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    Research Articles (2003-1)

    Predictors of remission in juvenile-onset recurrent respiratory papillomatosis.
    Arch Otolaryngol Head Neck Surg. 2003; 129(12):1275-8 (ISSN: 0886-4470)
    Ruparelia S; Unger ER; Nisenbaum R; Derkay CS; Reeves WC
    Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333, USA.

    OBJECTIVE: To determine factors associated with remission of juvenile-onset recurrent respiratory papillomatosis (JORRP). DESIGN: Longitudinal study. SETTING: Twenty-two tertiary care centers located across the United States.Study Participants and METHODS: The study included 165 patients diagnosed as having JORRP between January 1, 1997, and December 31, 2000. Kaplan-Meier curves and Cox proportional hazards models were used to determine associations between predictors and remission. INTERVENTIONS: Surgical excision and drug therapy. MAIN OUTCOME MEASURES: Remission of JORRP, defined as no surgical procedures for at least 1 year, as associated with age at diagnosis, drug therapy in the first year after diagnosis, number of surgical procedures in the first year after diagnosis, and number of anatomical sites of disease at diagnosis. Demographic factors (sex and race) and Medicaid status were also evaluated. RESULTS: Older age at diagnosis was positively associated with remission of JORRP (hazards ratio for every increase of 1 year in age, 1.13; 95% confidence interval, 1.03-1.23). CONCLUSIONS: Younger children were found to have persistent disease and often underwent an increased number of surgical procedures in the first year after diagnosis of JORRP. Sex and race were not important factors in determining remission.

    Intralesional cidofovir and surgical excision for laryngeal papillomatosis.
    Laryngoscope. 2003; 113(12):2174-81 (ISSN: 0023-852X)
    Naiman AN; Ceruse P; Coulombeau B; Froehlich P
    Department of Otolaryngology, Edouard Herriot University Hospital, 5 place d'Arsonval, 69437 Lyon Cedex 03, France.
    OBJECTIVE: To evaluate the efficacy of cidofovir intralesional therapy in recurrent respiratory papillomatosis and the role of surgical excision as an associated treatment. STUDY DESIGN: Prospective study and case series. METHOD: Twenty-six patients received intralesional cidofovir. Three endoscopies were performed at monthly intervals, with intralesion injections of cidofovir at 5 mg/mL. Further endoscopic evaluation was made at 3 or 6 months depending on whether there was persistent papillomatosis. Cidofovir was again injected in the case of persistent papillomas, and treatment was repeated as long as papillomas were observed. Surgical excision of the papilloma was only performed in cases of airway obstruction or in cases proving resistant to cidofovir. RESULTS: Complete remission was obtained in 8 (31%) patients after an average of 2.6 endoscopic treatment. Seventeen (65%) patients presented slight or mild disease at endpoint (final severity score 1-4). Significant results were obtained in both adults and children. A greater response was obtained in the supraglottis and glottis subsites than in subglottis, tracheal, and other sites. Patients conforming to the 1 month interinjection schedule showed better responses in supraglottis subsite than those receiving their injections with intervals longer than 1 month. Combined therapy (cidofovir plus excision) was necessary in persistent papillomas. No patients presented with any systemic or local side effects. CONCLUSIONS: Cidofovir therapy was an effective treatment in adults and in children, allowing papillomatosis to be controlled without observed side effects. Surgical excision associated with cidofovir injections remained necessary in persistent papillomatosis after cidofovir treatment.

    Diagnosis and management of pulmonary metastasis from recurrent respiratory papillomatosis.
    Otolaryngol Head Neck Surg. 2003; 129(6):622-9 (ISSN: 0194-5998)
    Silver RD; Rimell FL; Adams GL; Derkay CS; Hester R
    Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
    OBJECTIVE: We sought to review the current and proposed management, as well as bring about discussion, of managing the patient with distal tracheal and pulmonary parenchymal involvement by recurrent respiratory papillomatosis (RRP). DESIGN, SETTING, AND PATIENTS: We conducted a review of 6 patients with pulmonary metastasis from RRP at 3 academic tertiary care hospitals. Interventions included surgical and medical management with antiviral, chemotherapeutic, and/or immune-modulating agents. RESULTS: Although treatment with alpha-2-beta interferon, isotretinoin, and methotrexate have not proved to eradicate pulmonary involvement by RRP, possible epithelial stabilization and slowing of disease progression are noted. CONCLUSIONS: The rates of distal tracheal and pulmonary metastasis as seen in our cohort were higher than previously reported. Approximately 12% of our patients with RRP have distal tracheal spread and as many as 7% of all patients with RRP at our institutions have pulmonary dissemination. Also, high suspicion for malignant conversion to squamous carcinoma in the patient with pulmonary spread should be maintained. In addition, aggressive treatment, although not proved to eradicate the pulmonary disease, should be undertaken due to the high morbidity and mortality associated with pulmonary dissemination of RRP in our cohort.

    Development of a canine model for recurrent respiratory papillomatosis.
    Ann Otol Rhinol Laryngol. 2003; 112(12):1011-3 (ISSN: 0003-4894)
    Jahan-Parwar B; Chhetri DK; Hart S; Bhuta S; Berke GS
    Division of Head and Neck Surgery, Department of Surgery, University of California-Los Angeles School of Medicine, Los Angeles, California 90095, USA.

    A canine model for recurrent respiratory papillomatosis (RRP) was developed with canine oral papillomavirus (COPV) inoculated into the buccal mucosa and supraglottic larynx of 5 beagles. The animals received systemic immunosuppression with daily oral prednisone at doses of 0, 1, 2, 3, and 4 mg/kg. Buccal papillomata developed at 6 weeks in all animals and regressed by 10 weeks in the animals that received 0 and 1 mg/kg. The other animals had continuous growth of their buccal papillomata for 26 weeks. The animal that received 2 mg/kg developed papillomata on the lingual surface of the epiglottis that continued to grow through 26 weeks. Systemic oral prednisone successfully maintained COPV-induced oral and laryngeal papillomata in beagles. Thus, COPV-induced oral and laryngeal papillomata that are prednisone-maintained may have utility as a model for RRP.

    [Diagnosis and treatment of juvenile recurrent laryngeal papillomatosis]

    Zhonghua Er Bi Yan Hou Ke Za Zhi. 2003; 38(6):421-5 (ISSN: 0412-3948)
    Wang HG; Lin XQ
    Department of Otorhinolaryngology-Head and Neck Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. hgwang@stu.edu.cn

    OBJECTIVE: To evaluate some perplexing problems in the diagnosis and treatment of juvenil recurrent laryngeal papillomatosis (JRLP) and the relationship between juvenile onset recurrent respiratory papillomatosis(JORRP) and infantile laryngeal condyloma accuminatum (ILCA). METHODS: A group of 44 cases with JRLP were analyzed retrospectively from March, 1994 to March, 2002 in the light of literature review. RESULTS: The average age of first visit was 1.6 years. Average 5.3 operations had been performed per patient. There was an interval of average 2.4 months between two surgical excisions. Of 233 operations, the total incidence rate of all the complications was 3.9%. At present, the laryngeal lesion of 18 cases have withered away for over 1 year. 11 cases have being followed up. 10 cases have lost follow-up and 5 cases have died (11.4%). Combined laryngeal lesion excision with tracheotomy aiming at prolonging operative interval or Chinese traditional medicine has received more satisfactory effect than other therapies. There is an extensive similarity between JORRP and ILCA. CONCLUSIONS: To demondrate further whether JORRP and ILCA are the same identical disease has important significance in both theoretical study and clinic practice. The treatment for JRLP is still difficult. The tracheotomy for laryngeal obstruction resulted from the laryngeal lesion of JRLP should be avoided as far as possible. Combined laryngeal lesion excision with tracheotomy aiming at prolonging opertive interval or Chinese traditional medicine shows optimistic prospect.

    Overview of recurrent respiratory papillomatosis.
    Curr Opin Otolaryngol Head Neck Surg. 2003; 11(6):433-41 (ISSN: 1068-9508)
    Wiatrak BJ
    Department of Pediatrics and Surgery, University of Alabama at Birmingham, USA. brian.wiatrak@chsys.org

    PURPOSE OF REVIEW: The purpose of this article is to review recent literature regarding pediatric recurrent respiratory papillomatosis (RRP) published within the last year. By reviewing and assessing these articles, a more clear understanding regarding the etiology and management of pediatric RRP can be obtained, allowing physicians to better care for their pediatric RRP patients. RECENT FINDINGS: Pediatric RRP continues to be an extremely difficult management problem for otolaryngologists. This disease process continues to be a significant burden on the health care system and is a significant cause of morbidity in affected patients and their families. The incidence of RRP continues to be approximately 3.96 per 100,000 in the pediatric population. It has been noted recently that approximately 7 of every 1000 children born to mothers with vaginal condyloma develop pediatric RRP. Although the mainstay of surgical management has traditionally been the CO2 laser, newer surgical techniques have demonstrated efficacy in the management of pediatric RRP patients, including powered instrumentation and the pulse-dye laser. The traditional adjuvant medical therapies used for pediatric RRP continue to be commonly used, including interferon-alpha2a, retinoic acid, and indol-3-carbinol/diindolylmethane (I3C/DIM). Recently cidofovir has demonstrated efficacy in selected patients. In addition, current research regarding vaccine therapy for pediatric RRP has shown promise. Basic science research in the field of immunology has demonstrated multiple defects in cell-mediated immunity, which has shed further light on the etiology of pediatric RRP. SUMMARY: Pediatric RRP continues to be a highly morbid disease process. New surgical and medical therapies offer hope for better control of this disease in affected patients. Recent advances in immunologic research offer the hope of immune system modulation and augmentation as potential future treatment modalities to better control this disease process.

    HLA-DQ alleles in white and African American patients with juvenile-onset recurrent respiratory papillomatosis.
    Arch Otolaryngol Head Neck Surg. 2003; 129(11):1221-4 (ISSN: 0886-4470)
    Gregoire L; Reidy PM; Rabah R; Lancaster WD
    Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA. gregoire@genetics.wayne.edu

    OBJECTIVE: To determine HLA-DQalpha and -DQbeta1 allele associations in juvenile-onset recurrent respiratory papillomatosis (RRP) for risk, disease course, and human papillomavirus type. DESIGN: A nonrandomized controlled study was performed on DNA extracted from papilloma specimens of children with a history of RRP, and from peripheral blood of African American and white children without RRP. The frequencies of DQalpha and DQbeta1 alleles were compared between patients and ethnically matched controls. SUBJECTS: Records of 48 children treated for RRP at Children's Hospital of Michigan in Detroit (26 African American and 22 white) were reviewed. Control subjects consisted of 80 African American and 80 white children seen at the hospital for conditions other than RRP. RESULTS: African American and white patients with DQbeta1*050X (not *0501, *0502, *0503, *0504, or *0505) were at higher risk to develop RRP than controls (P =.01 and.03, respectively). DQbeta1*0402 was protective for African Americans (P =.01). Whites with DQalpha*0102 were at risk for RRP (P =.03). This allele was associated with disease remission in African Americans (P =.03). DQalpha*0101/0104 conferred protection in whites (P =.047). No association was seen for allele frequency and human papillomavirus type. Whites with haplotype DQalpha*0501/DQbeta1*0201 were at high risk for RRP (P =.002). No relationships were seen for African Americans or whites between haplotype frequencies and disease course or human papillomavirus type. CONCLUSIONS: HLA-DQalpha and -DQbeta1 alleles occur at different frequencies in African American and white children with RRP than controls. Specific alleles influence risk for RRP. Allele and haplotype frequencies have some influence on disease course, but were independent of human papillomavirus type.

    A scheduled protocol for the treatment of juvenile recurrent respiratory papillomatosis with intralesional cidofovir.
    Arch Otolaryngol Head Neck Surg. 2003; 129(10):1081-5 (ISSN: 0886-4470)
    Chhetri DK; Shapiro NL
    Division of Head and Neck Surgery, UCLA School of Medicine, Los Angeles, CA 90095, USA.

    OBJECTIVE: To assess the efficacy of treating juvenile recurrent respiratory papillomas with intralesional cidofovir using a scheduled treatment protocol. DESIGN: Prospective case series. SETTING: Tertiary care academic medical center. PATIENTS: Of 5 pediatric patients with recurrent respiratory papillomas, 2 had severe recurrent papillomatosis requiring long-term therapy of laser ablations every 2 weeks prior to cidofovir treatments. The 3 other patients were newly diagnosed or had milder disease. INTERVENTION: Intralesional cidofovir (1 mg/kg) was administered during each scheduled visit. The first 4 treatments were at 2-week intervals (week 0, 2, 4, and 6). Subsequent treatment intervals were each increased by 1 week (treatments took place at week 9, 13, 18, 24, etc). Concomitant laser ablation was used only for bulky lesions. MAIN OUTCOME MEASURES: Papilloma stage and need for laser ablation at each scheduled visit. RESULTS: The mean follow-up time was 66 weeks. The mean (SD) papilloma stage decreased from 9.2 (5.5) at initial presentation to 3.4 (2.6) within 2 weeks of the first injection (P<.05), and continued to decrease for the remaining of the follow-up period. Papilloma stage 0 was achieved in 4 of the 5 patients. The need for laser ablation of papillomas also decreased within 4 weeks of treatment initiation (P<.05). At 9 weeks, no patient required laser therapy. One patient was removed from the protocol after 58 weeks. CONCLUSION: An intralesional treatment protocol with cidofovir and increasing intervals between scheduled treatment was successful the long-term management of juvenile respiratory papillomatosis.

    Lower airway papillomatosis in children.

    Int J Pediatr Otorhinolaryngol. 2003; 67(10):1117-21 (ISSN: 0165-5876)
    Zawadzka-G?os L; Jakubowska A; Chmielik M; Bielicka A; Brzewski M
    Department of Paediatric Otorhinolaryngology, The Medical University of Warsaw, 24 Marsza?kowska Str., 00-576 Warsaw, Poland.

    Laryngeal papilloma in children is a frequent disease caused by human papilloma virus (HPV) type 6 or type 11. This disease has a tendency to recur and the changes are histologically benign. In some cases papilloma may affect the lower levels of the respiratory tract. In this study, among 90 patients treated for laryngeal papillomatosis, in four children papilloma of trachea, bronchi and lung tissue were detected in endoscopic and radiological examination. This constitutes 4.4% of all patients. Compact nodules and acquired cysts between 5 and 50 mm long were found in chest X-rays and in computerised tomography. These cysts appeared from 4 to 8 years after establishing a diagnosis of laryngeal papilloma, and 1 year after recognising papilloma in the trachea. In all four children the presence of nodules and cysts in the lungs was preceded by recurrent pneumonia, emphysema or atelectasis of the lungs. All children with laryngeal papillomatosis should have a chest X-ray. Detection of acquired cyst-like changes in lung tissue in children with laryngeal papillomatosis is a warning of future papilloma in the trachea and bronchi, with involvement of lung tissue. In differential diagnosis of these changes in the lungs we should take into consideration the presence of papilloma in the bronchi. A prognosis of papillomatosis in the lower airways in children is always serious.

    National registry for juvenile-onset recurrent respiratory papillomatosis.
    Arch Otolaryngol Head Neck Surg. 2003; 129(9):976-82 (ISSN: 0886-4470)
    Reeves WC; Ruparelia SS; Swanson KI; Derkay CS; Marcus A; Unger ER
    Viral Exanthems and Herpesvirus Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. wcr1@cdc.gov

    BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JORRP) is an infrequent but debilitating disease. Because JORRP is uncommon, it has proven difficult for studies at single institutions to accurately evaluate its natural history. OBJECTIVE: To characterize the clinical spectrum of JORRP. DESIGN: Standardized retrospective and prospective medical record abstraction. SETTING: Twenty-two tertiary-care pediatric otolaryngology centers throughout the United States.Patients All patients with JORRP younger than 18 years seen between January 1, 1996, and March 31, 2002. MAIN OUTCOME MEASURES: Demographics, age at diagnosis, anatomic sites of disease, longitudinal disease course, frequency of surgery, need for tracheotomy, and medication history. RESULTS: The registry includes 603 children. The mean age at diagnosis was 4.0 years. The children underwent a mean of 5.1 surgeries annually. Current age, rather than age at diagnosis, was the primary determinant of surgical frequency. The larynx was involved at the time of diagnosis in 96.1% of children, and 87.4% had only 1 anatomic site involved. Children with 1 site involved were significantly older at diagnosis (mean age, 3.9 years) than those with 2 sites (mean age, 2.9 years). Most (74.2%) had stable disease over time, 5.8% showed progression of papillomas to new sites, and 17.9% had no evidence of disease for at least 1 year. Children with disease progression were diagnosed at a significantly younger age than those who remained stable or became disease-free. Children who required tracheotomy were significantly more likely to have progressive disease. CONCLUSIONS: The registry has established the clinical course of JORRP in a large sample representative of the United States. Young age was the most important determinant of disease severity (frequency of surgery, extent of disease at diagnosis, and progression of disease). Addressing questions of pathogenesis and disease course will require a revised data collection instrument and molecular analysis of tissues.

    Long-term follow-up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir.
    Laryngoscope. 2003; 113(9):1583-7 (ISSN: 0023-852X)
    Pransky SM; Albright JT; Magit AE
    Children's Hospital and Health Center, San Diego, CA 92123, USA. spransky@chsd.org

    OBJECTIVE: Cidofovir is an acyclic nucleotide phosphonate antiviral medication that has been used intralesionally for the treatment of severe respiratory papillomatosis (RRP) in pediatric patients. The long-term efficacy of this medication was assessed in 11 children with severe RRP who previously required operative debulking every 2 to 6 weeks to maintain airway patency. STUDY DESIGN: Clinical case series. RESULTS: Ten of these children have completed therapy. Five are disease free over a mean follow-up period of 51.6 months. Five other patients with active RRP decreased their mean severity scores from 17.8 (range 11-26) to 4.0 (range 2-6) and no longer require cidofovir. One patient continues to receive cidofovir for recurrent disease after an initial favorable response. Throughout the 6-year observational period, no patients demonstrated any adverse effects, laboratory abnormalities, or evidence of carcinogenesis. CONCLUSION: Intralesional cidofovir is a useful adjunct for managing children with tenuous airways caused by previously uncontrolled papilloma.

    Recurrent respiratory papillomatosis.

    Ear Nose Throat J. 2003; 82(8):555-6 (ISSN: 0145-5613)
    Restrepo S; Palacios E; Mastrogiovanni L; Kaplan J; Gordillo H
    Department of Radiology, Louisiana State University Health Sciences Center, New Orleans, USA.

    Stepped-dose protocol of cidofovir therapy in recurrent respiratory papillomatosis in children.
    Arch Otolaryngol Head Neck Surg. 2003; 129(8):841-6 (ISSN: 0886-4470)
    Akst LM; Lee W; Discolo C; Knott D; Younes A; Koltai PJ
    Department of Otolaryngology and Communicative Disorders, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

    OBJECTIVE: To evaluate a stepped-dose protocol for intralesional injection of cidofovir in children with recurrent respiratory papillomatosis (RRP). DESIGN: Prospective, nonrandomized case series. SETTING: Tertiary care children's hospital. PARTICIPANTS: Eleven children undergoing evaluation for RRP from June 1, 2000, through December 31, 2001. INTERVENTION: Intralesional injection of cidofovir was performed after microlaryngoscopy and carbon dioxide laser treatment. Patients received 4 monthly injections at a concentration of 5 mg/mL and returned 1 month after the last injection for follow-up. Patients with recurrent or recalcitrant disease then started a series of 4 monthly injections at a concentration of 10 mg/mL. OUTCOME MEASURE: Papilloma stage (0-3) documented at multiple subsites by means of serial microlaryngoscopy. We calculated a severity score by summing the scores at all affected subsites. RESULTS: The severity score decreased in each of the 11 patients during the course of therapy, from a mean +/- SD of 13.7 +/- 6.0 at enrollment to 2.1 +/- 3.4 at 1-month follow-up. Six patients experienced complete resolution (stage 0) and 4 others had mild disease (stage, </=5) after 4 treatments at the 5-mg/mL concentration. Five patients with residual or recurrent RRP subsequently started a series of 4 cidofovir treatments at a concentration of 10 mg/mL, with a mixed response. CONCLUSIONS: Intralesional injection of cidofovir seems to reduce the burden of disease in children with RRP. Patients with persistent or recurrent disease may benefit from an increased cidofovir concentration of 10 mg/mL, although some aggressive papillomatous disease remains refractory to cidofovir treatment.

    Pulsed-dye laser in the treatment of recurrent respiratory papillomatosis of the larynx.
    Ear Nose Throat J. 2003; 82(8):558 (ISSN: 0145-5613)
    • Cohen JT; Koufman JA; Postma GN
    Center for Voice Disorders, Department of Otolaryngology, Wake Forest University Medical Center, Winston-Salem, N.C., USA.

    Intralesional cidofovir for the treatment of severe juvenile recurrent respiratory papillomatosis: long-term results in 4 children.

    Otolaryngol Head Neck Surg. 2003; 128(6):788-94 (ISSN: 0194-5998)
    Milczuk HA
    Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, OR 97239-3096, USA. milczukh@ohsu.edu

    OBJECTIVE: We sought to determine the efficacy of intralesional injection of cidofovir in improving resolution of recurrent respiratory papillomatosis (RRP).Study design and setting We conducted a prospective, observational trial at an academic tertiary children's hospital. RESULTS: Four children with RRP requiring more than 6 surgical excisions per year were treated with intralesional cidofovir. Cidofovir (5 mg/mL) was injected into airway sites where papillomas had just been excised using sharp technique. Each patient had 6 treatments performed 6 to 8 weeks apart. Biopsies confirmed benign papilloma lesions in all cases. During treatment with intralesional cidofovir there was diminished growth of the papillomas in each patient. Once cidofovir treatment was stopped, the rate of regrowth and frequency of surgical excision returned to pretreatment levels in 3 of the 4 patients. CONCLUSIONS: Intralesional cidofovir may provide benefit in reducing the rate of RRP growth while under treatment, but RRP severity returned to pretreatment levels once cidofovir treatment was stopped using this treatment program.

    Pulmonary involvement in a case of juvenile-onset recurrent respiratory papillomatosis.
    Ear Nose Throat J. 2003; 82(6):447-9 (ISSN: 0145-5613)
    McKay SP; Shinhar SY; Belenky WM
    Department of Otolaryngology, Children's Hospital of Michigan, Wayne State University, 5E UHC, 4201 St. Antoine, Detroit, MI 48201, USA. smckay@wayne.edu

    Juvenile-onset recurrent respiratory papillomatosis is primarily a disease of children and adolescents. Although most patients experience spontaneous regression at a later age, some patients continue to be affected throughout their lives. We report the case of a 35-year-old woman with a 33-year history of juvenile-onset recurrent respiratory papillomatosis who developed pulmonary dissemination with malignant transformation. Malignant transformation is the most feared sequela of pulmonary dissemination, and it should be addressed aggressively. If treated promptly, the patient can enjoy prolonged survival. Computed tomography is superior to plain radiography for detecting and evaluating the extent of disease.

    Reliability of a staging assessment system for recurrent respiratory papillomatosis.
    Int J Pediatr Otorhinolaryngol. 2003; 67(5):505-9 (ISSN: 0165-5876)
    Hester RP; Derkay CS; Burke BL; Lawson ML
    Department of Otolaryngology and Pediatrics, Children's Hospital of The King's Daughters, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 510, Norfolk 23507-1914, USA.

    INTRODUCTION: A staging system for the assessment of severity of disease and response to the therapy in recurrent respiratory papillomatosis (RRP) was proposed several years ago. It includes both a subjective functional assessment of clinical parameters and an anatomic assessment of disease distribution. The anatomic score can then be used in combination with the functional score to measure an individual patient's clinical course and response to the therapy over time. In using this system, it would be of benefit to know what level of variability can be expected from one surgeon to another in the assessment of an RRP patient and the assignment of a score. DESIGN: Ten videotaped recordings of endoscopic assessments of patients with RRP were reviewed by 15 pediatric otolaryngologists and scored based on the criteria of the staging assessment system. RESULTS: Analysis was conducted for 15 raters of scoring severity over 25 sites of 10 patients. The total score is the addition of scores over the 25 sites with a score equal to or greater than 20 representing high risk. For 8/10 (80%) of the subjects, there was a complete agreement about risk categorization (low risk) and agreement by 14/15 (93%) raters for categorization of one other patient. For 9/10 (90%) of subjects, the standard errors of the mean total scores were less than 1, meaning a low variance and subsequent high reliability of the total score. CONCLUSIONS: This staging system was able to achieve agreement by 15 pediatric otolaryngologists on 9 of 10 subjects in terms of degree of severity of RRP.

    Recurrent respiratory papillomatosis.

    Asian J Surg. 2003; 26(2):112-6 (ISSN: 1015-9584)
    Long YT; Sani A
    Department of Otorhinolaryngology, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. ytlong@tm.net.my

    A 6-year-review of patients who presented with recurrent respiratory papillomatosis (RRP) to our hospital from January 1996 to December 2001 was carried out. Ten cases were identified, of which six were juvenile-onset RRP. Hoarseness was the most common symptom, noted in nine (90%) patients. Other clinical presentations included cough, stridor and aphonia. All patients had glottic papillomas; two had multiple sites of involvement. One patient underwent a tracheostomy that revealed papillomas over the trachea, bronchus and lung parenchyma. Half of the patients were Chinese. Of the six cases of juvenile-onset RRP, three patients were Malay, two Chinese and one Indian. Three Chinese and one German patient had adult-onset RRP. Among the juvenile-onset RRP cases, the mean age at presentation was 2 years, while for adult-onset RRP, it was 42 years. Juvenile-onset RRP was more common in females. There were more papillomas over more sites in patients with juvenile-onset RRP than with adult-onset disease. Subglottic involvement was noted in the juvenile-onset RRP cases. All patients were treated with CO2 laser therapy, but there was complete remission of the papillomas in only two cases.

    Molecular transformation of recurrent respiratory papillomatosis: viral typing and p53 overexpression.
    Ann Otol Rhinol Laryngol. 2003; 112(4):298-302 (ISSN: 0003-4894)
    Go C; Schwartz MR; Donovan DT
    Department of Otolaryngology, Baylor College of Medicine, Houston, Texas 77030, USA.

    Recurrent respiratory papillomatosis (RRP) is a histologically benign disease of the larynx, trachea, and bronchi. Here we report on the histologic and molecular characteristics of 7 cases of malignant transformation of RRP to squamous cell carcinoma (SCCA). The clinical histories of 7 patients with RRP who developed SCCA were carefully reviewed. Sequential biopsies were available from 5 of the 7 cases of spontaneous transformation of RRP to SCCA and were reviewed. In addition, p53 protein overexpression and human papillomavirus (HPV) typing for all cases was examined. The average age of patients with juvenile-onset RRP was 3 years, and that of patients with adult-onset RRP was 31 years. The average age of onset of transformation to SCCA was 28 years. All patients had laryngeal involvement with RRP, and 3 of the 7 patients had tracheal extension of disease. Five patients were tracheotomy-dependent. Four of the 7 patients developed SCCA of the lung, while 3 patients developed laryngeal SCCA. There was no consistent histologic progression from squamous papilloma to papilloma with dysplasia, and all but 1 of the SCCAs were well differentiated. The overexpression of p53 protein was variable in each of the 5 patients. We detected HPV types 6/11 in papillomas from 3 patients, and HPV types 6/11, 16/18, and 31/33/51 in a papilloma of a fourth patient. No HPV DNA was detected in papillomas of 2 patients. We found HPV 6/11 in 4 of the carcinomas. We conclude that the spontaneous transformation of RRP to SCCA is not characterized by a histologic progression through dysplasia over time. Transformation can result in the loss of HPV expression. It does not appear that p53 is a molecular marker for monitoring the transformation process. Thus, these cancers may be very difficult to diagnose histologically and clinically early in the course of the transformation of the disease.

    Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis.
    Obstet Gynecol. 2003; 101(4):645-52 (ISSN: 0029-7844)
    Silverberg MJ; Thorsen P; Lindeberg H; Grant LA; Shah KV
    Department of Epidemiology, Baltimore, Maryland 21205-2179, USA. msilverb@jhsph.edu

    OBJECTIVE: To assess the risk of juvenile-onset recurrent respiratory papillomatosis conferred by a maternal history of genital warts in pregnancy, and to identify additional cofactors such as the method of delivery (cesarean versus vaginal) and procedures or complications during pregnancy. METHODS: A retrospective cohort design was used to evaluate maternal and infant characteristics associated with respiratory papillomatosis among Danish births between 1974 and 1993. Using data from Danish registries, we identified 3033 births with a maternal history of genital warts during pregnancy. Fifty-seven respiratory papillomatosis cases were identified by review of medical records from ear, nose, and throat departments. RESULTS: Seven of every 1000 births with a maternal history of genital warts resulted in disease in the offspring, corresponding to a 231.4 (95% confidence interval 135.3, 395.9) times higher risk of disease relative to births without a maternal history of genital warts. In women with genital warts, delivery times of more than 10 hours were associated with a two-fold greater risk of disease. Cesarean delivery was not found to be protective against respiratory papillomatosis, and no other procedures or complications during pregnancy were observed to increase the risk of respiratory papillomatosis. CONCLUSION: A maternal history of genital warts in pregnancy is the strongest risk factor for respiratory papillomatosis in the child. Future studies should examine the efficacy of genital wart treatment for the prevention of disease.

    HLA class II polymorphisms and susceptibility to recurrent respiratory papillomatosis.

    J Virol. 2003; 77(3):1927-39 (ISSN: 0022-538X)
    Gelder CM; Williams OM; Hart KW; Wall S; Williams G; Ingrams D; Bull P; Bunce M; Welsh K; Marshall SE; Borysiewicz L
    Infection & Immunity, University of Wales College of Medicine, Newport, United Kingdom. viralimmunol@cf.ac.uk

    Recurrent respiratory papillomatosis (RRP) is characterised by multiple laryngeal papillomas. Left untreated, the lesions enlarge, spread, and endanger the airway. Medical treatments are unsatisfactory, and repeated surgery remains the mainstay of therapy. RRP is caused by human papillomavirus (HPV) infection. However, since oral HPV infection is common and RRP is rare, other host and/or viral factors may contribute to pathogenesis. In an attempt to identify such factors, we have investigated 60 patients. The patients were HLA class I, II, and tumor necrosis factor TNF typed by sequence-specific primer PCR, and the results compared to those for 554 healthy controls by using Fisher's exact test. Peripheral blood mononuclear cell proliferative responses of 25 controls and 10 patients to HPV-11 L1 virus-like particles (VLP) were compared. Short-term VLP-specific T-cell lines were established, and recognition of L1 was analyzed. Finally, the L1 open reading frames of HPV isolates from four patients were sequenced. Susceptibility to RRP was associated with HLA DRB1*0301 (33 of 60 patients versus 136 of 554 controls, P < 0.0001). The three most severely affected patients were homozygous for this allele. A range of T-cell proliferative responses to HPV-11 VLP were observed in DRB1*0301-positive healthy donors which were comparable to those in DRB1*0301-negative controls. Individuals with juvenile-onset RRP also mounted a range of VLP responses, and their magnitude was negatively correlated with the clinical staging score (P = 0.012 by the Spearman rank correlation). DRB1*0301-positive patients who responded to L1 recognized the same epitope as did matched controls and produced similar cytokines. Sequencing of clinical isolates excluded the possibility that nonresponsiveness was the result of mutation(s) in L1.

    Chapter 7: Human papillomavirus and cancer of the upper aerodigestive tract.

    J Natl Cancer Inst Monogr. 2003; (31):47-51 (ISSN: 1052-6773)
    Herrero R
    Fundación Costarriccense para la Docencia en Ciencias de la Salud, PO Box 301-6151, Santa Ana, Costa Rica. rherrero@amnet.co.cr

    We discuss current evidence of the role of human papillomavirus (HPV) in some cancers of the upper aerodigestive tract, including the oral cavity, the pharynx, and the larynx. Cancers of the oral cavity and the pharynx are associated mainly with tobacco and alcohol exposure, but there is evidence from case series, from case-control studies, and from cohort studies that HPV plays a role in a fraction of these cancers, particularly cancer in the oropharynx and tonsil. The HPV type most commonly associated with cancers in these locations is HPV 16. Laboratory evidence indicates that the virus is integrated and that HPV oncogenes are transcriptionally active in these tumors. Many aspects of the association remain to be investigated, including the epidemiology and natural history of HPV infection in the mouth, the role of cofactors, and the potential use of HPV testing and vaccines in the prevention of these tumors. An analogous role for the virus at other anatomic sites in the upper aerodigestive tract such as the larynx is less clear. The relationship between HPV infection and laryngeal cancer is of particular interest, given that recurrent respiratory papillomatosis is clearly caused by benign proliferative growths induced by HPV 6 or 11 infection of the laryngeal epithelium. Although HPV genomic DNA has been detected in a proportion of laryngeal cancers and despite the many efforts made during the last 15 years, there is not yet compelling evidence that HPV plays a substantial role in laryngeal cancer.

    Argon plasma coagulation (APC) surgery in otorhinolaryngology.
    Surg Technol Int. 2003; 11:79-84 (ISSN: 1090-3941)
    Bergler WF
    Department of Otorhinolaryngology, University Hospital Mannheim, Mannheim, Germany.

    The Argon Plasma Coagulation (APC) technique has been used with success in open surgery and endoscopy for hemostasis and thermal devitalisation of pathological tissue. We developed techniques and instruments for the use of this technique in Otorhinolaryngology, because of its excellent hemostatic effects and devitalising properties. APC surgery is based on a monopolar high-frequency (HF) electrical current transmitted through ionized argon gas from the tip of an applicator to the tissue surface in a contact-free mode. Indications for the use of this technique include hyperplasia of the inferior turbinate in nasal obstruction, recurrent epistaxis in hereditary hemorrhagic telangiectasia, leukoplakia of the mucosa, recurrent respiratory papillomatosis (RRP) of the lower airway, in combination with flexible systems. A combined technique of blunt dissection and plasma coagulation has been designed for bloodless removal of the tonsils. This new technique offers a wide variety of advantages. The limited penetration depth makes APC surgery a safe procedure; damage to neighbouring tissue can be avoided. The APC technique is a useful and comparable inexpensive method to achieve devitalisation of tissues and easy to handle hemostasis.

    [The interaction of stilbazolium merocyanines with hyperproliferative laryngeal papilloma cells--preliminary study]

    Otolaryngol Pol. 2003; 57(6):823-7 (ISSN: 0030-6657)
    Szyd?owski J; Cofta J; Wiktorowicz K; Grzegorowski M
    Klinika Otolaryngologii Dzieciecej Instytutu Pediatrii AM im. Karola Marcinkowskiego w Poznaniu.

    Recently increasing interest focused in possible clinical application on photodynamic therapy was observed. Many scientists are looking for new chemical compounds effective in therapy and giving no side effects. Stilbazolium merocyanines belong to lipophilic dyes, binding to cell membranes. The aim of this study was to estimate the usefulness of the selected stilbazolium merocyanines to treatment on human recurrent respiratory papillomatosis. A patients group consisted of seven children, ages 10 months to 18 years, with moderate to severe recurrent disease. The patients were treated surgically. Tissue samples were analyzed for presence of Human papillomavirus (HPV). The incorporation of the dye into papillomas cells membranes was measured by flow cytometry. As a measure of fluorescence intensitivity the value "mean channel" was used. The hyperplastic tissue showed the highest fluorescence intensity than normal epithelium. Obtained results showed that continue to this preliminary studies is necessary.

    [Recurrent respiratory papillomatosis. Our experience and literature review]
    An Otorrinolaringol Ibero Am. 2003; 30(2):179-91 (ISSN: 0303-8874)
    Henríquez Alarcón M; Altuna Mariezkurrena X; Goiburu Mínguez M; Vea Orté JC; Camacho Arrioaga JJ; Algaba Guimerá J
    Servicio Orl, Hospital Donostia, San Sebastián.

    The recurrent respiratory papillomatosis is a benign lesion induced by virus, with predisposal factors not yet clear out. Several treatment have been used, being the endoscopic surgery with laser CO2 the most used technique. We present our experience with laryngeal papillomatosis patients operated with laser CO2 in the last 15 years. The high rate of recidive in the youth pattern and the possibility of malignant degeneration in the adults charactherises this patients. Meanwhile without not other concluyent works surgery will be the first therapeutic alternative, avoiding mutilant operations, and paying attention in detecting lesions suggesting malignancy.

    Treatment of recurrent respiratory papillomatosis in children with the microdebrider.
    Ann Otol Rhinol Laryngol. 2003; 112(1):7-10 (ISSN: 0003-4894)
    Patel N; Rowe M; Tunkel D
    Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, 601 N Caroline St, 6th Floor, Baltimore, Maryland 21287-0910, USA.

    The mainstay of treatment of children with recurrent respiratory papillomatosis has been CO2 laser laryngoscopy. Powered microdebriders allow precise removal of laryngeal lesions without thermal damage. The microdebrider may reduce costs by reducing operative time and limiting the need for expensive laser-related equipment. To compare the use of the microdebrider with that of the CO2 laser in children undergoing surgery for recurrent respiratory papillomatosis, we retrospectively reviewed the charts of 18 patients from 2 institutions covering a treatment period between December 1998 and October 2001. These patients were initially treated with the CO2 laser, but were switched to microdebrider resection during the review period. We recorded the number of procedures, the technique(s) of resection used, and the operative time for each procedure. We identified 18 patients, 11 male and 7 female, ages 18 months to 14 years. A total of 127 procedures were performed with the CO2 laser, and a total of 50 procedures were performed with the microdebrider. The mean number of procedures per patient was 10 (range, 2 to 17 procedures). The mean surgical time per procedure using the CO2 laser was 59.2 minutes (range, 8 to 130 minutes). The mean time per procedure with the microdebrider was 32.4 minutes (range, 12 to 47 minutes). This reduction in operative time was clinically and statistically significant (p = .0001, unpaired Student's t-test). We concluded that microdebrider resection of laryngeal papilloma in children allowed more rapid surgery with potentially reduced treatment costs. Other advantages of this technique include precise excision without thermal injury. Our report details useful refinements of technique with the microdebrider.

    Observations on the early results of treatment of recurrent respiratory papillomatosis using cidofovir.
    J Otolaryngol. 2002; 31(6):333-5 (ISSN: 0381-6605)

    El Hakim H; Waddell AN; Crysdale WS
    Department of Otolaryngology, The Hospital for Sick Children, Toronto, Ontario.

    OBJECTIVE: To document the response of two patients with severe recurrent laryngeal papillomatosis following treatment with intralesional cidofovir in conjunction with carbon-dioxide laser evaporation. Setting: Tertiary referral centre. METHODS: Retrospective review of treatment of two patients followed up over a 12-month period. INTERVENTION: Microlaryngoscopy and carbon-dioxide laser evaporation of lesions followed by intralesional injection of cidofovir. OUTCOME MEASURES: Photodocumentation and descriptive statistical representation of intervals between endoscopic treatment. The disease was staged according to severity on endoscopy. RESULTS: Initially, both patients showed a marked improvement of disease. However, the disease relapsed to a significant extent. Overall, there was no demonstrable change in the frequency of required endoscopies despite subjective improvement of the airway. CONCLUSION: Cidofovir may be of some benefit in the management of recurrent respiratory papillomatosis, but further studies are still required.

    Survivin expression in juvenile-onset recurrent respiratory papillomatosis.
    Ann Otol Rhinol Laryngol. 2002; 111(11):957-61 (ISSN: 0003-4894)
    Poetker DM; Sandler AD; Scott DL; Smith RJ; Bauman NM
    Department of Otolaryngology-Head and Neck Surgery, The University of Iowa Hospitals and Clinics, Iowa City 52242, USA.

    Recurrent respiratory papillomatosis (RRP), caused by the human papillomavirus, is characterized by unregulated growth of wartlike neoplasms on laryngeal mucosa. Apoptosis is important in normal cellular homeostasis, and dysregulation of this process is thought to govern the behavior of certain neoplasms. This study evaluates the expression of several pro-apoptotic and anti-apoptotic factors in papillomas of patients with RRP, with a specific interest in survivin, a cell cycle-regulated anti-apoptotic factor. Three anti-apoptotic and 6 pro-apoptotic messenger RNA (mRNA) species were quantified by ribonuclease protection assay in 11 RRP papilloma specimens and 5 normal laryngeal specimens. Anti-apoptotic and pro-apoptotic mRNA ratios were quantified by normalizing to the ribosomal protein L32 and compared between specimens. Protein expression of survivin in tissue samples was also evaluated. The mean (+/- SD) expression of survivin was almost fivefold greater in the RRP papillomas than in normal tissue (14.2% +/- 2.5% versus 3.0% +/- 0.8% of L32, p = .003). The RRP specimens also had greater expression of XIAP, Fas, and p53 than did the normal tissue. Survivin protein was differentially expressed in the papilloma specimens, and was greatest in a papilloma that underwent malignant transformation. Survivin was absent in all normal laryngeal tissue tested. Apoptotic factors in general appear to be upregulated in papillomatous tissue as compared to normal laryngeal tissue and may suggest a higher proliferation rate and cell turnover. Survivin is abundant in papillomas and absent in normal laryngeal tissue. Dysregulation of apoptosis as determined by abnormal expression of anti-apoptotic factors like survivin and XIAP probably favors papilloma growth and survival. Such factors may represent potential targets in the treatment of this disease.

    Molecular events in the progression of recurrent respiratory papillomatosis to carcinoma.
    Arch Pathol Lab Med. 2002; 126(10):1184-8 (ISSN: 0003-9985)
    Lele SM; Pou AM; Ventura K; Gatalica Z; Payne D
    Department of Pathology, University of Kentucky College of Medicine, Lexington 40536, USA. slele2@uky.edu

    CONTEXT: Identification of the type of human papillomavirus (HPV) by polymerase chain reaction and sequencing to determine coinfection or superinfection (by more than 1 HPV type) and other molecular events have not been reported in a series of patients exhibiting the morphologic spectrum of recurrent respiratory papillomatosis progressing to carcinoma. DESIGN: Four cases of juvenile-onset recurrent respiratory papillomatosis progressing to carcinoma (no history of smoking or irradiation in 2 cases) were studied. Morphologically distinct foci (squamous papilloma, pulmonary papillomatosis, squamous dysplasia subjacent to carcinoma, and squamous carcinoma) were subjected to laser capture microdissection and polymerase chain reaction amplification using general primers in addition to type-specific primers for HPV types 16 and 18. Direct sequencing of polymerase chain reaction products identified the type of HPV. The tissue sections were immunostained using antibodies to p53, pRb, p21(WAF1), and p16 proteins with a semiquantitative assessment. RESULTS: Human papillomavirus 11 was the only type of HPV identified in all lesions of all cases associated with recurrent respiratory papillomatosis. There was a marked increase in p53 protein expression in foci of dysplasia and carcinoma as compared to squamous papilloma and pulmonary papillomatosis. An inverse correlation between p53 and p21(WAF1) protein expression was noted in all lesions. pRb protein expression increased from the benign to the malignant end of the spectrum. p16 protein was expressed in all lesions. CONCLUSIONS: Infection by HPV-11 may be an early event associated with progression of recurrent respiratory papillomatosis to carcinoma. Increased expression of p53 and pRb proteins and a reduced expression of p21(WAF1) protein appear to be significant subsequent events.

    Analysis of CD4(+) T-cell responses to human papillomavirus (HPV) type 11 L1 in healthy adults reveals a high degree of responsiveness and cross-reactivity with other HPV types.
    J Virol. 2002; 76(15):7418-29 (ISSN: 0022-538X)
    Williams OM; Hart KW; Wang EC; Gelder CM
    Infection and Immunity, University of Wales College of Medicine, Cardiff CF14 4XX, Wales, United Kingdom.

    Human papillomavirus type 11 (HPV-11) infection causes genital warts and recurrent respiratory papillomatosis. While there is compelling evidence that CD4(+) T cells play an important role in immune surveillance of HPV-associated diseases, little is known about human CD4(+) T-cell recognition of HPV-11. We have investigated the CD4(+) T-cell responses of 25 unrelated healthy donors to HPV-11 L1 virus-like particles (VLP). CD4(+) T-cell lines from 21 of 25 donors were established. Cell sorting experiments carried out on cells from six donors demonstrated that the response was located in the CD45RA(low) CD45RO(high) memory T-cell population. To determine the peptide specificity of these responses, epitope selection was analyzed by using 95 15-mer peptides spanning the entire HPV-11 L1 protein. No single region of L1 was immunodominant; responders recognized between 1 and 10 peptides, located throughout the protein, and peptide responses fell into clear HLA class II restricted patterns. Panels of L1 peptides specific for skin and genital HPV were used to show that the L1 CD4(+) T-cell responses were cross-reactive. The degree of cross-reactivity was inversely related to the degree of L1 sequence diversity between these viruses. Finally, responses to HPV-11 L1 peptides were elicited from ex vivo CD45RO(+) peripheral blood mononuclear cells, demonstrating that recognition of HPV-11 was a specific memory response and not due to in vitro selection during tissue culture. This is the first study of CD4(+) T-cell responses to HPV-11 in healthy subjects and demonstrates marked cross-reactivity with other skin and genital HPV types. This cross-reactivity may be of significance for vaccine strategies against HPV-associated clinical diseases.

    Novel treatments for recurrent respiratory papillomatosis.

    Expert Opin Investig Drugs. 2002; 11(8):1139-48 (ISSN: 1354-3784)
    Armbruster C
    Mantlergasse 23/2/12, A-1130 Vienna, Austria. christine.armbruster@gmx.at

    Recurrent respiratory papillomatosis is a rare but often severe disease. Although benign in histology, epithelial proliferations may result in progressive hoarseness, stridor, obstruction of the airway and respiratory distress. The current standard of care is surgical therapy with a goal of complete removal or debulking of papillomas and preservation of normal structures. Frequent recurrences and the need for repeated surgical interventions make this treatment a frustrating experience for both the patient and the physician. Many adjuvant therapies have been investigated but no single treatment modality proved to be effective in eradicating recurrent respiratory papillomatosis. In contrast to HIV, cytomegalovirus and hepatitis B pharmaceutical research has been less successful with human papilloma virus vaccines for a variety of reasons. This review focuses on the current status of recurrent respiratory papillomatosis and on future directions of prevention and therapy.

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