Recurrent respiratory papillomatosis: pathogenesis to treatment John H. Lee and Richard J. Smith

Purpose of review Introduction Recurrent respiratory papillomatosis remains a serious Recurrent respiratory papillomatosis (RRP) is a disease disease and is commonly treated by otolaryngologists. The process of the airways that affects persons of all ages goals of this review are to update physicians on current and is characterized by recurrent benign epithelial growths. understandings regarding viral pathogenesis, patient risks, The disease course can vary greatly between individuals. and current trends in treatment strategies. In many instances, spontaneous clearance occurs after Recent findings only a few surgical procedures. In other cases, however, Surgical debulking still remains the foundation of the continue to grow, spreading throughout treatment; however, newer surgical approaches the airway and ultimately affecting surgically inaccessible utilizing microdebriders are replacing laser ablation. and untreatable areas, where eventual degeneration to Genetic studies have identified individuals with specific squamous cell portends the death of these immune cell alleles to be at greater risk for persistent patients. In this paper, we summarize the epidemiologic infection. Our understanding of the viral pathogenesis risk factors, viral-related pathogenesis, immunologic risks, has increased by the identification of a viral mechanism and established treatment regimens for this debilitating to downregulate antigen expression in cells infected with disease. human papillomavirus, thus possibly allowing decreased immune detection. Although the viral types responsible for recurrent respiratory papillomatosis have been Epidemiology identified, the mechanism by which they alter cellular Papillomatosis of the human airway tract epithelia is a sig- growth has not been identified. Research studies nificant medical problem that has a prevalence rate of 3 to investigating adjuvant medical therapies aimed at 5 per 100 000 population and accounts for at least $123 reducing required surgical therapy intervals and million per year in medical expense [1–4]. The etiologic possibly helping cure the infection are being completed. agent, human papillomavirus (HPV) types 6 and 11, can A safe, effective adjuvant therapy is still currently not infect the entire , although the squamous– available. columnar junction of the is the most common site Summary of involvement [5]. Airway involvement by other subtypes Improved surgical approaches have slightly enhanced of HPV is very rare. Infection with HPV11 is more likely to patient care; however, more research is needed to be associated with the development of aggressive distal understand how human papillomavirus causes disease so disease than HPV6 [1,6,7]. Another factor associated with that these therapies can be developed. distal spread of disease is diagnosis prior to the age of three [3,8•]. Keywords laser ablation, microdebriders, papillomatosis, recurrence, Although RRP is very rare, exposure of the upper airway to respiratory, viral pathogenesis HPV6 or HPV11 happens frequently during life. In fact, it is likely that exposure of the upper airway to HPV6 or Curr Opin Otolaryngol Head Neck Surg 13:354——359. ª 2005 Lippincott Williams HPV11 may be as common as exposure to other & Wilkins. such as rhinovirus; studies have shown that HPV DNA

Department of Otolaryngology — Head and Neck Surgery, University of Iowa, can be detected in the upper airway of as many as 25% Iowa City, Iowa, USA of normal nonaffected children and adults [9,10]. This fre- quency of exposure compounds the difficulty in identify- Correspondence to John H Lee, Department of Otolaryngology-HNS, 200 Hawkins Drive, Iowa City, IA 52242, USA ing why some persons experience RRP but the majority do Tel: 319 356 2174; fax: 319 356 4547; e-mail: [email protected] not. For example, exposure of a neonate to HPV during

Current Opinion in Otolaryngology & Head and Neck Surgery 2005, vaginal delivery to a mother affected with condylomata 13:354——359 does occur [11,12]; however, the relative risk for the devel- Abbreviations opment of RRP is 7 in 1000, corresponding to an odds ratio HPV human papillomavirus of 231 compared with children born vaginally without IC3 indole-3-carbinol condylomata [13]. This low risk has fueled a debate over MHC major histocompatibility complex RRP recurrent respiratory papillomatosis whether cesarean section should be recommended in the presence of active condylomata, with some reports sug-

ª 2005 Lippincott Williams & Wilkins. gesting a higher rate of RRP in children delivered vaginally 1068-9508 [13] and others citing a statistically higher rate in children

354 Recurrent respiratory papillomatosis Lee and Smith 355 delivered by cesarean section [9,14]. For adult-onset RRP, Altered cell growth oral sexual practices have been associated with a slightly The mechanisms by which HPV produces a papillomatous higher risk for the development of papillomas [15] but growth are also poorly understood. In cells with high-risk have not been definitively implicated in disease patho- HPV16 genomes, the development of condylomata requires genesis. In general, given that the incidence of RRP is rare an alteration in cellular growth and differentiation. Two compared with the exposure risk to HPV6 or HPV11, key viral genes responsible for this change in growth and other factors must contribute to the development of per- differentiation are E6 and E7. These proteins bind to sistent papillomatous disease. and alter the function of two key apoptotic proteins, Rb and P53 [5,24,25]. The E6 and E7 from HPV6 and HPV11 do not readily degrade these key cellular genes Viral pathogenesis [26,27,28•], however, which implies that the mechanisms The has three vital components that cause human leading to altered growth in the airway are likely different. disease: (1) persistence causing a protracted disease course, (2) altered cellular growth resulting in airway papillomas, Significant data also suggest that the presence of HPV6 or and (3) viral reproduction allowing the disease to spread. HPV11 in airway epithelial cells is not sufficient alone to A clearer understanding of the factors that control viral induce papillomatous growth, because specimens genome persistence–associated cellular change and viral from normal mucosa of the distal airway and separate from reproduction in human airway is critical to sites of also contain HPV genomes [29,30•]. our understanding of disease pathogenesis and the devel- Several authors have hypothesized that the virus may opment of novel treatment options. remain in a latent state [29,30•], although the factors that activate papilloma growth in virus-infected normal cells remain unknown. Like the factors controlling viral replica- Viral genome replication, maintenance and production tion, the mechanisms required for altered cellular differ- To cause long-standing disease, the HPV genome must entiation by HPV6 or HPV11 in airway cells require more persist during host cell division. In most papillomas, persis- basic research so that mechanism-specific treatment strat- tence is achieved as an episome (extrachromosomal circular egies can be developed. HPV genome) [16,17•]. The maintenance and replication of this episomal genome under the nondifferentiating con- dition requires the expression of at least two early genes, Immune relationship E1 and E2. This vegetative state of reproduction is thought It is probable that most persons have been exposed to, or to represent the type of replication that occurs in nondif- infected with, low-risk HPV viruses. As with most viruses; ferentiated basal cells [18,19]. the disease course for each person varies. Most persons clear the virus exposure completely, but in some individ- Part of the mechanism of episomal maintenance has been uals the virus persists. In a fraction of this latter group, recently clarified. The viral gene E2 binds the becomes active and papillomas form. One possible genome to host chromosomal DNA so that it is segregated reason for viral persistence may be the inability to present and maintained during mitosis [20••]. When keratinocytes viral antigens in major histocompatibility complexes differentiate, the viral genome is amplified in the supra- (MHCs). Population studies have identified certain MHC basal cells by way of rolling-circle amplification that syn- alleles that are found in a higher percentage of RRP thesizes a sufficient quantity of viral genome for packaging patients than in the general population [31,32]. Despite [21,22]. This differentiation-dependent change in genome this association, however, HPV persistence requires more amplification has been linked to the expression of a late than a specific MHC allele, because many people with E1–E4 splice isoform. It has been hypothesized that cel- at-risk alleles do not develop disease. lular differentiation activates this late viral gene produc- tion, thus allowing assembly of virus [23]. Part of the answer may be related to the ability of HPV to downregulate the immune response. Recent work has Much of what is currently known about HPV has been shown that the low-risk HPV viral protein E7 interacts reported by the use of high-risk HPV16 and HPV31 in with TAP-1, resulting in a decrease in this protein in anogenital keratinocytes; the actual HPV6 or HPV11 the infected cell. Because TAP-1 plays an important role mechanism of replication, maintenance, and viral produc- in shuttling antigen from a proteasome to the endoplasmic tion in airway cells is largely unexplored. For instance, it is reticulum, where it assembles with the MHC, a decrease still unknown whether airway cells produce infectious in TAP-1 may make a cell more tolerant to HPV infection particles. More research focusing specifically on these [33]. These findings suggest that immune modulation is low-risk HPV types in airway cells is needed to determine likely to play a role in the ability of HPV to persist, although whether virus–airway cell interactions are similar to or this association also raises the question why so many peo- different from disease in the anogenital area. ple are able to clear the virus. 356 Pediatric otolaryngology

Surgical approaches the first 6 months of therapy [40,41]. Unfortunately, ces- No disease-specific definitive medical therapy exists for sation of therapy quickly resulted in disease relapse RRP; therefore, multiple palliative surgical procedures to pretherapy growth rates. In addition, significant side are required to remove the papillomas. Several principles affects were encountered with prolonged use [39•]. hold regarding papilloma removal. First, in contradistinc- tion to malignant lesions, with HPV, margins should not Indole-3-carbinol be obtained. Multiple studies have shown that HPV is Indole-3-carbinol (I3C) has been approved by the United present in the normal mucosa [9,10] and it is currently States Food and Drug Administration as a nutritional sup- not possible to distinguish infected cells with a normal plement; it is found in high concentrations in cruciferous appearance from unaffected epithelia. Second, although vegetables like broccoli, cabbage, and cauliflower. It alters pathologic confirmation of the diagnosis should be estab- estrogen metabolism by shifting the p450-dependent lished at the first resection, repeat biopsy is not indicated hydroxylation of estrone from 16 a-hydroxyestrone to with every procedure but should be obtained at defined 2-hydroxyestrone, which in turn alters cellular prolifera- intervals to evaluate for disease progression to . tion and DNA synthesis [42]. In animal models, 2-hydrox- Third, every attempt to maintain laryngeal function is cru- yestrone inhibits the estrogen-dependent growth of cial. This dictum may require leaving residual disease to tumors [43], and because the viral life cycle is intercon- prevent anterior or posterior web formation. Last, trache- nected with epithelial differentiation, several investiga- ostomy should be avoided because this procedure is asso- tors have hypothesized that I3C would decrease RRP ciated with a substantially increased risk of distal tracheal disease burden. spread [34,35]. Although several reports have shown that treatment with The techniques to remove papillomas have evolved over I3C may be beneficial, these studies were not prospective time. The use of the operating microscope first provided randomized placebo-controlled trials, and the potential improved functional outcomes for patients with RRP by efficacyofI3Cshouldbeviewedwithcaution[44•]. increasing visibility. With the advent of laser surgery, abla- Importantly, the supplement is safe and has virtually no tion of papillomas in a relatively blood-free field became side affects [44•]. Both the possible benefit and the mech- possible [36]. Today, a laryngeal and tracheal microde- anism of benefit for I3C need well-designed studies brider blade has replaced laser ablation as first-line surgical before it can be recommended as a true therapy for RRP therapy. This change reflects a safety perspective (there is patients. no risk of airway fire or inadvertent laser injury with the debrider), a cost perspective (the microdebrider is much less expensive to use because operating room time is Ideally, a drug that specifically targets the HPV genome decreased and fewer personnel are needed), and an out- for removal would cure RRP without causing concomitant come perspective (functional studies have shown improved cell damage to uninfected cells. Currently, a pharmaceu- functional outcome with the microdebrider in comparison tical inhibitor that is approved specifically for HPV infec- with the laser [37,38]). A recent survey of pediatric oto- tion is not available. Initial trials using the cytosine analog laryngologists showed that the majority have embraced cidofovir (1-[(S)-3-hydroxy-2 (phosphonomethoxy) propyl] this change [39•]. cytosine dihydrate) have been undertaken [45–49]. Cido- fovir has been approved by the United States Food and Drug Administration to treat retinitis in Adjuvant therapies AIDS patients. The mechanism of action for this drug Because of the rarity and clinical variability of RRP, prov- in cytomegalovirus is through selective inhibition of the ing efficacy for adjuvant therapies requires well-designed herpesvirus DNA polymerase [50]. In these cytomegalo- studies that are properly controlled. Unfortunately, most virus-infected cells, cidofovir inhibits herpes DNA poly- therapies that are used have not been rigorously tested merase at least two times more potently than human and are described only in small series or as anecdotal case DNA polymerase, thus leading to selective inhibition of reports without proper controls. viral replication [50]. HPV does not encode a viral poly- merase, however; instead, it uses host cell DNA polymer- ase to replicate the viral genome. This constraint means a- that the mechanism of action of cidofovir in HPV cells The use of a-interferon has been the most extensively cannot be selective inhibition of a viral polymerase. Nev- investigated adjuvant therapy for RRP. a-Interferon has ertheless, an initial trial of cidofovir for treatment of pap- the theoretic benefits of modulating both the immune illoma formation in the cottontail rabbit papillomavirus system and epithelial development. The results of a double- model showed promising inhibition of papilloma growth blinded placebo-controlled study for RRP showed a dose- [51]. Initial reports in small noncontrolled clinical studies dependent decrease in severity for papilloma growth over have also suggested some usefulness [47,48,52]. Recurrent respiratory papillomatosis Lee and Smith 357

The utility of this cytosine analog in the treatment of properly controlled studies aimed at testing efficacy and HPV-infected cells in vitro has been evaluated. Both trans- safety. formed cells and cancer cells containing integrated HPV have shown preferential growth inhibition with cidofovir in comparison with non-HPV cancer cells. These studies Recent vaccination trials investigating the persistence of suggest a selective method of cidofovir-mediated toxicity HPV16 in cervical cells has suggested that immuniza- when cell death in immortalized HPV-positive cells is tion with viral coat proteins can protect against infection compared with that in either HPV-negative immortalized [65••–67••]. These breakthrough studies suggest that HPV16 cells or primary keratinocytes [53–55]. These studies, diseases can be prevented with immunization. Although however, did not attempt to correlate cell replication rates this approach is promising for prevention, its feasibility to cidofovir toxicity. Recent work has made an attempt for use with established HPV disease is untested. Many to understand a mechanism of action for cidofovir in questions remain before immunization strategies can be HPV-containing cells [56••]. It has been shown that determined to be helpful for RRP. For example, differ- cidofovir is incorporated into episomal DNA at a slightly ences between RRP and cervical HPV disease include higher rate than genomic DNA, and cidofovir may slightly age at exposure, viral type, and disease progression, all inhibit viral genome replicationincomparisonwith issues that must be considered when an immunization human genome replication. Replication of the viral strategy for RRP is designed and planned. genome quickly returns to baseline after drug removal, however. In a recent multi-institution study using a vaccination strategy to develop an immune response to established The transient nature of this inhibition suggests that any RRP disease [68], participants were vaccinated with an clinical application aimed at inhibition of viral genome immune modulating heat shock protein linked to the replication using cidofovir would require prolonged expo- E7 protein of HPV16. In preclinical mouse models, similar sure and frequent administration; thus, the potential strategies were able to eradicate established diseases in for carcinogenic side effects would be increased. Recent mice by improving cellular and humoral immunity to viral studies [56••] have shown that papilloma cells were more antigens, thus allowing mice to clear viral-infected cells sensitive to cidofovir than normal cells; however, the [69–71]. In the human trial, 27 RRP patients received mechanism was related to incorporation during rapid three sequential injections with 500 mcg of HPV-E7 pro- cell turnover rather than by way of an HPV-selective tein, with an observed increase in surgical intervention mechanism. Like all cytosine analogs, cidofovir primarily time and safety. As with most therapies aimed at RRP, blocks DNA replication through incorporation into the however, the response varied on an individual basis: two genome, thus preferentially targeting rapidly dividing persons required no further therapy after the vaccination, cells. Multiple rapidly dividing cell lines derived from and approximately 40% of patients had at least one surgi- not related HPV infection have been shown to cal intervention lengthened [2]. No severe adverse reac- be sensitive to the cytotoxic effects of cidofovir, such tions were encountered. as B16 , hemangiosarcoma, and nasopharyn- geal carcinoma [57–60]. Therefore, it is likely that cido- This strategy warrants further study, including a study fovir kills papilloma cells more effectively than normal design with a placebo–control arm and the creation of a cells in the surgical wound because the papilloma vaccine composed of heat shock protein linked to the viral cells are dividing more rapidly and are susceptible to proteins of HPV6 and HPV11. Although HPV16 E7 pro- cidofovir. tein has some similarity (;40%) with the HPV6 or HPV11 protein and antigen crossover may occur, using the correct Clinical therapy of cidofovir to induce non-HPV-specific antigen would more likely give a stronger and more spe- cell death in the more rapidly dividing cells of a papilloma cific response. As stated earlier, it is likely that the HPV may have clinical utility; however, multiple studies have virus decreases antigen presentation; therefore, immune- challenged the safety of using this compound. Prolonged enhancing strategies such as these hold great promise therapy has identified several potential adverse effects, for the treatment of established RRP. including renal toxicity [61–63] and developed in rats that were given the equivalent human Conclusion dose over 26 weeks [63]. Besides these in-vivo results, Recurrent respiratory papillomatosis is a that several in-vitro assays have predicted that cidofovir is a carries severe morbidity and occasional mortality. Improve- carcinogen [64]. Possible additional carcinogenic effects ments in surgical approaches have slightly improved the in HPV-containing cells, lacking normal p53 and pRb, have overall care of these patients; however, cure is possible not been investigated. Prior to noninvestigational use, only with disease-specific medical therapy. To that end, cidofovir needs further studies aimed at elucidating a more research is needed to understand how HPV causes potential mechanism of cell death specific to HPV and disease so that these therapies can be developed. 358 Pediatric otolaryngology

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