The relationship between tracheotomy and RRP distal to the larynx is well established. Tracheotomy is performed when a patient suffers airway obstruction. Airway obstruction may be a direct result of the bulk of the papilloma but may also be the result of scarring related to surgical treatment of the papilloma. Some have argued that those patients who require tracheotomy actually may have more aggressive disease from the outset (Blackledge and Anand 2000; Shapiro et al. 1996). Alternatively, the tracheotomy has been suggested to activate or somehow contribute to the spread of papilloma into the lower respiratory tract. Tracheobronchial extension is linked to a previous tracheotomy in as many as 95% of reported cases (Blackledge and Anand 2000; Cole et al. 1989; Soldatski et al. 2005; Weiss and Kashima 1983). It is rare that tracheal or bronchial papilloma are identified at the time of initial tracheotomy.

Most who care for patients with RRP agree that avoidance of tracheotomy is optimal. When a patient does require tracheotomy, the indication has been reported to be either “stabilization of airway” or glottic stenosis secondary to previous surgical intervention for their disease (Blackledge and Anand 2000). In those patients who require tracheotomy, every effort is made to expedite safe decannulation. Tracheal spread of papilloma has been reported to occur in as few as 7 weeks post-tracheostomy (Cole et al. 1989) but is certainly not universally encountered in patients who undergo tracheostomy.

There is a clear association between previous tracheotomy and distal spread of papilloma. The predominant theory underlying this relationship is that by disrupting the tracheal mucosa to place the artificial airway, an iatrogenic transformation zone is created (Kashima et al. 1993). The damaged mucosa is an entry point for or the perfect environment for the virus to replicate and cause cellular proliferation and papilloma. As injured mucosa is the entry point, it has been hypothesized that tracheal mucosa injured by any means may be at increased risk for development or spread of papilloma. While this appears to be the case for chronic disruption at the distal tip of the tracheotomy tube, there does not appear to be any proven increase in neonates who require prolonged endotracheal intubation. Nor do other open airway procedures necessarily demonstrate the same increased risk. For instance, Boston et al. demonstrated that a cohort of children with RRP who also had severe subglottic stenosis successfully underwent laryngotracheal reconstruction (Boston et al. 2006).

It has also long been known that HPV viral subtype 11 is more aggressive than viral subtype 6. Numerous studies have demonstrated more aggressive distal complications as well as more common malignant degeneration in patients who are infected with HPV 11. While there was initially some debate in the literature regarding whether a particular subtype was significantly more likely to develop tracheobronchial extension, most agree that this is the case. The relationship was first suggested by Mounts and Kashima who found then labeled HPV subtype 6C (which has since been identified as subtype 11) to be linked with a more obstructive course (Mounts and Kashima 1984). Other studies went on to show that the infecting HPV subtype had little influence on the clinical outcomes (Rimell et al. 1992). Ultimately, studies using polymerase chain reaction were successful in correlating HPV subtype 11 with a significantly more aggressive disease course (Rimell et al. 1997). It is generally well accepted that HPV subtype 11 has a more aggressive clinical course both in tracheobronchial extension and in conversion to malignancy.

RRP may have its onset in childhood, even in the neonatal period, or in adulthood (Derkay 1995). Generally, those with onset in childhood suffer a more aggressive form of the disease, with the less aggressive form typically occurring in adults. The age of onset of the disease is known to be a significant risk factor in prognosticating the aggressiveness of disease. Presentation in the neonatal period poses a higher risk for tracheotomy and associated morbidity and mortality (Reeves et al. 2003; Ruparelia et al. 2003). Diagnosis before age three years versus after has been associated with 3.6 times higher likelihood of needing more than four surgical procedures per year and almost 2 times greater likelihood of having two or more anatomic sites affected (Derkay 1995). Additionally, children with disease progression are generally diagnosed at younger ages than those who remain stable or become disease-free (Wiatrak et al. 2004).

As surgical intervention is the primary mode of treatment, one measure of aggressiveness is the frequency with which a patient requires surgical intervention. One threshold for consideration of adjuvant therapies is when a patient undergoes more than four surgeries in a 12-month period. According to the National Registry for Children with RRP, which includes patients of 22 pediatric otolaryngology practices, children with RRP undergo an average of 4.4 procedures per year (Derkay 1995; Armstrong et al. 1999), thereby concluding that the majority of children could be considered for adjuvant therapy.

The presence of RRP beyond the larynx has been noted more commonly in those who are diagnosed with the juvenile-onset form of the disease as well as in those who undergo tracheotomy. There may be commonality in these groups, as Kashima et al. noted that 15% of patients with the juvenile form of the disease require tracheotomy for airway complications and management (Kashima et al. 1993).

Surgical therapy remains the mainstay of treatment for all aerodigestive papilloma that are accessible through typical endoscopic means. Surgical treatment initially involved cold surgical excision. The carbon dioxide (CO2) laser replaced cold instruments as the method of choice for removing RRP of the larynx, pharynx, upper trachea, and nasal and oral cavities (Schraff et al. 2004). Advances in the delivery of the laser, both using the micromanipulator on the operating microscope and the flexible fiber delivery system, have allowed for “vaporization” of RRP lesions with minimal bleeding and maximal precision. Drawbacks to the CO2 laser are threefold and relate to patient and caregiver safety. The first is the risk of inadvertent deflection of the laser to injure the surgical team or patient, including the indwelling endotracheal tube, which (if not appropriately protected) may ignite in an oxygen-rich environment causing an airway fire. Second, the “plume” of smoke generated by the laser has been proven to contain active viral DNA, which is a potential source for infection (Hallmo and Naess 1991; Kashima et al. 1991; Sawchuk et al. 1989). Lastly, the laser-generated heat could cause injury to deeper laryngotracheal tissues, leading to scarring, spread of viral particles to previously unaffected tissues, and delayed local tissue healing. Other lasers, such as the potassium titanium phosphate (KTP), 585 nm flash dye, or argon laser, have also been used to treat RRP. The treatment of distal bronchial lesions has benefitted from these advances in technology. In particular, the use of lasers delivered via fiber that can also be coupled with a ventilating or flexible bronchoscope has improved the success of more distal surgical resection. More recently, powered endoscopic microdebrider has been used with good success, as shown by several groups (Pasquale et al. 2003; Patel et al. 2003; El-Bitar and Zalzal 2002). Powered microdebrider is also limited to subglottic and proximal tracheal involvement due to the physical space restraints required for exposure and the size/length of the instrument. Use of any of these methods must keep in mind that almost all patients require multiple surgical interventions and that the risks associated with overly aggressive resection and resultant scar are not worthwhile. Surgical treatment of distal airway papilloma is required to maintain or recreate distal airway patency where possible. Distal spread, however, is considered an indication for the initiation of adjuvant medical therapy.

In patients with tracheobronchial extension, adjuvant therapy is considered. There is no single adjuvant therapy that has proven to be effective across patients or disease processes. These therapies include intralesional and systemic antivirals (interferon, ribavirin, acyclovir, and cidofovir), photodynamic therapy, dietary supplements (indole-3-carbinol), celecoxib, retinoids, vaccines (mumps and HPV), as well as aggressive anti-reflux regimens (Derkay and Wiatrak 2008). Radiation therapy has also been used. Each of these therapies has proven some benefit in select patients but also forces the patient and caregiver to contend with some untoward side effects. Most patients with aggressive disease have been trialed on one or more of these therapies. Interferon has historically been the most commonly used adjuvant treatment. The introduction of the vaccinations against HPV has opened a new opportunity with a very low side effect profile. Some have shown a good response with increased interval between surgical treatments and even induced remission in some (Hallmo and Naess 1991). Most recently, there have been reports of good response to intralesional bevacizumab (Rogers et al. 2013) and a handful of patients treated with systemic bevacizumab (Mohr et al. 2014; Zur and Fox 2016) with very promising results.

Despite multiple small studies showing promise for intralesional and systemic cidofovir, the only blinded randomized trial by McMurray et al. was unable to show any significant improvement in outcomes with cidofovir, although administered at a low dose (McMurray et al. 2008). Additionally, concern has been raised about the potential for malignant transformation of RRP lesions in patients who have undergone treatment with cidofovir (Wemer et al. 2005).

Human papillomavirus initially infects the basal layer of epithelia through minor abrasions. The acquisition of HPV-related RRP is either through vertical transmission in juvenile-onset RRP (Sajan et al. 2010; Lee and Smith 2005; Venkatesan et al. 2012; Byrne et al. 1987; Gerein et al. 2007), or in adult-onset RRP, through mucosal-mucosal contact or reactivation of latent viral infection (Sajan et al. 2010; Lee and Smith 2005; Venkatesan et al. 2012).

In the upper layers of squamous epithelia, virions are produced, which are freed through normal desquamation processes, causing inflammation. The virus produces E6 and E7 proteins which are recognized as oncoproteins. These proteins inactivate interferon regulatory factor allowing HPV infection to remain persistent and asymptomatic. Viral genomes can replicate in an episomal or integrated manner. When viral genomes replicate episomally, as do most cases of HPV types 6 and 11, they show relatively low levels of E6 and E7 gene expression. In most cases with low levels of E6 and E7, infection resolves spontaneously by an effective immune system. However, when viral DNA is introduced into the host genome, in most cases, it often displays a strong expression of E6 and E7 genes. In these cases, carcinogenic transformation progresses rapidly. The E7 protein promotes cell division by binding pRb, while virus protein E6 binds and inhibits p53 protein which is active in repressing the cell cycle in case of DNA damage. This leads to prevention of apoptosis and cell cycle dysfunction (Mirghani et al. 2014; Lele et al. 2002). That increased expression of oncoproteins E6 and E7 is likely to occur in the progression of RRP to carcinoma is well understood. There are two mechanisms by which this could occur: (1) duplication of the upstream regulatory region in episomally active HPV which will result in increased expression of E6 and E7 (DiLorenzo et al. 1992) or (2) mutation in the upstream regulatory region or integration of HPV into the host cell genome with resultant increased expression of E6 and E7 oncoproteins (Kitasato et al. 1994).