Virology of Human Papillomavirus

RRP was first confirmed to contain HPV DNA in 1980 by Quick and coworkers, with further characterization and typing by Gissmann and coworkers and Mounts and coworkers in 1982, although it had been the presumed etiology for decades. HPV is an icosahedral (20-sided) DNA capsid virus that is categorized based on genetic homology into greater than 180 identified genotypes, which correspond to different tissue preferences and clinical manifestations. HPV types 6 and 11 account for the most cases of RRP. HPV-11 occurs most commonly (52%–62% of isolates) and runs the most aggressive clinical course, followed by HPV-6 (24%–48%). HPV types 16, 18, 31, and 33 have also rarely been reported in RRP.

Malignant transformation occurs in cervical cancers most commonly with HPV types 16 and 18, with HPV-6 and -11 described as low-risk and HPV-31 and -33 intermediate-risk. In RRP this has generally been reported in adults with other risk factors, such as tobacco use or exposure to radiation, but also occurs in children who commonly have prolonged, extensive disease with distal spread. The etiology of transformation is thought by some authors to follow a gradual molecular transformation. In one example this involved integration of HPV-11 DNA into the host genome in malignant tissue samples and mutation of the p53 proto-oncogene. In their largest series of nine patients, Reidy and colleagues found HPV-11 to be present in all evaluable malignant samples, and RNA assays showed evidence of HPV integration in three of seven sufficient samples. No evaluation of p53 status was performed in this study. In five sufficient samples from seven patients with malignant transformation, Go and colleagues agreed with the consistent expression of HPV-11 in malignancy, and found p53 expression to be variable, but was not able to demonstrate a progressive histologic appearance in serial samples. The palliative treatment of the common clinical course of recurrent airway obstruction and hoarseness in RRP is redirected when malignant transformation occurs with conventional head and neck cancer treatment superseding original treatment goals. Most squamous cell carcinomas arising with a history of RRP are well-differentiated, and when occurring in the lung, these seem to have a refractory clinical course.

Transmission

Transmission of RRP classically occurs in the vaginally delivered first-born child of a teenage mother of low socioeconomic status. This has been reported in 30% to 75% of JORRP cases, although recent data have questioned the association of socioeconomic status and disease severity. The classic explanation for AORRP transmission occurs in patients with multiple oral sexual partners. D’Souza and colleagues in a recent case-control study published in the New England Journal of Medicine found a significant association between lifetime vaginal-sex and oral-sex partners and oropharyngeal squamous cell carcinomas. HPV-16 infection produced an odds ratio of 33.6 ( P <.05) for the development of squamous cell carcinomas in those studied. Neither of these theories is sufficient, however, to explain onset of disease in patients without these exposures or why most patients with these exposures do not develop RRP. Shah and colleagues has suggested that one in several hundred children born to a mother with active HPV condylomata develops RRP. HPV prevalence in the United States is alarmingly high with 60% of women of childbearing age (80 million) found to be HPV antibody positive but DNA negative; 10% (14 million) DNA positive; and 1% with active genital papillomas. Condylomata have been found in pregnant women at a rate of 1.5% to 5%. With 3.6 million annual births in the United States, these values do not account for the observed RRP incidence of 4.3 per 100,000 children. Development of clinical RRP is clearly a multifactorial process that is still poorly understood. Elective cesarean section delivery does not prevent every case of RRP, and is not routinely indicated at this time for at-risk mothers, although this decision warrants discussion with an individual’s birth care provider.

Patient Assessment

Airway endoscopy

The next step in most cases is endoscopy in the operating room. If emergent or urgent, this may be arranged as soon as the operating room can be made ready with supportive care in the emergency department until that time. If stable, the procedure may be scheduled to occur days or weeks in the future depending on the location, extent of disease, and expected progression. Informed consent is obtained detailing the risks of bleeding complications, infections, scarring, or stenotic complications; likely need for further procedures; possible tracheotomy; anesthesia complications; and airway compromise or death. Once in the operating room, anesthesia is induced and the airway is evaluated by the surgeon generally using a Parsons laryngoscope and zero-degree telescope with photographs taken before any intervention for diagnostic and staging purposes ( Fig. 1 ). Once the diagnosis is confirmed and documented, debridement is performed as indicated.

Endoscopic photograph of laryngeal recurrent respiratory papillomatosis.

Staging and severity

Several methods of staging RRP have been proposed that vary in complexity and usefulness. The goals of each are to provide a standardization of RRP evaluation and improve effectiveness in communication between otolaryngologists, clinical monitoring, and research protocol performance. One of the most popular and the authors’ preferred method for staging was developed out of a committee of the American Society of Pediatric Otolaryngology (ASPO) in 1998. It has been included in a software package developed at the University of Washington (Seattle) and licensed to ASPO to ease data input and tracking for patients with RRP. This scheme identifies a 0- to 86-point score with 4 clinical and 25 anatomic components ( Fig. 2 ). It has been shown to have good reliability between surgeon raters and good prognostic value for some elements to predict decreased surgical interval.

Coltrera-Derkay staging and severity scheme. ( From Derkay CS, Malis DJ, Zalzal G, et al. A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope 1998;108:935–7; with permission.)

Patient Assessment

Airway endoscopy

The next step in most cases is endoscopy in the operating room. If emergent or urgent, this may be arranged as soon as the operating room can be made ready with supportive care in the emergency department until that time. If stable, the procedure may be scheduled to occur days or weeks in the future depending on the location, extent of disease, and expected progression. Informed consent is obtained detailing the risks of bleeding complications, infections, scarring, or stenotic complications; likely need for further procedures; possible tracheotomy; anesthesia complications; and airway compromise or death. Once in the operating room, anesthesia is induced and the airway is evaluated by the surgeon generally using a Parsons laryngoscope and zero-degree telescope with photographs taken before any intervention for diagnostic and staging purposes ( Fig. 1 ). Once the diagnosis is confirmed and documented, debridement is performed as indicated.

Endoscopic photograph of laryngeal recurrent respiratory papillomatosis.

Staging and severity

Several methods of staging RRP have been proposed that vary in complexity and usefulness. The goals of each are to provide a standardization of RRP evaluation and improve effectiveness in communication between otolaryngologists, clinical monitoring, and research protocol performance. One of the most popular and the authors’ preferred method for staging was developed out of a committee of the American Society of Pediatric Otolaryngology (ASPO) in 1998. It has been included in a software package developed at the University of Washington (Seattle) and licensed to ASPO to ease data input and tracking for patients with RRP. This scheme identifies a 0- to 86-point score with 4 clinical and 25 anatomic components ( Fig. 2 ). It has been shown to have good reliability between surgeon raters and good prognostic value for some elements to predict decreased surgical interval.

Coltrera-Derkay staging and severity scheme. ( From Derkay CS, Malis DJ, Zalzal G, et al. A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope 1998;108:935–7; with permission.)

Anesthetic Techniques

The intricacies of anesthetic management are just as important as the surgical intervention in the complicated and dangerous airways of RRP patients. Using an experienced anesthesia team and communicating early and clearly are crucial to the safe management of this disease. In practices that had experienced an RRP-related death, anesthesia-related complications were the second most common cause accounting for 7 (22.6%) of 31 deaths reported in an ASPO survey.

Traditional techniques for airway management used laser-safe endotracheal tubes. Reports have now cast suspicion on increased airway instrumentation contributing to distal spread of disease (including tracheotomy as discussed later). The most preferred methods of anesthesia among current members of ASPO are spontaneous or intermittent apneic ventilation (63.5% of respondents in a recent survey), with 24.3% using jet ventilation and 9.6% laser-safe endotracheal tubes.

Classic Surgical Techniques

In the absence of any medically curative treatment, surgical resection of obstructing papillomatous lesions has been the mainstay of palliative treatment for RRP. The goals of surgery are to ensure an adequate airway and functional voice for the greatest possible period before papillomas recur without damaging any healthy underlying tissue that would predispose the patient to long-term complications of scarring, stenosis, and dysphonia.

Placement of a tracheotomy tube is the oldest treatment modality for RRP disease. Although generally avoided today, it is occasionally still necessary for advanced disease or stenotic complications. Concern has been raised regarding the role of tracheotomy tubes in potentiating distal spread of RRP. Cole and colleagues reviewed their experience with 12 tracheotomized patients with RRP, of whom six developed distal spread of disease. They found distal spread to associate with subglottic disease at the time of tracheotomy, and this was observed to progress from involvement of stomal mucosa to the mid-trachea in an average of 10 weeks. Tracheotomy introduces a novel squamocolumnar junction into the airway with a predilection for RRP involvement as discussed previously. Shapiro and colleagues questioned the etiology of distal spread by noting that in 13 of 35 patients reviewed who required tracheotomy, presentation occurred at an earlier age with more advanced disease often involving the distal airway. Distal spread occurred in 50% but was generally limited to the tracheotomy site. The review by Chen and Liu, however, continued to demonstrate the strong association between tracheotomy and distal disease (80.9%). In the palliative treatment of RRP, consideration of tracheotomy placement is one of the most important surgical decision points. Most authors would agree that tracheotomy is necessary in the worst obstructive and most rapidly refractory cases of RRP, and generally still have good outcomes. But this still should be avoided when the disease is able to be managed transorally.

Microsurgical excision was the earliest transoral management option for RRP and is still a preferred treatment in AORRP with limited involvement. Standard microlaryngeal instruments and techniques may be used completely to excise laryngeal papillomata with good voice results, and in one recent series complete remission was observed in 2-year follow-up of six primary AORRP patients. This treatment is not as effective in recurrent or extensive disease, and may result in web formation or scarring of the superficial layer of the lamina propria.

Emerging Techniques

The carbon dioxide (CO ₂ ) laser has been a mainstay of treatment for RRP since its introduction to endolaryngeal surgery in the 1970s. Laser energy is absorbed by water in the tissues resulting in ablation, and when coupled with an operating microscope, may result in precise, hemostatic vaporization of papillomas with minimal damage to underlying normal tissues. Newer ultrapulsed laser models with a micromanipulator allow for less surrounding tissue destruction with beam-shaping capabilities to form a dot, line, circle, or arc to increase even further the precision of tissue ablation. Fiber delivery systems are also being developed for the CO ₂ laser (Omniguide, Cambridge, Massachusetts), which have shown good cutting efficacy and healing characteristics in early studies and may provide additional flexibility for ablating papilloma disease in difficult locations endoscopically.

The microdebrider is a device that uses suction and rotating cold blade excision precisely to remove papillomas. The 4-mm laryngeal Skimmer blade (Medtronic, Jacksonville, Florida) has been designed for microlaryngeal use. With its slightly angulated tip, it allows mobile papilloma tissue to be drawn by the suction into the cutting blade and leaves firmer underlying native tissues undisturbed. A prospective comparison found that use of the microdebrider resulted in equivalent postoperative pain with greater improvements in voice quality, shorter procedure times, and a lower overall procedure cost compared with the CO ₂ laser. Use of the microdebrider has recently supplanted the CO ₂ laser (previously favored by 92% of respondents) as the most popular device for excision of papillomas in JORRP according to a survey of ASPO members.

Recent years have seen an increase in the use of angiolytic lasers for treatment of RRP. These include the 585-nm pulsed dye laser and the 532-nm pulsed potassium-titanyl-phosphate laser, which are absorbed selectively by hemoglobin, causing selective tissue ablation in the highly vascular papilloma lesions.

In a series of 47 patients treated with office-based pulsed dye laser with a mean 13.2-month follow-up, 60% of 117 procedures were performed for RRP with good effect. Thirty percent of cases had anterior commissure involvement, and no incidences of scarring or webs were reported (pulsed dye laser is actually indicated as a treatment for hypertrophic scarring). No complications were noted in RRP patients, with only one complication in the series noted in a patient with Reinke’s edema who developed worsening airway edema and required admission for observation and corticosteroid therapy.

The 532-nm pulsed potassium-titanyl-phosphate laser therapy has been used for in-office and general anesthetic management of AORRP. In a pilot study by Burns and colleagues of 55 procedures in 37 patients with RRP, disease regression and improvement in subjective dysphonia were noted in all patients who had appropriate follow-up with 80% showing disease regression of 90% or more. Ninety-three percent of the patients had anterior commissure disease, and no occurrence of synechiae or web formation was found in near-term follow-up (defined as 1–3 months). This laser has been approved by the Food and Drug Administration (FDA) for ablation of vascular lesions of the upper airway including papillomas. Further basic science and clinical work is ongoing for operating room and in-office application of this therapeutic option.

Angiolytic lasers are an exciting advancement with documented efficacy. In adults or tolerant older children these lasers may be used for in-office management of RRP with significant advantages in cost and patient convenience. This technology may change the face of adult management of RRP in coming years as financial accessibility increases.