Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Recurrent Respiratory Papillomatosis Recurrent respiratory papillomatosis (RRP) is a relatively rare disease caused by members of the human papilloma virus family. The disease is characterized by the growth of benign squamous papillomas in the respiratory tract and shows a tremendous predilection for the larynx. It is, in fact, the most common benign neoplasm of the larynx. As the name implies, this disease is recurrent and may behave aggressively- to the point of precipitating airway obstruction. The impact of RRP on patients, their families, and the health care system is immense. Unfortunately, despite extensive investigational studies, no cure is available for the disease. In the late 1800's, Morrell Mackenzie first identified papillomas as the most common benign tumor of the larynx in children. But it was not until the early 1940s that Chevalier Jackson in his publication "Diseases and injuries of the larynx." referred to this disease as "juvenile laryngeal papillomatosis." Today the disease is recognized as a disease of both children as well as adults and exhibits a bimodal age distribution. The first peak of RRP occurs at less than 5 years of age with approximately 25% of these cases presenting during infancy. The second peak occurs between the ages of 20 and 30 years. It is estimated that approximately 2300 new pediatric cases and 3600 new adult cases are diagnosed in the U.S. in a 1-year period. Boys and girls appear to be nearly equally affected in juvenile onset papillomatosis in contrast to adult-onset RRP, which is a sexually transmitted disease preferentially affecting men by a margin of approximately 3 to 2. Interestingly, nearly 75% of affected children are first-born, vaginally delivered infants of teenage mothers- a clinical triad recognized as a risk factor for the disease. RRP is caused by subtypes of the HPV, which is a member of the papova virus family. It is an icosahedrally shaped virus with a circular, double stranded DNA genome surrounded by an outer capsid of protein. As the name implies, the papillomaviruses are species specific and HPV have not been propagated in tissue culture or in standard experimental animals- a factor that has made HPV difficult to characterize. More than 70 distinct types of HPV have been identified-although many vary only slightly in their DNA sequence. HPV types 6 and 11 and rarely 16 have been implicated in causing RRP. Verifying the role of HPV in RRP has been arduous. An infectious etiology had been proposed but not confirmed until 1923 when Ullmann injected homogenized papillomata from a child's larynx into his forearm. Approximately 90 days later cutaneous wart-like lesions appeared. These findings supported the theory of transfer and subsequent growth of an infectious agent. By the 1950s a viral cause was suspected and in 1973, intranuclear, icosahedrally-shaped inclusions were identified by electron microscopy. In 1980, the presence of HPV DNA in laryngeal papillomata was confirmed by Southern blot hybridization. HPV DNA was also identified in condyloma acuminata, suggesting a similar infectious cause for both diseases. By 1982, Dr. Mounts identified the HPV genome present in laryngeal papillomata as HPV type 6 and type 11. Vertical transmission of juvenile-onset RRP from an active or latent maternal anogenital HPV infection was first recognized in 1956 by a physician managing an 18 month-old child whose mother reported the development of condyloma acuminata during the final trimester of pregnancy. Subsequent retrospective studies have supported this association and a history of active or prior genital HPV infection can be obtained in approximately 50% of mothers of affected children. Because delivery through a colonized birth canal has been popularized as a method of disease transmission, some investigators have supported elective cesarean section as a protective measure. One study found only 1 child out of 109 cesarean deliveries to mothers with genital HPV infection developed RRP, supporting the protective role of cesarean section in preventing transmission of HPV. Alternatively, in-utero spread of HPV via an ascending infection or hematogenous passage has also been proposed to occur. The hypothesis of in utero transmission has been supported by the demonstration of HPV DNA in umbilical cord blood from infants delivered to mothers with asymptomatic HPV infections and the demonstration of HPV DNA in amniotic fluid samples from infected mothers. Host factors must play an essential role in the risk of development of RRP. Active or latent HPV cervical infection is found in approximately 10 to 25% of women of childbearing age in the U.S., but only 1 in 400 infants delivered to these women is estimated to be at risk for subsequent RRP. This relative risk is much lower than that of other sexually transmitted diseases such as congenital herpes which affects 1 in 20 children born to mothers with cervical herpes. Factors that may render some children more likely to develop clinical infections include disruption in mucosal membranes, immune system defects, and specific HLA haplotypes. The majority of patients with respiratory papillomas present with hoarseness or a weak cry. Other patients may present with chronic cough, paroxysms of choking, recurrent respiratory infections or failure to thrive. These presenting features often lead to a misdiagnosis of asthma, laryngitis, bronchitis or croup. Massive papilloma accumulation may cause stridor and can precipitate acute airway obstruction. In children with RRP who are otherwise healthy, a routine physical examination may be remarkable only for hoarseness and dysphonia. Signs of partial airway obstruction include stridor, tachypnea, chest retractions, and nasal flaring. Indirect or fiberoptic laryngoscopy may be diagnostic by revealing characteristic, wart-like lesions concentrated on the free margins of the true vocal folds. Microscopically, papillomas appear as fingerlike projections of stratified squamous epithelium overlying a fibrovascular core. The normal epithelial maturation is often absent and the basal zone is frequently hyperplastic. Papillomata are prone to develop at junctional sites between squamous and respiratory epithelia, which explains the predilection for laryngeal involvement of the true and false vocal folds, subglottis and laryngeal surface of the epiglottis. Less frequently, papillomas develop in the nasal vestibule, nasopharynx, bronchi and oropharynx. Although RRP is considered a benign process, the disease is capable of undergoing malignant degeneration. Histologically, it may be difficult to distinguish between benign and malignant processes given the presence of cellular atypia characteristic of even benign disease. Frequent recurrences and exacerbations characterize the clinical course of this disease. Most affected children require laser laryngoscopy and bronchoscopy every 2 to 3 months during periods of disease activity. Occasionally, weekly surgical intervention is necessary to prevent airway obstruction from rapidly growing papillomata. Spontaneous remission has been reported but its occurrence is highly variable and unpredictable. Possible triggers include endocrine, immunologic or hormonal factors. In the past patients were advised that hormonal factors at the time of puberty were likely to lead to regression or remission with resolution of the papillomas. More recent studies, however, have shown that there is no such tendency for regression during puberty. Interestingly, women with adult onset papillomatosis commonly experience severe exacerbations of their disease during the hormonal fluctuations of pregnancy. In patients who enjoy remission of the disease, HPV genomic DNA can still be detected in normal appearing mucosa of the aerodigestive tract. Although laryngeal disease is the hallmark of RRP, papillomas may appear throughout the upper and lower aerodigestive tract. HPV 11 is believed to have a greater propensity for distal pulmonary spread and a poorer prognosis for ultimate remission. Tracheal involvement occurs in 2% to 17% of patients without tracheotomies and appears as cobblestoning of the mucosa coupled with the presence of papillomata as seen here. More distal bronchopulmonary involvement is reported in 4% to 11% of children with longstanding disease. Radiographically these lesions may appear as solid or cystic pulmonary masses. Prior to malignant degeneration, papillomas exhibit increasing degrees of atypia. Histologically, the papilloma demonstrate an increase in the nuclear-cytoplasmic ratio, nuclear hyperchromatism and chromatin clumping (PON). In adults, malignant degeneration usually involves the larynx unlike children where cancer usually develops in the bronchopulmonary tree. Malignant degeneration in children usually involves the bronchopulmonary tree. Approximately 20 pediatric cases of malignant degeneration have been reported-all of which have been fatal. The currently proposed mechanism of malignant transformation involves oncoproteins E6 and E7. HPV types 6 and 11 produce transforming oncoproteins E6 and E7 that have been implicated in growth dysregulation through their abilities to inactivate the tumor suppressor proteins p53 and the retinoblastoma tumor-suppressor gene product (pRb). The inactivation of the tumor suppressor genes results in a loss of control over proliferation and cell division and contributes to the development of the oncogenic phenotype. It is also becoming clear that the E6 and E7 proteins function to promote tumorigenesis through direct interactions with cell-cycle regulatory proteins The mainstay of treatment for patients with RRP is repeated surgical removal of papillomas under microscopic visualization. Although sharp dissection can be performed, laser vaporization is more commonly employed as it is thought to increase precision and provide hemostatic control. Carbon dioxide lasers are preferred because they have a short extinction coefficient and deliver minimal thermal injury to adjacent tissues. By maintaining great care and using low power settings, complications such as anterior vocal cord webbing or obliteration of the normal vocal fold mucosal wave can be minimized. Also, when working at the anterior commissure, it is important not to excise papilloma on both the right and left true vocal cords as there is an increased risk of web formation. Tracheotomy is sometimes performed to provide a secure airway for patients who require weekly or monthly surgical procedures. This is an issue which has been viewed with trepidation in the management of RRP since the literature has suggested that the injury associated with the tracheotomy site may initiate the progression of disease to the distal airway. Alternatively, patients who require tracheotomy for RRP may be predisposed to distal spread because of the aggressive nature of their disease. A review from the Children's Hospital of Pittsburgh found that although distal spread occurred in 50% of patients, it was generally limited to the tracheotomy site and overall outcome was satisfactory. The temporizing role of surgical excision in the management of RRP has prompted investigators to seek more effective alternative or adjuvant therapies. The problem in determining the efficacy of various treatments has been the erratic natural history of RRP and the lack of properly controlled trials. Some of the modalities used in the past but which failed to provide any benefit include ultrasonography, cryosurgery, antibiotics, steroids, podophyllum, lymphokines, and irradiation. More recent developments in adjuvant therapy have been shown to provide some benefit in controlling RRP although no therapies have been able to eradicate the HPV genome from mucosal tissues. The adjuvant therapies include alfa-interferon, acyclovir, indole-3-carbinol, Retinoic acid, methotrexate, photodynamic therapy and cidofovir. Alfa-Interferon has been the most extensively investigated form of adjuvant therapy. Alfa-interferons are naturally occurring polypeptides that are produced by human leukocytes in response to an antigenic challenge. Although IFN has no direct antiviral action, it does induce synthesis of intracellular enzymes that act to control viral growth. Alfa-interferon has an antiproliferative property that inhibits the division of tumor cells grown in culture. Alfa-interferon decreases the growth of papillomata and increases the time interval between surgical procedures. The beneficial role of IFN in the management of RRP was first reported in a Scandinavian trial in 1981. In 1988, the results of a multicenter randomized clinical trial were published. This study concluded that interferon slowed the growth of papillomata only during the first 6 months of therapy. In 1991, another multi-institutional study reported patients with severe RRP may have a sustained response longer than 6 months to treatment with alfa-interferon. A review of recent studies reported that IFN induces complete resolution of clinical disease in approximately 30% to 50% of patients and partial resolution in 20% to 42%. The magnitude and duration of the effect of IFN has varied in the trials testing its efficacy as have many other clinical variables including the dose and duration of IFN administration, the study design, the patient selection and length of follow-up. Responders to IFN therapy continue to harbor the HPV genome in normal appearing mucosa and theoretically, activation of this latent infection may explain the rate of disease recurrence. Some studies estimate the recurrence rate as approaching 50%. Fortunately, most patients who develop recurrences after cessation of IFN therapy respond to another course of therapy. Currently, IFN therapy is recommended for patients requiring four or more surgical procedures in 12 months. Recombinant alfa-interferon is administered subcutaneously, daily, beginning at a dosage of 1 MU/m2 BSA and increasing weekly until the target dose of 3 MU/m2 is reached - a Mega Unit is a measurement based on the biologic activity of interferon. Alfa-interferon administration is recommended for a minimum of 6 months and in partial responders should be continued as long as a beneficial response is evident. The most common side effect of Alfa-interferon therapy is a flu-like syndrome manifested as fever, fatigue, chills, malaise, myalgia, and headache. The severity of this side effect may be lessened by nighttime administration of the IFN until tolerance develops, which usually takes place within 2 weeks of initiating the therapy. Other side effects include neurtropenia, elevation of hepatic transaminases, renal insufficiency, nausea, vomiting, diarrhea and seizures. These side effects usually respond to temporary reduction in the dosage of alfa-IFN and rarely require cessation of therapy. Acyclovir has recently been shown to reduce the recurrence of papilloma following surgical excision. The mechanism by which it slows the recurrence is unknown. Acyclovir is a purine nucleoside analog that inhibits DNA replication of the human herpes simplex virus. Coinfection with HSV is found in 50% of adult patients with RRP and in 38.5% of pediatric patients. It is postulated that herpes simplex virus augments HPV replication and that inhibition of HSV with acyclovir may indirectly slow the growth of HPV. The clinical efficacy of acyclovir in slowing the growth of papillomas seems to correlate well with the presence of HSV co-infection. The usual dose of acyclovir is 800 mg daily for patients greater than 5 years of age and 400 mg for those under the age of 5 years. Indole-3-carbinol (I-3-C) is a derivative of cruciferous vegetables such as cabbage, cauliflower and broccoli and an encouraging form of adjuvant therapy for RRP. Its ability to slow papilloma growth is believed to be directly related to its influence on estradiol metabolism. I-3-C is a potent inducer of the cytochrome p450 metabolism of estrogen. By altering the site of estradiol hydroxylation, I3C decreases the production of 16 alpha-hydroxyestrone (which has been shown to induce hyperproliferation of epithelial cells) and increases the production of 2 hydroxyestrone (which has had an antiproliferative effect in breast tumors). The influence of I3C on laryngeal papillomata was explored by comparing growth of HPV 11 virons implanted under the renal capsule of mice fed a control diet versus those fed and I-3-C enriched diet. Papillomata developed in all of the mice fed the control diet but in only 25% of those fed the enriched diet. The preliminary results of a phase I trial using I-3-C for treatment of RRP are promising as 33% of the patients in this study had a cessation in their papilloma growth over the mean follow up time of 14.6 months, 33% had a slowing of the growth rate and 33% showed no response. I-3-C is best administered as a dietary supplement. The recommended daily dose is 200 to 400 mg for adults and 100 to 200 mg for children weighing less than 25 kg. Overall, I-3-C is very well tolerated with few side effects. Retinoic Acid, a vitamin A derivative has also been proposed as an adjunctive form of therapy in the management of RRP. It has many proposed mechanisms of action including modulating expression of epithelial growth factor receptors, reversing epithelial hyperplasia and inhibiting abnormal epithelial differentiation. The response rate of RRP to Retinoic acid therapy has been variable. While some studies have demonstrated a complete or partial response, a randomized study failed to demonstrate any efficacy and found a high incidence of side effects such as dry skin and chelitis. A pilot study by Dr. Lippman and Dr. Donovan among others, combined the use of Retinoic Acid with Alfa-interferon in the treatment of three patients (two juveniles and one adult) with severe RRP, two of whom had failed treatment with alfa-interferon alone. The results were encouraging. All 3 patients showed a twofold increase in surgical intervals and a substantial reduction in composite scores of disease severity. The dose of isoretinoin (accutane) used was 1 mg/kg/day. Methotrexate is an antimetabolite used in the treatment of neoplastic diseases. It acts by inhibiting dyhrodrofolate reductase that blocks the synthesis of purine nucleotides and subsequently interferes with DNA synthesis and repair. Actively proliferating cells and DNA are more sensitive to the effects of methotrexate than normal cells. The rationale for using methotrexate in the treatment of RRP is that the more rapidly proliferating viral-containing epithelial cells will be preferentially affected, leaving the normal epithelium intact. Little is reported in the literature concerning methotrexate therapy for RRP. However, the response to methotrexate in a limited number of patients with severe disease has been dramatic. Three patients with severe progressive disease refractory to interferon therapy responded to methotrexate by doubling the surgical interval and decreasing the amount of disease present. The recommended dose is 1 mg/kg given once or twice weekly. Side effects of methotrexate include stomatitis, rash, alopecia, nausea and diarrhea, as well as hepatic and neurologic toxicities at high doses. Larger trials and long-term follow-up are needed to determine whether methotrexate is as beneficial in the treatment of RRP as it appears to be in the few patients studied. The ability of photodynamic therapy to reduce cutaneous papillomata in animal studies prompted its trial in the treatment of respiratory papillomata. Delivery of photodynamic therapy involves the intravenous administration of a photosensitizing agent such as dihematoporphyrinether (DHE) that concentrates in rapidly growing tissues such as laryngeal papillomata. The larynx is subsequently light activated, usually with an argon-pumped dye laser and tissues concentrating the photosensitizing agent are destroyed. Although HPV persists in normal appearing mucosa after PDT, the growth rate of papillomata is slowed by approximately 50%. The main side effect of PDT is the persistence of photosensitivity, sometimes for several months. It is manifested by cutaneous erythema, pruritus, ocular discomfort and occasionally, skin blistering. Cidofovir is a nucleoside phosphate derivative with antiviral acvitity currently used in the treatment of CMV retinitis. It has been shown to suppress the growth of tumors induced by rabbit papillomaviruses as well as human papillomaviruses. In a Belgian study, the efficacy of cidofovir was assessed in patients with severe respiratory papillomatosis by direct injection in the different laryngeal papillomatous lesions during microlaryngoscopy. The results have been promising with 14 of 17 patients in the study entering clinical remission with a mean duration of 13.6 months. A Phase I/II multi-center trial research protocol investigating the effectiveness of cidofovir is currently underway in the U.S. Dr. De Jong and Dr. Duncan are currently using intrapapillomatous injections of cidofovir on an experimental basis for patients who have failed other adjunctive therapies. What lies ahead? Although the treatment strategies described above have significantly helped to reduce the recurrence of papillomata growth, they have been unable to inactivate or eradicate the HPV genome from respiratory mucosa. In a recent study, however, SDS -Sodium dodecyl sulfate, a detergent, has been shown to inactivate rabbit, bovine and human papillomaviruses after brief treatment with dilute solutions of SDS. The effectiveness of SDS is attributed to its ability to denature viral capsid proteins. Effective concentrations were nontoxic to rabbit skin and to STSG of human foreskin epithelium. Based on these findings, testing with humans is being proposed. These strategies focus on the treatment of the disease, but how about preventing the disease? HPV vaccines are still in an early stage of development, but have a firm base according to results obtained with vaccines for animal papillomaviruses. Phase I studies of therapeutic vaccines using HPV 6 proteins are currently ongoing. In summary, RRP is a devastating disease caused by HPV types 6, 11 and occasionally 16. Despite extensive investigation, much remains to be understood regarding the precise mechanism of viral transmission, and the risk of disease expression in infants delivered to mothers with cervical HPV infection. Characterized by the relentless growth of papillomatous lesions, RRP induces hoarseness and sometimes, life-threatening airway obstruction. The diagnosis of RRP in pediatric patients is often delayed because of its ability to mimic other respiratory disorders. Surgical excision of the papillomata remains the mainstay of therapy, but even when all visible disease is removed, recurrences are the rule. Multiple exciting new forms of adjuvant therapy have been advocated to aid in disease control, although none are universally curative. Case Presentation D.G. is a 30-year-old African-American man born by vaginal delivery. He was healthy as an infant but at the age of three years, his parents noticed the development of progressively worsening hoarseness. He was initially treated for multiple upper respiratory infections but the hoarseness failed to resolve. At the age of four he was evaluated by an otolaryngologist and diagnosed with respiratory papillomatosis. His disease was controlled initially with surgical removal of papillomas by endoscopic laser vaporization every month. However, one year after the diagnosis was made, his disease progressed to the point where he required a tracheotomy for large obstructing lesions. He was decannulated successfully at eight years of age. His disease continued to progress, and at the age of 22, he was treated at an outside hospital with alfa-interferon in conjunction to monthly endoscopic carbon dioxide laser vaporizations of papillomata. After beginning interferon, the frequency of endoscopy declined slightly to 8-week intervals. An attempt was made to discontinue the interferon therapy after a 6-month trial, but the disease progressed rapidly. He subsequently returned to Ben Taub for treatment. 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