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Review

Recurrent Respiratory Papillomatosis

Alkotob, M. Luay MD; Budev, Marie M. DO, MPH*; Mehta, Atul C. MD, FCCP, FACP*

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Abstract

Recurrent respiratory papillomatosis (RRP) was initially described in early 17th century medical essays as a colorful clinical entity of “warts in the throat.” 1 It was not until almost a century later that laryngeal papillomatosis was differentiated from other laryngeal masses and termed “papilloma.” 2 Today, RRP has evolved to become the most common benign neoplasm of the larynx and the most common tumor of the upper respiratory tract in children. 3 Although more commonly thought of as a pediatric disease, RRP has as common a propensity for the adult population. It is now well established that RRP is caused by human papillomavirus (HPV) subtypes 6 and 11, which are responsible for the exophytic growths associated with the disease. 4,5 RRP classically presents with laryngeal involvement with the true vocal cords being the most commonly affected (Fig. 1). Notoriously difficult to cure, RRP often recurs and could spread throughout the entire respiratory tract extending into the trachea, the bronchi, and lung parenchyma. The natural history of RRP could include, for some fortunate individuals, a spontaneous remission, but many others have multiple recurrent episodes necessitating extensive surgical procedures to maintain airway patency or to prevent permanent hoarseness. 5 Although considered a benign histologic entity, RRP has the potential for significant morbidity and mortality because if its unpredictable clinical course and potential, although rare, for malignant conversion. 6,7

FIGURE 1.
FIGURE 1.:
Papillomas of the larynx. Note the “bunch of grapes” appearance.

Medical expenditure related to RRP exceed $100 million per year alone with over 15,000 surgical interventions performed annually for RRP. 8 Surgery, although not curative, remains a mainstay in symptomatic relief. Although eradication of HPV is not yet possible, recent promising therapies, including less destructive surgical interventions, and selective immune-enhancing and antiviral treatments, have emerged to help clinicians deal with this devastating disorder.

EPIDEMIOLOGY

Recurrent respiratory papillomatosis can affect patients of virtually any age. The youngest patient afflicted with RPR was diagnosed at the age of 1 day and the oldest at 84 years. 8 The clinical onset of RRP can be either during childhood or adulthood with the age of onset having significant implications on the clinical course of the disease Adult-onset RRP, in general, is less aggressive and more likely to go into remission. In contrast, juvenile-onset RRP usually is more aggressive and recurs with multiple lesions, whereas adult-onset RRP lesions are usually singular and less likely to recur after therapy. Childhood RRP is frequently diagnosed more commonly between the ages of 2 and 4 years with a delay in diagnosis from the time of symptoms onset of approximately 1 year. 7 Both males and females are equally affected with childhood-onset RRP. Children diagnosed with RRP before the age of 3 are more than 3.6 times as likely to have greater than 4 surgical interventions a year and 2 times more likely to have multiple affected anatomic sites in contrast to children diagnosed at an older age. 4 Therefore, an earlier age of diagnosis of RRP seems to be a harbinger of a more destructive disease course. 6 Anecdotal reports seem to indicate that most patients are born to young, first-time mothers from a lower socioeconomic status. 8 Males and females are affected equally with childhood disease, and gender does not seem to have a bearing on disease or surgical outcomes.

Adult-onset RRP usually presents between the third and fifth decade of life with a slight predilection for the male gender. Adult-onset RRP is usually less aggressive than the childhood form of the disease. However, an aggressive form of the disease could also occur in adults with RRP (defined as disease necessitating a cumulative average of more than 40 airway procedures in a lifetime). 9 Approximately equal numbers of adults and children seem to have an aggressive form of RRP (17% of children vs. 19% of adults). 8

The overall true incidence and prevalence of RRP is relatively uncertain. In a Danish population-based study, the incidence of laryngeal papillomatosis averaged approximately 3.84 cases per 100,000 individuals with the rate among children of 3.62 per 100,000 individuals and in adults a slightly higher rate of 3.94 per 100,000 individuals. 10 In the United States, according to the Recurrent Respiratory Papillomatosis Foundation, it is estimated that the incidence in the pediatric population is approximately 4.3 cases per 100,000 children and 1.8 per 100,000 adults with over 2300 newly diagnosed cases per year. 11 These numbers translate into over 20,000 currently active cases of RPR in the United States. 11

ETIOLOGY

In the early 1920s, Ulmann first suggested that RRP was the result of an infectious etiology. Following Cook's postulate, Ulmann injected homogenized papillomata taken from a child's larynx into his own forearm and subsequently had an outbreak of wart-like lesions grow 90 days later at the site of his original injection. 12 It was not until the 1990s that HPV was confirmed as the causative agent in RRP. It had been suspected that RRP was likely to be viral in origin but technology prior to the 1990s did not allow for culturing the virus in vitro and persistently failed to demonstrate the presence of viral particles within papilloma particles by electron microscopy or HPV antibodies. With advances in molecular biology, researchers were able to isolate HPV from papilloma tissue and in addition have the ability to determine different viral subtyping. The most common viral subtypes isolated from RRP samples are HPV 6 and 11, which are the same viral subtypes responsible for genital warts. 13,14 Initial evidence for this was found by electron microscopy, immunocytochemistry, and by Southern blot technique. Recently, in situ hybridization and polymerase chain reaction techniques have established the presence of HPV type 6 and 11 in RPR. 8 Initially, it was believed that papillomas resulting from HPV 11 had a tendency to cause a more aggressive disease course than HPV 6. 4,15 Children with HPV 11-induced disease appeared to have a more obstructive airway course and required tracheostomy earlier. 4 However, the relationship between HPV subtyping and disease severity still remains controversial. 16

A clear association between maternal cervical HPV infection and the incidence of childhood RRP exists. 17,18 Mothers with active genital HPV or latent infection are most likely to transmit the infection to newborns during vertical transmission through the birth canal. Strong et al. demonstrated that 50% of patients younger than age 5 years were born to mothers with active genital condyloma at the time of delivery. 19 It has been demonstrated that HPV viral shedding is highest during the later stages of pregnancy and in newly formed lesions. 20 Kahima and coworkers described a predisposing triad consisting of first-born, vaginally delivered children to primigravid young mothers. The authors described the prolonged labor of primigravid mothers significantly contributing to the prolonged virus exposure and subsequent higher risk of HPV infection in the newborn. 10 Overall, the estimated risk rate of transmission in mothers with active viral condylomata is thought to be approximately 1 in 400 vaginal births. 21 Evidence of HPV had been in found in up to 25% of all women of childbearing age. In fact, 30% of infants exposed to HPV by vertical transmission demonstrate evidence of HPV in nasopharyngeal secretions. However, it is important to note that although genital warts are central to the transmission and actual development of RRP, the development of clinical RRP is rare in general, possibly indicating that other factors might have to be present to acquire clinically active respiratory disease, including genetic defects, infant immunologic profile, timing, viral load and time of exposure, as well as local trauma during vertical transmission. 22 The use of cesarean section to avoid vertical transmission does seem to reduce the risk but is associated with higher morbidity and mortality and economic costs compared with vaginal delivery. Development of RRP is rare in vitro, although a few isolated reports do exist. 23 The presence of paternal genital condyloma and RRP has not been studied as yet.

The etiology of adult-onset RRP most likely represents either reactivation of a virus present since birth or infection acquired during adolescence or adult life in the form of a sexually transmitted disease. 8 Adult-onset RRP is reported in a larger number of lifetime sexual partners and a higher incidence of sexual practices involving oral sex compared with healthy control subjects. 8 Oral secretions from adults with RRP are not considered infectious to spouses or household members. 6

HISTOLOGY

Human papilloma virus is a nonenveloped, icosahedral capsid virus containing double-stranded DNA. The pathogenic mechanism of airway HPV and genital HPV is similar. The virus invades and establishes itself with the basal layer of squamous epithelium. 24 Viral replication with the epithelial cells causes production of abnormal cells. In addition, viral DNA is also present within morphologic normal tissue adjacent to papillomata, possibly providing the reason for the frequent recurrence of lesions after ablation. 25 Latency of the virus appears to be the key determinate of recurrence of this disease. Therefore, attempts at curing RRP will rely on eliminating this latency period and not just the mechanical removal of papillomata.

Grossly, papillomas appear as flesh-colored, pedunculated, exophytic lesions that are often found at anatomic borders where there is juxtaposition of ciliated and stratified squamous epithelium. 26 Anatomic areas of predilection include the limen vestibuli of the nose, the nasopharyngeal area of the soft palate, midline of the epiglottis, and margins of the larynx and undersurface of the vocal cords and false cords, the carina, and upper trachea, especially tracheostomy sites. Distal tracheal spread of RRP reportedly occurs in 15% to 26% of juvenile-onset RRP patients and 25% of adults with RRP 9 (Fig. 2). Approximately 1% to 5% patients with RRP will have the presence of bronchopulmonary RRP with evidence of pneumatoceles and parenchymal masses (Figs. 3 and 4). Pneumatoceles are cystic foci in the lung usually resulting from necrosis of the bronchopulmonary tissue during infection resulting in an air-filled cystic space as a result of obstruction of the distal airways. High expiratory pressures resulting from proximal airway obstruction is thought to be the underlying cause for the formation of these cystic lesions. 27

FIGURE 2.
FIGURE 2.:
Papillomas involving the trachea. Note the “mulberry” appearance
FIGURE 3.
FIGURE 3.:
Chest x-ray revealing bilateral multiple pulmonary parenchymal nodules resulting from distal airway papillomatosis.
FIGURE 4.
FIGURE 4.:
Computed tomography scan of the chest revealing cystic lesions of papillomatosis involving the lung parenchyma bilaterally.

Light microscopy of RRP lesions demonstrate finger-like projections of stratified squamous epithelium overlying a vascular connective tissue stroma (Fig. 5). Basal hyperplasia, koilocytosis, and varying degrees of cellular dysplasia could be present. The degree of atypia could be associated with pre-malignant tendency. Abnormal keratinization could be part of the abnormal proliferative process, but any evidence of intra-epithelial keratin pearls could indicate the possibility of squamous carcinoma 6 (Fig. 6).

FIGURE 5.
FIGURE 5.:
Squamous papillomas with hyperplastic squamous mucosa surrounding a fibrovascular core. The squamous epithelial cells have an organized pattern with only mild cytologic atypia and a focal area of koilocytosis (20×, hematoxylin and eosin stain).
FIGURE 6.
FIGURE 6.:
Squamous papilloma with carcinoma in situ. The nuclei have high-grade features with a disorganized pattern, marked atypia, and numerous mitoses (200×, hematoxylin and eosin stain).

Although RRP has been thought to be a benign entity, malignant degeneration in approximately 3% of cases has been described in both children and adults. Smoking and radiation exposure have been noted to be significant risk factors contributing to malignant transformation. 28,29 One study found that irradiated patients have a 16-fold increased risk of subsequent carcinoma of the respiratory system. 30 Rady and coworkers found the presence of a mutation in the p53 suppressor gene and HPV 11 DNA in malignant lesions. 31 In general, malignant transformation appears to be associated more commonly with HPV 16, a rare cause of RRP, but has also been linked with HPV 6 infections.32 Although malignant transformation is rare, careful clinical and histologic detection for atypia is paramount. If advancing degrees of atypia are found, closer observation and further workup is mandated.

CLINICAL PRESENTATION

The initial disease presentation and subsequent clinical course in adult RRP compared with childhood-onset RRP is markedly different. Adults almost always present with dysphonia or lesions of the oral cavity or nasal vestibule that could have been incidentally discovered. Although the disease can be aggressive in adults, the majority of patients with adult-onset RRP will have a limited number of complications as a result of their disease. In 1 study of 24 adult RRP patients, only 4 patients, the majority of whom had onset of their disease before the age of 15 years, reported over 100 disease recurrences. 33

In children, RRP is the second most common cause of hoarseness. However, in young children, this change in voice could go unnoticed. The second clinical symptom to develop after dysphonia is stridor, which could begin during inspiration and progress to include both inspiratory and expiratory components of the respiratory cycle as the disease progresses. Other clinical manifestations of childhood RRP include chronic cough, recurrent postobstructive pneumonia, failure to thrive, worsening dyspnea, and acute respiratory failure, which could infrequently be the initial presentation of RRP. Often, children with RRP are misdiagnosed with asthma or croup initially. The average duration of symptoms until time of diagnosis ranges from 1 to 8 years. 10 Overall, RRP follows a slow, progressive course, further delaying the diagnosis in children until respiratory distress ensues as a result of obstruction of the major airways. As a result, tracheotomy could be the only option for these children. In 1 study, investigators found a relatively high need for tracheotomy in patients who were younger and presented with widespread disease, including involvement of the distal airways. In this same study, the investigators did not find any evidence that tracheotomy contributed to the spread of RRP to structures outside the larynx. 34 Significant controversy exists surrounding the role of tracheotomy and activation of disease and spreading of disease to the lower tract. Cole and coworkers found that tracheal papillomata developed in over half their tracheotomy patients and in fact, despite attempts to try to avoid this procedure, over 21% of patients in the study needed long-term tracheotomy. 35 Currently, most experts have agreed that tracheotomy is a procedure that should be considered only if absolutely necessary and also advocate early decannulation to limit disease spread. Gastroesophageal reflux disease has also been found to be a potential risk factor for RRP recurrence, although evidence is limited. 36

The spread of RRP beyond the larynx occurs in approximately 30% of children and 16% of adults with the most frequent sites of involvement being the oral cavity, trachea, and bronchi. 8,37 Tracheal extension has been observed more often in cases with subglottic papillomas, patients with tracheotomy, and in patients with a history of frequent surgical resections. 38 Recurrent respiratory papillomatosis has been described as well in immunodeficient patients and in various immunosuppressed states. 9 Death in patients with RRP is usually linked with a complication of frequent interventions or caused by respiratory failure as a result of progression of distal disease.

HISTORY

The presence of stridor or hoarseness in children and the presence of dysphonia in adults are the most common signs and symptoms of RRP. Respiratory failure is more likely in childhood disease before disease diagnosis. A complete history should be obtained during evaluation regarding prior intubation, trauma to the airway, changes in crying, and history of maternal HPV infection. In cases in which respiratory failure ensues, or tachypnea, failure to thrive, or recurrent pneumonia are issues, the larynx should be inspected. Adult-onset RRP could have a variable presentation. Often, patients will incidentally discover an asymptomatic papilloma in their mouth or nose. Change in voice or dysphonia is the most common presenting symptom. Factor, including childhood intubation and an airway trauma history as well as use of tobacco should be obtained.

PHYSICAL EXAMINATION

The respiratory status of the patient is the first step in evaluation, especially in cases of juvenile-onset RRP. If respiratory distress is an issue, laryngeal examination should be performed in the controlled setting of an operating room. Auscultation of the chest could provide some clues regarding the site of obstruction. Pulse oximetry could also provide further information regarding oxygenation status of the patient. Adult patients presenting with nonemergent symptoms warrant a complete head and neck examination, including fiberoptic evaluation of the larynx. The diagnosis of RRP can be easily suspected from its characteristic “mulberry” or “bunch of grapes” appearance (Fig. 7). Biopsy should be performed for histologic confirmation and to rule out evidence of malignancy, although controversy does exist among clinicians regarding the need to send a tissue biopsy with each papilloma surgery. It is recommended that a biopsy specimen be sent at the time of diagnosis of RRP. Therefore, HPV typing could be performed at the initial diagnosis and could have some value in predicting prognosis. Documentation and consistent staging and severity scale should be documented at each procedure to follow the progression of the disease. A computerized tracking system on CD-ROM can simplify this procedure by standardizing the nomenclature for the description of RRP and could aid in physician-to-physician communication. Fiberoptic examination might need to be performed frequently initially every 2 to 4 weeks or if the patient's symptoms recur. Once the patient has reached a plateau in their clinical status, treatment and further interventions are dictated by changes in this plateau.

FIGURE 7.
FIGURE 7.:
A large number of papillomas removed using a Nd:YAG laser and biopsy excision.

TREATMENT

Multiple modalities have been attempted in the treatment of RRP in attempts to cure the disease. There is no cure for RRP and HPV eradication is still not possible, although remission of disease can occur in a few cases. Although surgical therapy remains the mainstay of therapy, new developments in medical therapy, including selective antiviral therapy and immune-enhancing therapies, could provide another option in the treatment of RRP.

Surgical management of RRP involves surgical removal of symptomatic papillomas with preservation of the normal airway as much as possible in an effort to avoid excessive scarring of the airways and vocal cords. The aim of surgery is to relieve obstruction of the airway, alleviate vocal cord disease burden and airway tumor burden, and possibly promote remission. Because one definitive procedure does not exist for the complete eradication of HPV, it might be justifiable to accept some residual papilloma rather than risk further damage to the airway and produce extensive scarring. In the past, sharp dissection using cup forceps and podofillinum was the preferred method of surgical therapy. 39 Today, carbon dioxide (CO2) laser is the preferred method of papilloma removal from the oral and nasal cavities, larynx, and upper trachea. The CO2 laser allows for the application of a thermal burn to the base of the papilloma while also cauterizing tissue surfaces and minimizing bleeding. In addition, the CO2 laser minimizes other potential complications, including airway stenosis, airway perforation, pneumothorax, pneumonia, and airway fire. 40 Other lasers, including the argon, neodynium:yttrium aluminum garnet, and potassium titanyl phosphate laser, have also been used to remove papillomas. 6 These alternative methods do not seem to offer an advantage in achieving disease remission. Criticism of the CO2 laser includes causing diffuse thermal damage to the tissues that surround treated papillomas. The 585-nm pulse dye laser (PDL) transmits radiation through a standard silica optical fiber and usually confines damage to the walls of the papilloma being treated within the microvessels and nearby perivascular space, providing less surrounding trauma in comparison to the CO2 laser.41 The PDL should be considered a palliative therapy for HPV because the virus continues to stay latent in the surrounding normal tissue. However, overall, PDL could cause less scarring, and be safer and less costly than CO2 laser. Further research is being performed with PDL and RRP treatment.42 In addition, appropriate safety precaution should be used when treating RRP with laser therapy because HPV genomic DNA has been identified in the laser plume.14 Anesthetic techniques to consider for laser laryngoscopy include the use of specialized laser endotracheal tubes to reduce the risk of airway fire. In addition, consideration should be given to the use of apneic anesthesia and the minimal use of jet ventilation resulting from the potential risk for distal spread of disease. For distal disease, rigid bronchoscopy might be needed for access for treatment of more distal lesions by laser therapy.

The CO2 laser intervention is usually repeated for recurrent disease. However, measures including phonomicrosurgery, submucosal infusion, and microinstrumentation including microdebriders with miniaturized shavers should be considered to limit airway and vocal cord scarring in adults with RRP and are currently the preferred method of therapy for many clinicians. Zeitels and coworkers reported complete remission of RRP in 6 adults treated with these methods followed for 2 years after primary resection. 43 Microdebriders have the advantage of providing rapid, effective therapy for RRP with minor bleeding and can be used with a telescope with or without an endotracheal tube present. Photodynamic therapy with the use of photosensitive dyes like dihematoporphyrin (DHE), which localize in hyperplastic HPV-infected tissue versus surrounding normal tissue, can be used in the treatment of RRP. When DHE is activated by argon laser light at 630 nm, its cytotoxic properties cause tissue destruction and death. In a recent study, patients with advanced RRP showed the greatest response to photodynamic therapy in a dose-dependent manner. 44 Patients are usually treated with 4.25 mg/kg DHE before photoactivation is started with the argon pump dye laser. Drawbacks of therapy include marked photosensitivity in patients for a period of 2 to 8 weeks that can significantly limit daily activity. 45 It is important to remember that the upper digestive tract should always be examined for lesions as well.

Approximately 10% of patients with RRP will require adjuvant therapy as a result of failure to surgically control the disease. 8 Criteria to consider adjuvant therapy should be individualized and based on the need for more than 4 surgical procedures per year, distal multifocal disease, and rapid regrowth of papillomata leading to airway compromise. In addition, children who present with tracheal disease should be considered for adjuvant therapy. The choice of adjuvant therapy depends on informed consent and current evidence-based research. It is important to enroll patients in clinical studies whenever feasible when considering newer treatment options. The most common adjuvant therapy are the recombinant α-interferons, which were a group of proteins produced by the leukocytes with nonspecific antiviral activity that are now produced using recombinant DNA techniques. Since 1981, interferon has been demonstrated in several large randomized and nonrandomized trials as an effective therapy for this disease, but 46 α-interferons are mainly indicated for treatment of advanced cases of RRP and in children with obstructive disease resulting from RRP. Viral eradication does not occur with α-interferon use, and relapse could occur after therapy is discontinued or even after extended periods of use. 47,48 Treatment is initiated at 3 to 5 million units per square meter of body surface area subcutaneously daily for 28 days and then 3 days per week for a total of 6 months of therapy. Depending on the clinical response, treatment dosages could be reduced with slow weaning of the medication. Side effects of interferon therapy include acute reactions, including fever and flu-like symptoms, and additionally chronic reactions, including stunted growth in children, elevated transaminases, and leukopenia. Modified interferon combinations, including peglylated interferon (polyethylene glycol linked interferon) and the use of intralesionally injected interferon, are also undergoing further investigation at the present time. 49

Cidofovir or (s) −1-(3 hydroxy-2-phosphonylmehtoxy-propyl) cytosine (HPMPC) is the leader in a new class of acyclic phosphate analogs with an extensive antiviral range of activity, including HPV. 50 Cidofovir is designed to be injected into the papilloma bed after debulking surgery. Cidofovir reduces papillomata without residual scarring or fibrosis. Snoeck et al. reported in a study of 14 patients with severe RRP who were treated with 2.5 mg/mL cidofovir intrapapilloma injections after laser surgery experienced a complete response to therapy. 51 Other investigators have reported similar remission outcomes 18 to 22 months after treatment in pediatric populations treated with similar doses of cidofavir. 52 The exact dosing of cidofovir is uncertain and debatable in many studies as a result of leakage at the injection site. Chhetri and coworkers recently published a study in which intralesional 1 mg/kg cidofovir every 2 weeks for 4 treatments and then every 3 weeks for another 4 treatments with concomitant laser ablations for bulky lesions provided successful long-term management of juvenile RRP. 53 Most recently, Naiman and coworkers found that cidofovir therapy had a greater response in the supraglottis and glottis subsite use than in subglottis, tracheal, or other sites. No patients in this study presented with side effects of therapy on 5 mg/mL cidofovir intralesional injection dose. 54 The mechanism of action of cidofovir against HPV is still unclear. 55 Nephrotoxicity is dose-dependent and can be treated with concomitant administration of oral probenecid, intravenous fluids, changing dosing intervals, and early discontinuation of cidofovir. 56

Indole-3-carbinol (I3C), a nutritional supplement derived from cruciferous vegetables, has been shown to alter the growth of papilloma in mice by altering estrogen metabolism through induction of the cytochrome P450 metabolism of estrogen and 2- hydroxylation of estrodiol. 57 The recommended dosage of medication is 200 to 400 mg per day for adults and 100 to 200 mg per day for children under 20 kg. Initial phase 1 trials of indole 3 carbinol for RRP showed a 33% complete response and 33% partial response rate using a condensed pure form of I3C. 58

The retinoids are derivatives of vitamin A that have the ability to inhibit epithelial cell proliferation and subsequently limit growth and differentiation of these cells. Cis-retinoic acid (isotretinoin) has been used in patients with RRP with limited results. 59,60 Combination therapy with α-interferon could be synergistic and an option in patients with severe RRP. 61 Gastroesophageal reflux disease could promote papilloma growth through inflammation. Borkowski and coworkers found a decrease in papilloma recurrence rate in a small population of patients treated for reflux. 36 Harcort and coworkers found that cimetidine, a histamine-2 receptor antagonist, could have an immunomodulatory effect that could have led to improvement in tracheobronchial disease in 1 series. 62

HspE7, a recombinant fusion protein of Hsp65 form M. bovis BCG and E7 protein from HPV-18, has currently completed a phase 3 trial in the treatment of RRP. A recent multi-center trial studied 27 patients with RRP who initially underwent laser debulking surgery, and then treatment with 500 μg HspE7 subcutaneously monthly for 3 months found that the majority of patients experienced a statistically significant decrease in the number of posttreatment surgeries needed to control RRP. 63 A recent case series by Pashley demonstrated the use of intralesional mumps vaccination injection in addition to serial laser excision therapy resulting in a remission rate of 77% of 49 adult and pediatric patients with RPR. 64 This limited case series does not establish the cause and effect relation of an intervention, and further, more rigorous research designs should be used to further study the potential of this treatment.65,66

In addition to surgical and adjunctive therapy for RRP, speech and language therapy should be offered early in the course of disease to preserve phonation. Families should be encouraged to engage in frank and open discussions of this challenging and often frustrating disease entity and should be offered further support through resources such as the Recurrent Respiratory Papilloma Foundation (609-530-1443). Further investigations of HPV vaccinations such as HspE7 have renewed efforts and optimism within the scientific community in developing a means of treating RRP.

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Keywords:

papillomatosis; human papilloma virus; benign airway tumors

© 2004 Lippincott Williams & Wilkins, Inc.