaining a biopsy of the papilloma evaluated is important to detect squamous metaplasia or progression to carcinoma.

Imaging Studies

• If any papilloma is diagnosed on flexible fiberoptic nasopharyngoscopy, no imaging studies are necessary for initial diagnosis.
• For children with airway obstructive symptoms for which no lesion is observed in the glottic larynx, certain imaging studies can be obtained for diagnosis of airway obstructive lesions of the trachea.
• Fluoroscopy with barium swallow can be used to diagnose gastroesophageal reflux disease (GERD) and vascular abnormalities that compromise the trachea or esophagus. This test may also help diagnose dynamic or static tracheal stenosis.
• Bronchoscopy is the single best diagnostic tool to initially evaluate a child in respiratory distress who has no lesion in the larynx.
• CT scanning and MRI are not good initial imaging evaluators for a child with airway distress. For children with distal spread of papillomas into the trachea and bronchus, a CT scan of the chest is an appropriate method to evaluate for pulmonary disease.

Diagnostic Procedures

• The diagnostic procedure of choice for recurrent respiratory papillomatosis (RRP) is initial flexible laryngoscopy in the clinic. If this is not diagnostic, the secondary diagnostic procedure of choice is a rigid bronchoscopy in the operating room with biopsy of the lesion.

Histologic Findings

The histologic appearance of laryngeal papillomas is characterized by papillary fronds of multilayered benign squamous epithelium that contain fibrovascular cores. No surface keratinization is observed. Koilocytes (vacuolated cells with clear cytoplasmic inclusions that signal presence of viral infection) are observed.

Biopsies for histologic evaluation taken during surgical excision should occur frequently enough to detect squamous metaplasia, dysplasia, or conversion to squamous cell carcinoma (SCC). The exact timing of biopsy intervals is not well documented. Surgical patterns of biopsy range from taking a biopsy during every surgical procedure to never taking a biopsy because the diagnosis is already known.

Staging

A uniform staging system for laryngeal or tracheal papilloma does not exist. Both Kashima and Wiatrak have proposed staging systems to quantify disease for comparison of treatments.³ Many studies evaluating medical therapy have their own internal scale or staging system.

Treatment

Medical Therapy

Several medical therapies have been tried as adjuvant therapy for laryngeal recurrent respiratory papillomatosis (RRP). The actual effectiveness of any reported medical therapy for recurrent respiratory papillomatosis (RRP) is difficult to determine because the underlying aggressiveness of the disease is poorly understood. A patient's disease may wax and wane for no known apparent reason. Until this aspect of the disease is more defined, any success or failure of medical therapy must be carefully examined. Despite this problem, medical therapy for papillomas has the best chance of leading to a breakthrough in RRP treatment.

Interferon

Interferon (IFN) is a class of proteins manufactured by leukocytes in response to a variety of stimuli, including viral infections. The produced enzymes block viral replication of RNA and DNA. IFN also alters the cell membrane, thus making them less susceptible to viral penetration.

• Interferon was first used in a Scandinavian trial in 1976.
• Trials in the early 1980s showed good results.
• IFN is the most widely used and the most widely studied adjuvant therapy for RRP.
• IFN-alfa showed best results. Two commercially available products are IFN-alfa 2a and IFN-alfa 2b.

Interinstitutional studies

• Two large studies were performed within major children's hospitals and academic centers across the United States.
• One large interinstitutional trial showed no benefit from IFN, while the other showed improvement from IFN. However, when IFN was stopped, the papillomas tended to recur. Dose of IFN is different in different trials; however, for both the large trials, IFN was administered every day for 1 month at 5 million U/m²/d IM, then 3 times weekly for 5-6 months. Patients were treated for 6 months; then, they were observed for 6 months.
• Papillomas were removed with carbon dioxide laser.
• Overall, 70% (46 of 60) of patients had a response (complete response, 35%; partial response, 40%). Partial responses were observed at 3 and 4 months. For the 22 patients that had a complete response, 18 (86%) showed a partial response by 4-6 months of treatment. Out of the 35% of patients that had a complete response, 75% were free of disease for as long as 6.5 years.
• Both human papillomavirus (HPV) types 6 and 11 had the same response rate.
• Response was better in older children (aged 4-15 y), who demonstrated a 95% response rate. Younger children (aged 1-3 y) had a 46% response rate.

Adverse effects of interferon

• Acute adverse effects decrease with long-term use.
• Viral syndromes may occur, accompanied by fever, chills, malaise, and nausea.
• Delayed adverse effects include systemic lupus erythematosus (SLE), rash, dry skin, alopecia, fatigue, decreased growth rate (reversed when IFN is discontinued), liver dysfunction (15%), leukopenia (10%), thrombocytopenia, neurologic problems, and spastic diplegia.

Intralesional therapy

• One study described a 2-year nonrandomized noncontrolled trial of intralesional injection of 3 microunits of IFN-alfa in 11 patients (6 children, 5 adults).
• Endoscopies were performed every 3 months and injections approximately every other endoscopy.
• Four to 5 adults had complete remission.
• One of 6 children had complete remission.
• Adverse effects were flu-like symptoms.

Other therapies

Photodynamic therapy

• Photodynamic therapy (PDT) uses a photosensitizing agent, such as dihematoporphyrin ether (DHE) or M-Tetra hydroxyphenyl chlorine (MTHPC), which is taken up preferentially in rapidly dividing tissues (eg, papillomas). These drugs are administered intravenously, 24 hours before photocoagulation in the operating room. At endoscopy in the operating room, a tunable pump-dye laser system emits a red light at 630 nanometers.
• DHE (ie, Actifed) produces singlet oxygen, causing local vascular stasis and tumor destruction.
• Most of this work has been accomplished by Abramson, Shikowitz, and Steinberg at Long Island Jewish Medical Center, where they have observed a small decrease in papilloma growth, especially in a more aggressive disease.⁴
• Complications include photosensitivity. Thus, patients using this process must avoid sunlight for 6-9 months, while using the drug.
• SLE-like reactions have occurred because of light sensitization.
• A new drug, MTPHC, may have fewer adverse effects and be more effective. Photosensitization usually occurs over 2-3 weeks.
• Clinical trials are ongoing.

Indole-3-carbinol

• Indole-3-carbinol (I3C) is a compound found in cruciferous vegetables (eg, cabbage, Brussels sprouts, broccoli, cauliflower) and sold in health food stores.
• I3C affects the ratio of hydroxylation of estradiol, promoting C-2 over C-16 hydroxylation of this hormone.
• C-16 hydroxylation produces a genotoxic compound, promoting unscheduled DNA synthesis and hyperproliferation.
• C-2 hydroxylation is associated with a decreased risk of endometrial cancer.
• Epidemiologic studies found breast cancer rates decreased in populations that consume large amounts of cruciferous vegetables.
• Animal studies have evaluated the effects of I3C on laryngeal tissue infected with the human papillomavirus (HPV). The papillomas were implanted under the renal capsule of nude mice. Half the mice ate a diet rich in I3C; the other half did not. Mice on the I3C diet showed a 75% decrease in the amount of papilloma growth compared to the other mice.
• In cell cultures of laryngeal epithelium, the product of C-2 hydroxylation is antiproliferative.
• Over the past 3 years, the University of Pittsburgh (under the direction of Clark Rosen) and the University of Tennessee (under the direction of Gail Woodson and Jerome Thompson) have conducted combined phase 1 and phase 2 trials with I3C. Exact results are unknown but promising.
• Adverse effects with large doses of I3C include dizziness, headache, ataxia, and possible bone loss.
• Diindolymethane (DIM) is a form of I3C that develops naturally in an acidic environment such as the stomach. DIM is more stable and more absorbable than is I3C. A prospective trial is underway at the University of Iowa (under the direction of Richard Smith).

Ribavirin

• Ribavirin is an analogue of guanosine (1 of 4 basic-building blocks of DNA).
• Currently, ribavirin is available only in aerosolized form and costs over $1000 per day to use.
• Ribavirin inhibits viral nucleic acid synthesis and many aspects of RNA and DNA transmission and translation, particularly in respiratory syncytial viruses.
• An early evaluation was provided by a small pilot study of 4 patients with very aggressive disease who were treated for 6 months, after an initial IV bolus of the antiviral. All 4 patients had a response to the drug, 2 partial and 2 complete. The disease returned upon cessation of treatment.
• Frank Rimell, MD, has completed a larger study of 20 patients that has not shown increased efficacy over standard surgical excision with carbon dioxide laser.
• Because ribavirin is a teratogen, adverse effects have caused fetal malformations in rabbits and rodents. Additionally, ribavirin has caused transient headaches, mild fatigue, anemia, and an increase in reticulocytes.

Acyclovir

• Acyclovir (acycloguanosine) is a purine nucleoside analogue used to treat herpes virus infection.
• Acyclovir binds to herpetic thymidine kinase and is phosphorylated and incorporated into replicating DNA molecules, where it breaks replication.
• Human thymidine kinase does not activate acyclovir.
• Mechanisms of action in recurrent respiratory papillomatosis (RRP) are unknown. In 1995, Pou, Rimell, and Jordan showed that a coinfection of human papillomavirus (HPV) and herpes virus could occur, thus accounting for effectiveness of the drug.⁵
• Four studies were performed with a total of 26 patients.
• Adults received 800 mg per day; children received 10 mg/kg or 400 mg per day, depending on the trial.
• Three of 4 studies showed benefit when taken orally, either completely eradicating or decreasing the disease.
• The largest study had 12 patients and showed remission for the entire length of follow-up (as long as 2 y), after taking the prescribed treatment for 6 months.
• Intralesional acyclovir has also been used, increasing the time interval between surgical excisions.

Methotrexate

• Methotrexate is an antimetabolite that inhibits dihydrofolic acid reductase, blocks the synthesis in purine nucleotides, and interferes with DNA synthesis and repair.
• Active proliferating cells are most affected by methotrexate.
• The only study of methotrexate examined 3 patients who were refractory to IFN. These patients had a marked response to methotrexate, doubling the time interval between excisions and decreasing the papilloma load.

Isotretinoin

• Isotretinoin (cis -retinoic acid) is a vitamin A derivative that regulates growth and differentiation of epithelial cells by inhibiting epithelial proliferation. Isotretinoin has no direct antiviral properties.
• In randomized trials, no significant clinical improvement over placebo has been observed.
• Of 2 nonrandomized studies, one had a 60% response rate, and the other had no response.
• Significant toxicity exists, including fetal birth defects, photosensitivity, cheilitis, arthralgias, and rare liver, kidney, and hematologic abnormalities.

Mumps vaccine

• In Denver, Nigel Pashley, MB, BS, FRCSC, is using mumps vaccine intralesionally with some success.
• No formal report has been published yet.

Cidofovir

• This is the newest antiviral being investigated through prospective interinstitutional trials.⁶
• Cidofovir is an acyclic phosphonate analogue of deoxynucleoside monophosphate.
• Cidofovir has broad-spectrum antiviral activity against herpes, pox, and papilloma viruses.
• Cidofovir is a Food and Drug Administration (FDA)–approved drug for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.
• Once carbon dioxide laser excision has been performed, Cidofovir is injected into the area of papilloma.
• A small noncontrolled study showed partial or complete response in all patients.
• The current interinstitutional trial (headed by Seth Pransky at the Children's Hospital of San Diego) involves surgically debulking the disease and administering monthly injections of Cidofovir each month for as long as 6 months.
• Nephrotoxicity has been found with IV use.
• Large single doses apparently are less toxic than small doses on a repeated basis.
• Some studies have reported uveitis with systemic use.
• Laboratory studies on the medicine include CBC count, chemistry profile, and urinalysis, specifically to look for proteinuria.
• This drug should be used with caution because of the risks involved.

Vaccines and immunostimulant drugs

• Vaccines and immunostimulant drugs such as HspE7, a recombinant fusion protein of (1) Hsp65 from Mycobacterium bovis bacille Calmette-Guérin (BCG) and (2) E7 protein from HPV type 16, are being evaluated in animal and clinical trials.

Surgical Therapy

Excision by carbon dioxide laser is the most commonly employed removal method.

Carbon dioxide laser

• The carbon dioxide laser is well absorbed by most tissues of the body because of the high water content of the tissues.
• Because this laser is invisible to the human eye, a helium-neon aiming beam is necessary for precise application.
• Investigators have reported fewer complications and less local injury of tissue with suspension microlaryngoscopy with the carbon dioxide laser, as compared with gross surgical debulking without the microscope.
• The carbon dioxide laser must be used precisely (performed best with the microspot micromanipulator) to prevent mucosal scarring, fibrosis, and laryngeal web malformation.
• In children, carbon dioxide laser is effective for removing papillomas on the supraglottis, glottic larynx, and subglottic larynx. Tracheal lesions below the mid tracheal area are more difficult to laser. Laryngoscopes must be changed to eradicate disease in the larynx and trachea.
• Bulky laryngeal lesions are best treated with microlaryngeal techniques and then use of the carbon dioxide laser or surgical microdebrider.

Surgical microdebrider

• The surgical microdebrider has recently been used for laryngeal and tracheal papillomas.
• First used in orthopedic surgery, the surgical microdebrider (colloquially referred to as a "hummer") was used widely by otolaryngologists for removal of tissue in the sinuses, especially for polyps. The microdebrider uses suction and cutting mechanisms for tissue removal, allowing the surgeon to quickly remove tissue, while providing good visualization of the area because of the suctioning of secretions during cutting.
• A long laryngeal blade is now available for use in the larynx and trachea.
• When papillomas are simultaneously present in the larynx and trachea, use of the surgical microdebrider is the best method to remove them without having to reposition the patient. In adults, however, the microdebrider is difficult to use in the mid-to-distal trachea because the blade is too short to reach past the upper trachea.
• Distal tracheal and bronchial lesions are more difficult to remove with any technique. Techniques employed include the use of optical forceps removal through rigid bronchoscopy or use of many different types of laser (eg, carbon dioxide, potassium-titanyl-phosphate [KTP]) with a microfiber down the side port of a bronchoscope.
• Avoid tracheotomy at all cost because it can cause a spread of disease. If necessary, this means performing surgery every 2-4 weeks.

Preoperative Details

The entire team of the anesthesiologist, surgeon, surgical scrub nurse, surgical circulator, and laser technician must be well versed in airway obstructive problems.

• Do not allow the child into the operating room before all equipment necessary for an airway emergency is prepared. Necessary equipment includes appropriately sized bronchoscopes, laryngoscopes, and visualization equipment.
• Inform parents of the risks of surgery, including the risks of tracheotomy. (Tracheotomy is only used to save a child's life.)
• Prepare the operating room for laser safety. All operating room personnel must wear eye protection when working with lasers.
• Airway obstructive details between the surgeon and anesthesiologist should be discussed, including need for emergent bronchoscopy and protocol for airway fire.

Intraoperative Details

Goals of intraoperative removal include reducing the papilloma burden, creating a safe airway, improving voice quality, and increasing the time interval between surgical procedures.

• Remove papilloma without sacrificing or damaging any vital structures. Because total removal is difficult and need for future surgeries unquestionable, leave only small amounts of papilloma in locations where significant complications could occur (eg, anterior commissure, posterior glottis).
• Intraoperatively, the surgeon controls use of the laser. The surgeon must maintain good communication with the operating staff or laser technician who runs the laser. Prepare the patient to prevent injury. Preparation includes wet eye patches and wet towels surrounding all exposed body parts.
• Various anesthetic and surgical suspension techniques have been used in removing papillomas. In 1998, Derkay polled otolaryngologists around the United States, who stated they used spontaneous ventilation in 12% of cases, apneic technique in 16%, jet ventilation in 26%, and lasering with premanufactured airway or laser safety endotracheal tubes in 46%.⁷ The only reported airway fires have been with premanufactured airway tubes by wrapping a red rubber catheter with metallic tape in which a portion of a catheter was exposed.
• Consider a biopsy before removal of the papilloma with laser ablation, excision with surgical microlaryngeal instruments, or surgical microdebrider.
• When using laser, a smoke evacuator should be present because human papillomavirus (HPV) particles have been recovered in the smoke plume.
• Accomplish hemostasis during surgery with neurosurgical cottonoids soaked in vasoconstrictive agents (eg, oxymetazoline). Use these cottonoids over the area of bleeding, while avoiding obstruction of the laryngeal inlet, unless an endotracheal tube is present. Always consider intraoperative IV steroids before removing papillomas.
• Take care to avoid directing the laser beam down the airway when aiming onto papillomas because scattered laser shots into the trachea can cause pneumothorax or create a squamous epithelium site. Kashima demonstrated that recurrent respiratory papillomatosis (RRP) has an increased incidence at squamo-mucocillary junctions.²
• When using jet ventilation, employ intermittent endotracheal intubation and ventilation to decrease the carbon dioxide that accumulates in the lungs.

Postoperative Details

Any young child or child with severe disease should be observed in the hospital overnight. Occasionally, children and adults can experience hoarseness that may or may not resolve with edema resolution, depending on the nature of underlying disease. A sore throat or neck pain may or may not occur for a few days.

Follow-up

Aggressive papillomas have been defined as those occurring in patients who require 4 surgical procedures or more per year. In children, scheduling surgery on a regular basis (eg, every 4-6 wk) initially may be beneficial until the interval is defined. If the disease progression changes, intervals can be changed.

Children who have less need for surgical excision may be monitored in an otolaryngology clinic with flexible fiberoptic laryngoscopy to monitor disease progression and to schedule surgery as needed. Certainly, a child with airway obstruction problems must be treated immediately. Notify patients and parents about support groups for this devastating disease. The RRP Foundation, an international volunteer organization composed of researchers, medical care providers, and families with affected members, has a helpful Internet site. Another help site is www.rrpwebsite.org, which "provides a venue through which patients, families, and RRP health care professionals may become better informed, and in which they can exchange information and communicate on a level playing field."

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

Complications

Disease progression can occur at sites from laryngeal to tracheal to pulmonary. Weiss and Kashima report tracheal disease spread in up to 26% of patients and bronchopulmonary spread in less than 5%. Pulmonary disease manifests as solid or cystic pulmonary masses on plain radiography or chest CT scanning.

Progression of papilloma to squamous cell carcinoma (SCC) can occur but is rare. Squamous cell carcinoma (SCC) has most frequently occurred with distal pulmonary spread. Whether this is a transformation of the tumor or a result of squamous metaplasia or dysplasia created by necessary repeat surgical excision of disease is unknown. In one case, a change in the human papillomavirus (HPV) from a type observed in benign lesions (ie, type 6) to a type present in malignant lesions (ie, type 16) occurred when the papilloma converted to a squamous cell carcinoma (SCC).

Complications of disease and surgical procedures include posterior glottic stenosis, anterior glottic web or stenosis (most common, at 20-30% of cases), subglottic stenosis, or tracheal stenosis. Intraoperative complications include pneumothorax and airway fire, which could result in devastating tracheal or pulmonary injury. Postpone surgical repair of complications until the disease has been quiescent for several years.

Outcome and Prognosis

Patients with recurrent respiratory papillomatosis (RRP) have a variable course. The juvenile aggressive form appears to recur more rapidly and to require more surgical intervention. The adult form is usually cured with several surgical procedures. An aggressive form of recurrent respiratory papillomatosis (RRP) observed in adults behaves similarly to the juvenile form in children.

Regardless, children often require surgical excision as often as every 2-4 weeks. Occasionally, children have as many as 150 total surgeries, until the disease becomes quiescent in adolescence. Many of these children with severe disease eventually develop the complications listed above.

Once diagnosis is made in young children, prognosis is variable. The disease must be closely monitored to determine its aggressiveness; various techniques have been used to do accomplish this. Some surgeons follow up patients in the clinic, assessing the need for the next surgical procedure based on the patient's symptoms of airway obstruction and on what is observed with flexible fiberoptic laryngoscopy. For young children who most likely will have aggressive disease, initial routine bronchoscopies in the operating room at 4- to 6-week intervals can be used to assess disease progression. This practice decreases the need for in-clinic fiberoptic examinations while awake that can add to the stress of parents and patients dealing with an already stressful disease.

Outcomes of patients on varying medical therapies are listed in Treatment. Because children and adults have different aggressiveness of disease, the effect of medical therapy on adults cannot be extrapolated to children.

Future and Controversies

The key to treatment of recurrent respiratory papillomatosis (RRP) in adults and children, but especially in children, is the use of medical therapy to eradicate the human papillomavirus (HPV) because latent papilloma virus is found in 20% of normal-appearing mucosa, and extensive disease is difficult to eradicate completely.

All studies evaluating adjuvant medical therapy are limited by the fact that recurrent respiratory papillomatosis (RRP) is a rare disease that has variable clinical aggressiveness. Improvement or lack of improvement may be related to the specific aggressiveness of the recurrent respiratory papillomatosis (RRP) found in a subset of patients in a study and not necessarily to the medicine itself. Hence, no medical therapy can be accurately evaluated until the mechanisms of aggressiveness have been determined genetically or biochemically.

References

1. Shah KV, Stern WF, Shah FK, et al. Risk factors for juvenile onset recurrent respiratory papillomatosis. Pediatr Infect Dis J. May 1998;17(5):372-6. [Medline].

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Keywords

recurrent respiratory papillomatosis, RRP, laryngeal papillomas, laryngeal papillomatosis, tracheal papillomas, tracheal papillomatosis, larynx, trachea, HPV, human papillomavirus

Contributor Information and Disclosures

Author

John E McClay, MD, Assistant Professor, Department of Otolaryngology, Division of Pediatric Otolaryngology, Children's Medical Center, University of Texas Southwestern Medical School
John E McClay, MD is a member of the following medical societies: American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Ted L Tewfik, MD, FRCS(C), Professor, Department of Otolaryngology, Director of Continuing Medical Education of Otolaryngology, McGill University Medical School; Director, Director of Professional Affairs of Otolaryngology, Department of Otolaryngology, Montreal Children's Hospital; Senior Staff, Montreal General Hospital and Royal Victoria Hospital
Ted L Tewfik, MD, FRCS(C) is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Society of Pediatric Otolaryngology, Canadian Medical Association, Canadian Society of Otolaryngology-Head & Neck Surgery, Quebec Medical Association, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Gregory C Allen, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine
Gregory C Allen, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, American Cleft Palate/Craniofacial Association, American College of Surgeons, American Laryngological Rhinological and Otological Society, American Medical Association, Christian Medical & Dental Society, and Colorado Medical Society
Disclosure: Nothing to disclose.

CME Editor

Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders
Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation unstricted gift unknown

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