Recurrent respiratory papillomatosis is a disease of viral etiology, caused by human papillomavirus (HPV) types 6 and 11, and is characterized by the proliferation of benign squamous papillomas within the aerodigestive tract.¹^–³ Although it is a benign disease, RRP has potentially fatal consequences because of its involvement of the airway and because of the risk, albeit low, of malignant conversion.⁴ In addition to the emotional burden to the patients and their families associated with the need for repeated surgery,⁵ the economic cost of this relatively rare chronic disease is high, having been estimated at $150 million annually.⁶

RRP is both the most common benign neoplasm of the larynx among children and the second most frequent cause of childhood hoarseness.⁷ The disease is often difficult to treat because of its tendency to recur and spread throughout the aerodigestive tract. Although it most often involves the larynx, RRP may involve the entire aerodigestive tract. The course of the disease is variable, with some patients experiencing spontaneous remission, whereas others may suffer from aggressive papillomatous growth and respiratory compromise, requiring multiple surgical procedures through many years.

RRP may have its clinical onset during either childhood or adulthood. It may affect people of any age, with the youngest patient identified at 1 day of life and the oldest at 84 years.⁶ Two distinct forms of RRP are generally recognized: a juvenile or aggressive form and an adult or less aggressive form. The aggressive form, although most prevalent in children, can also occur in adults. Children whose RRP was diagnosed at younger ages (younger than 3 years) have been found to be 3.6 times more likely to have more than four surgical procedures per year and almost two times more likely to have two or more anatomic sites affected than children whose RRP was diagnosed at older ages (older than 3 years).⁶ Similarly, children with disease progression are generally diagnosed at younger ages than those who remain stable or become disease-free.⁸^–¹⁰ In most pediatric series, the delay in diagnosis from the time of onset of symptoms averages about 1 year.^6,¹¹ In 75% of children with RRP, diagnosis was made before the fifth birthday.¹²

The true incidence and prevalence of RRP are uncertain. It is estimated that between 80 and 1500 new cases of childhood-onset RRP occur in the United States each year.^6,¹³ While the incidence among children in the United States is estimated at 4.3 per 100,000 children, the incidence among adults is 1.8 per 100,000.^6,¹⁴ These figures are comparable with those found in a Danish survey. In a subpopulation incorporating 50% of the population of that country, the rate among children was 3.62 per 100,000, whereas adult-onset cases occurred at a rate of 3.94 per 100,000.¹⁵ The National Registry of children with RRP, composed of the clinical practices at 22 pediatric otolaryngology sites, calculates a mean number of procedures at 19.7 per child with an average of 4.4 procedures per year.^6,¹⁴ Based on the incidence data, this translates into more than 10,000 surgical procedures annually for children with RRP in the United States.

Virology of Human Papillomavirus

HPV, belonging to the Papovaviridae family, is a small deoxyribonucleic acid (DNA)-containing, nonenveloped, icosahedral (20-sided), capsid virus with a double-stranded circular DNA of 7900 base-pairs long. HPV is epitheliotropic (infects epithelial cells). The HPVs have been grouped on the basis of shared genetic code homology, with viruses that share less than 90% identity in specific regions of the virus being defined as separate types. On this basis, the HPVs are numbered to distinguish them. Nearly 100 different HPV types have been identified. Grouping HPV types based on their DNA homology has allowed us to identify closely related types. Functionally, these groupings correlate with their tissue preference as well as similar pathophysiology.¹⁶ The HPVs are members of a large family of papillomaviruses that infect vertebrates ranging from birds to humans, causing epithelial neoplasms that can be benign or malignant. These viruses are designated by their natural host species (e.g., bovine papillomavirus, murine papillomavirus, and human papillomavirus). Each papillomavirus is specific for its host species, and this specificity is thought to be absolute. Within each species, similar types of papillomavirus exhibit specificity for epithelial tissues of different sites (e.g., oral mucosa, genital mucosa, or skin). In humans, this tissue specificity is less absolute, and some HPV types exhibit more of a preference for certain tissues.

Until the 1990s, HPV had been suspected but not confirmed as the causative agent in RRP. This uncertainty resulted from an inability to culture the virus in vitro and from the failure to demonstrate viral particles consistently in papilloma lesions using electron microscopy or HPV antibodies. With the advent of molecular probes, HPV DNA has been identified in virtually every papilloma lesion studied. The most common types identified in the airway are HPV 6 and HPV 11—the same types responsible for more than 90% of genital condylomata. Specific viral subtypes may be correlated with disease severity and clinical course. Children infected with HPV 11 appear to have a more obstructive airway course early in the disease and a greater likelihood of undergoing tracheotomy to maintain a safe airway.^10,¹⁷

In addition to the HPV group that includes HPV 6 and 11, two other major groups of HPV are associated with mucosal lesions in the aerodigestive and genital tracts. HPV 6 and 11, responsible for the majority of RRP, are members of a group believed to have a low malignant potential compared with some other groups. In contrast, the group that contains HPV 16 and HPV 18 is associated with malignancies in the genital and aerodigestive tracts.¹⁶ The group that contains HPV 31 and HPV 33 exhibits malignant potential that lies somewhere in between.

HPV is thought to infect stem cells within the basal layer of mucosa.^18,¹⁹ After infection of the stem cells, the viral DNA can either be actively expressed or it can exist as a latent infection in mucosa that remains clinically and histologically normal. To produce viral proteins or to replicate the virus, the viral DNA must somehow reactivate the host replication genes. The viral genome consists of three regions: an upstream regulatory region and the two regions named according to the phase of infection in which they are expressed—early (E) and late (L) regions. The E-region genes are involved in the replication of the viral genome, interaction with the host cell intermediate filaments, and transforming activities, and are potential oncogenes, depending on the HPV type. The L-region genes encode the viral structural proteins.²⁰^–²²

The induction of cellular proliferation is a fundamental property of HPV, although the mechanism of action remains unclear. We are slowly gathering information regarding the interaction of viral gene products with cellular proteins. For example, several of the viral E-region gene products have been shown to bind and inactivate certain cellular tumor-suppressor proteins.^21,²³ Conversely, HPV has been shown to activate the epidermal growth factor (EGF) receptor pathway, known to be associated with proliferation of epithelial cells.³ Thus there are likely several mechanisms by which HPV induces cellular proliferation in the aerodigestive mucosa.

Histologically, this mucosal proliferation results in multiple “fronds” or finger-like projections with a central fibrovascular core, covered by stratified squamous epithelium (Fig. 204-1).¹⁸ When papillomas are microscopic, they may assume a superficial-spreading configuration, with a velvety appearance (Fig. 204-2). When they exhibit a more macroscopic or exophytic growth pattern, they appear grossly as “cauliflower” projections (see Fig. 204-2). Papilloma lesions may be sessile or pedunculated and often occur in irregular exophytic clusters. Typically, the lesions are pinkish to white in coloration. Iatrogenic implantation of papilloma may be preventable by avoiding injury to nondiseased squamous or ciliated epithelium adjacent to areas of frank papilloma. Ciliated epithelium undergoes squamous metaplasia when exposed to repeated trauma and is replaced with nonciliated epithelium that creates an iatrogenic squamocellularly junction. This may also explain the observation that RRP flourishes in the presence of uncontrolled gastroesophageal reflux. Most RRPs do not exhibit dysplasia, abnormal mitoses, or hyperkeratosis.¹⁸ Without exception, RRP exhibits delayed maturation of the epithelium, resulting in significantly thickened basal cell layer and nucleated cells in the superficial layers.²⁴ This is thought to be in part because of the interaction of HPV gene products with the EGF receptor pathway.³ The sum result of these cellular effects is that, although HPV-infected cells do not rapidly divide, there is a disproportionate increase in the number of dividing basal cells. Thus expansion of the RRP tissue mass may occur very rapidly, because of the large number of dividing cells.¹⁹

Figure 204-1. Histopathology of human recurrent respiratory papillomatosis. Micrograph of laryngeal mucosa infected with human papillomavirus.

Figure 204-2. Gross appearance of respiratory papillomas during laryngoscopy. Appearance of massive, exophytic papillomatosis of the larynx.

During viral latency there is very little viral RNA expressed. Even so, HPV DNA can be detected in normal-appearing mucosa in RRP patients who have been in remission for years, and unknown stimuli can result in reactivation and clinical recurrence following years of remission.^25,²⁶ Thus activation of viral expression can occur any time after the establishment of latent infection. Gene products of early region gene E6, E7, and possibly E5 are required for papilloma induction, but the details of the mechanism of HPV activation are unknown. To “cure” RRP, it is necessary to modulate the host response to the virus and, ideally, eliminate latent infection.

It is likely that the host immune system plays an important role in the pathogenesis of HPV-induced lesions. Both the humoral and the cellular immune responses may be compromised in children with RRP, and the patient’s immunocompetence may be associated with the clinical course of the disease. The role of cytokines, such as interleukin-2, interleukin-4, and interleukin-10, and expression of the major histocompatibility complex (MHC) antigens in the dysfunction of the cell-mediated immune response in children with RRP has been demonstrated.^27,²⁸

Transmission

An association between cervical HPV infection in the mother and the incidence of RRP has been well established. However, the precise mode of transmission is still not clear.¹⁸ The universality of HPV in the lower genital tract rivals that of any other sexually transmitted disease in humans. It is estimated that at least one million cases of genital papillomas occur per year in the United States.²⁹ These are most commonly manifested as condylomata acuminata involving the cervix, vulva, or other anogenital sites in women or the penis of male sexual partners of affected women. Colposcopic (subclinical) changes are seen in about 4% of women, whereas DNA positive biopsies without a visible lesion are seen in 10% of women. HPV antibody positivity (without DNA or a clinical lesion) is estimated in 60% of women (81 million). HPV has been estimated to be present in the genital tract of as many as 25% of all women of child-bearing age worldwide. One study reported that the incidence of HPV infections in sexually active young college women is highest, with a cumulative incidence of 43% during a 36-month period.³⁰ Clinically apparent HPV infection has been noted in 1.5% to 5% of pregnant women in the United States.³¹ More than 30% of American women are currently infected with HPV with 7.5 million 14- to 24-year-olds currently infected and one fourth of women younger than 60 years of age infected at any given time.³² Up to 90% of lesions are undetectable clinically at 2 years. The highest prevalence is in women 20 to 24 years of age. More than 50% of women will initially acquire HPV within 4 years of their first sexual intercourse. As in RRP, HPV 6 and HPV 11 are the most common subtypes identified in cervical condylomata.

Vertical transmission occurring during delivery through an infected birth canal is presumed to be the major mode of transmitting the infection in children whereas in utero and transplacental transfer of HPV, sexual abuse, and direct contact are thought to play a minor role. The support for vertical transmission lies in the fact that overt maternal condyloma are seen in more than 50% of mothers who give birth to children with RRP.³³ The same subtypes (HPV 6 and 11) are involved, and cesarean delivery of children seems to be preventive to some extent.³⁴

Patients with childhood-onset RRP are more likely to be first born and vaginally delivered than are control patients of similar age.^35,³⁶ Kashima and others hypothesized that primigravid mothers are more likely to have a long second stage of labor and that the prolonged exposure to the virus leads to a higher risk of infection in the first-born child. They also suggested that newly acquired genital HPV lesions are more likely to shed virus than longstanding lesions, accounting for the higher incidence of papilloma disease observed among the offspring of young mothers of low socioeconomic status—the same group that is most likely to acquire sexually transmitted diseases such as HPV.^35,³⁶

Despite the close association between maternal condylomata and the development of RRP, only a small portion of children exposed to genital condylomata at birth actually go on to development of clinical RRP.³⁷ Although HPV could be recovered from the nasopharyngeal secretions of 30% of infants exposed to HPV in the birth canal, the number of infants expected to manifest evidence of RRP is only a small fraction of this population.³⁷ Clearly, other factors (patient immunity, timing, length and volume of virus exposure, local trauma) must be important determinants in the development of RRP. Even though cesarean section delivery would seem to reduce the risk of transmission of the disease, this procedure is associated with a higher morbidity and mortality for the mother and a much higher economic cost than elective vaginal delivery. Furthermore, reports of neonatal papillomatosis suggest that, in at least some cases, transmission may occur in utero.¹ However, with such a high rate of subclinical maternal HPV infection and such a low rate of actual new cases of childhood RRP, elective cesarean delivery as a means of preventing RRP is currently not practical or recommended.¹ The risk of a child contracting the disease from a mother who has an active genital condyloma lesion during vaginal delivery is only approximately 1 in 231 to 400.^22,^34,³⁶ The characteristics that distinguish this one child from the other 230 to 399 remain elusive. In summary, a better understanding of the risk factors associated with RRP is needed before the efficacy of cesarean delivery or other preventive measures can be fully assessed.

Prevention

The new quadrivalent HPV vaccine (Gardasil, Merck and Co., Inc.), is licensed and indicated for the prevention of cervical cancer, adenocarcinoma in situ, and intraepithelial neoplasia grades 1-3; vulvar and vaginal intraepithelial neoplasias grades 2-3; and genital warts associated with HPV 6, 11, 16, and 18. The CDC Advisory Committee on Immunization Practices (ACIP)³² has recommended vaccination for all girls ages 11 to 12, girls and women ages 13 to 26 who have not yet been vaccinated, and girls as young as age 9, in whom the physician believes it would be appropriate. Based upon the pivotal clinical studies, the vaccine is predicted to reduce the incidence, morbidity, and mortality of cervicovaginal HPV disease. An added and often overlooked benefit may be a concomitant decrease in the incidence of RRP and HPV-associated head and neck cancers.

The ability of the quadrivalent vaccine to prevent HPV 6/11/16/18-associated cervical and genital disease was established in the phase 3 FUTURE I and II trials, and their immunogenicity in the target group of vaccinees was established in immunogenicity bridging trials.³⁸ In FUTURE I, the quadrivalent vaccine was 100% effective in preventing cervical intraepithelial neoplasia (CIN) or worse, genital warts, and vulvovaginal neoplasia. In FUTURE II, the vaccine was 100% effective in preventing HPV 16/18-associated CIN. Both Future I and II were conducted in women in the age range at highest risk for HPV acquisition.^38,³⁹ However, it appears that the vaccine will be most effective if administered to individuals who have not yet become sexually active. Immunogenicity bridging studies were conducted to assess the immunogenicity of the vaccine in this population, and established that immunogenicity among younger girls was equal to if not superior to the response among 16- to 23-year-old women, suggesting that the quadrivalent HPV vaccine is immunogenic in this population and thus likely to be effective in preventing disease.⁴⁰ A separate study in 9- to 15-year-olds established that in this younger population immunogenicity lasts at least 18 months.⁴¹

There is also a bivalent HPV vaccine currently in phase 3 trials. This vaccine provides protection against HPV 16 and 18, but not 6 and 11.³⁸ Early phase 2 data for this vaccine suggest that it is 100% effective in preventing incident and persistent cervical HPV 16 and 18 infections in the according-to-protocol (ATP) sample, and 93% effective in preventing HPV 16- or 18-related disease in the intention-to-treat analysis; efficacy against disease was not presented for the ATP cohort. This vaccine’s efficacy against HPV 16 and 18 suggests that, like the quadrivalent vaccine, it may reduce the incidence of HPV-associated head and neck cancers. However, because the bivalent vaccine does not protect against HPV 6 and 11, it will not likely affect the vertical transmission of HPV 6 or 11 from mother to child.

Widespread use of the quadrivalent HPV vaccine promises to dramatically reduce the morbidity and mortality of cervical cancer and drastically reduce the incidence of genital warts. If the vaccine is as effective in preventing HPV infection of the oral cavity as of the cervix and genital tract, then, vaccination could be expected to reduce the incidence of HPV-associated oropharyngeal cancers by as much as 30%. In addition, a near-universal vaccination program providing the quadrivalent vaccine should all but eradicate RRP in future generations. Thus vaccination against HPV offers additional benefits above and beyond prevention of cervical cancers, some of which are unique to the quadrivalent vaccine.

Clinical Features

Inasmuch as the vocal fold is usually the first and predominant site of papilloma lesions, hoarseness is the principal presenting symptom in RRP.⁴² The child’s voice may be described as hoarse or weak from the time of birth. Particularly in very young children, changes in voice may go unnoticed. Stridor is often the second clinical symptom to develop, beginning as an inspiratory noise and becoming biphasic with progression of the disease. Less commonly, chronic cough, recurrent pneumonia, failure to thrive, dyspnea, dysphagia, or acute life-threatening events may be the presenting symptoms. The duration of symptoms before diagnosis varies. Not uncommonly, a mistaken diagnosis of asthma, croup, allergies, vocal nodules, or bronchitis is entertained before a definitive diagnosis is made. However, the initial presentation in infants, whose airway dimensions are small, may be with acute respiratory distress during an otherwise routine upper respiratory tract infection. The natural history of RRP is highly variable. After presentation, the disease may undergo spontaneous remission or persist in a stable state requiring only periodic surgical treatment. At the other extreme, RRP may become extremely aggressive, requiring frequent surgical treatment (every few days to weeks), prompting early institution of medical adjuvant therapy. A waxing-waning clinical course of remissions and exacerbations is common for RRP.

Because of the rarity of RRP and the slowly progressive nature of the disease, some cases may go unrecognized until respiratory distress results from papillomas obstructing the airway. The result is a relatively high need for tracheotomy to be performed in these children. Shapiro and others noted that RRP tracheotomy patients presented at a younger age and with more widespread disease, often involving the distal airway before tracheotomy.⁴³ In their experience with 13 patients, they did not believe that the tracheotomy itself led to spread of disease outside the larynx. In the CDC National RRP Registry, children with tracheotomy were initially diagnosed with RRP at a younger age (2.7 years) than those without a tracheotomy (3.9 years).¹⁴ Others have suggested that tracheotomy may activate or contribute to the spread of disease lower in the respiratory tract.⁴⁴ Cole and colleagues reported that tracheal papillomas developed in half of their tracheotomy patients and that, despite attempts to avoid this procedure, 21% of their patients still required a long-term tracheotomy.⁴⁵ Prolonged tracheotomy and the presence of subglottic papillomata at the time of tracheotomy have been associated with an increased risk of distal tracheal spread. Most authors agree that tracheotomy is a procedure to be avoided unless absolutely necessary. Interestingly, Boston and colleagues from Cincinnati noted successful laryngotracheal reconstruction in a series of children with subglottic stenosis and RRP.⁴⁶ When a tracheotomy is unavoidable, decannulation should be considered as soon as the disease is managed effectively with endoscopic techniques. Children with bronchopulmonary dysplasia who require prolonged endotracheal intubation may also be at increased risk for development of RRP.⁴⁷ Through interruption of the continuous respiratory mucosal surface, an endotracheal tube may have the same role in the mechanical dissemination-implantation of RRP as tracheotomy, as a risk for distal spread of disease. Several authors have noted an association between RRP caused by HPV 11 (as opposed to HPV 6) and distal spread of papilloma.¹⁰

Extralaryngeal spread of respiratory papillomata has been identified in approximately 30% of children and in 16% of adults with RRP.⁶ The most frequent sites of extralaryngeal spread were, in decreasing order of frequency, the oral cavity, trachea, and bronchi (Fig. 204-3).^6,⁴² Pulmonary papilloma lesions begin as asymptomatic noncalcified peripheral nodules.⁴⁸ These lesions eventually enlarge to undergo central cavitation and central liquefactive necrosis with air-fluid levels on a computed tomography scan (Fig. 204-4). These patients present clinically with recurrent bronchiectasis, pneumonia, and declining pulmonary status. The clinical course of the pulmonary spread of RRP is insidious and may progress through the years, but eventually manifests in respiratory failure because of destruction of lung parenchyma. For this reason, the finding of pulmonary lesions in a patient with RRP is a grave development with no currently available treatment modality that has shown more than anecdotal promise. Furthermore, pulmonary dissemination is anecdotally associated with a higher risk of malignant transformation of RRP.

Figure 204-3. Tracheal spread of recurrent respiratory papillomatosis. Note nodular, exophytic lesions in distal trachea.

Figure 204-4. Pulmonary spread of recurrent respiratory papillomatosis. Note lytic, cavitary lesions on computed tomography.

Malignant transformation of RRP into squamous cell carcinoma has been documented in several case reports. A total of 26 patients was identified as having progressed to squamous cell carcinoma in the task force survey.⁶ Dedo and Yu reported malignant transformation in 4 of 244 (1.6%) RRP patients treated during 2 decades.⁴⁹ When death occurs in a patient with RRP, it is usually as a complication of frequent surgical procedures or caused by respiratory failure because of distal disease progression. RRP presenting in the neonatal period is thought to be a negative prognostic factor, with a greater likelihood for mortality and need for tracheotomy.^8,⁹

Patient Assessment

History

Persistent or progressive stridor and dysphonia, with the possible development of respiratory distress, are the most consistent signs and symptoms of RRP in children (see the Practice Pathway Flow Chart, Fig. 204-5). In the absence of severe respiratory distress, a careful history should be obtained. Information regarding the time of onset of symptoms, possible airway trauma including a history of previous intubation, and characteristics of the cry are obviously important. Hoarseness, although a common and often benign clinical complaint in young children, always indicates some abnormality of structure or function. Because of the precision of laryngeal mechanics, hoarseness may result from a remarkably small lesion and thus be an early sign in the course of a disease process. On the other hand, if the lesion’s origin is remote from the vocal cords, hoarseness may present as a late sign. Although histologically the same lesion, a papilloma that produces hoarseness in one patient may produce stridor and obstruction in another, depending on the size and location of the lesion. The quality of the voice change may give only limited clues to its etiology, whereas other characteristics such as age of onset, rate of progression, associated infection, history of trauma or surgery, and the presence of respiratory or cardiac distress may be of much greater significance. A low-pitched, coarse, fluttering voice suggests a subglottic lesion, whereas a high-pitched, cracking voice; aphonia; or breathy voice suggests a glottic lesion. Associated high-pitched stridor also suggests a glottic or subglottic lesion. Although stridor that has been present since birth is more often associated with laryngomalacia, subglottic stenosis, vocal cord paralysis, or a vascular ring, it should be realized that neonates can also present with papillomatosis. Associated symptoms such as feeding difficulties, allergic symptoms, vocal abuse, and the presence of hereditary congenital anomalies may help distinguish RRP from alternative diagnoses, including vocal fold nodules, vocal fold paralysis, subglottic cysts, subglottic hemangioma, and subglottic stenosis. In the absence of any history suggesting these lesions, review of the perinatal period may reveal a history of maternal or paternal condylomata. If the onset of stridor and dysphonia is gradual and progressive through weeks or months, then neoplastic growth compromising the airway must be considered and investigated.