Recurrent Respiratory Papillomatosis Surgery Treatment & Management

Updated: Sep 14, 2021
  • Author: John E McClay, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Medical Therapy

Several medical therapies have been tried as adjuvant therapy for laryngeal recurrent respiratory papillomatosis (RRP). [5] 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 (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

See the list below:

  • 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. [15]

  • 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. [16]

  • 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 (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 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 (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. [17]

  • 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 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 (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.


  • This is the newest antiviral being investigated through prospective interinstitutional trials. [18]

  • 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. [4]

Carbon dioxide laser

See the list below:

  • 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

See the list below:

  • 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. [19]


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%. [20] 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. [13]

  • 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.



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, 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."

Long-term (average 40 years) follow-up has recently been published by a group in Finland in 2011. [21] Children who had been followed or treated for juvenile respiratory papillomas were reevaluated as adults with videostroboscopy, acoustic analysis, perceptual voice analysis, and a voice handicap index questionnaire to determine both their voice quality and general quality of life. Techniques for removal of papilloma varied widely and included cryocauterization, electrocauterization, CO2 lasers, other lasers, and, most recently, the microdebrider. Only 3 of their 18 patients received adjuvant medical therapy, all getting interferon.

The study did show that voice quality in these patients was impaired compared to age-matched controls and that a higher number of procedures did worsen voice quality. However, the age at diagnosis in childhood, whether at age 2 years or age 16 years, showed no correlation with voice quality. The good news is that the difference in voice quality did not impact their quality of life, and the patients did not feel handicapped because of their voice quality.

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



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.

Because of the disease or treatment, a child's voice may never be the same.


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.

Farrel Buchinsky and an interinstitutional papilloma study group made up of surgical subspecialists interested in this disease are trying to determine the genetic predisposition and susceptibility of this disease in certain individuals via genetic studies. [22]

Also, with the new human papillomavirus (HPV) vaccine recommended for preteen and teenage girls ages 10-12 years of age targeting human papillomavirus (HPV) types 6,11,16,18, a hope of eradicating this horrendous disease in a generation or two exists.

Controversy still exists concerning the best mechanism of surgical removal for papillomas at various sites in the airway. Current techniques include the carbon dioxide laser, other lasers (eg, KTP, diode), removal with microlaryngeal instruments, or surgical microdebrider.