Prevalence and clinical implications of low-risk human papillomavirus among patients with recurrent respiratory papillomatosis in Rio de Janeiro,Brazil

ObjectiveThe aim of this study was to investigate the presence of human papillomavirus (HPV) in biopsy specimens from juvenile and adult patients with histopathological diagnosis of recurrent respiratory papillomatosis (RRP) treated in two public hospitals in Rio de Janeiro, Brazil.MethodsWe performed the detection and genotyping of HPV by PCR technique for the types 6, 11, 16, and 18 in biopsy specimens from 41 RRP patients.ResultsThe juvenile onset RRP (JoRRP) corresponded to 61% and the adult onset RRP (AoRRP) corresponded to 39% of the study group. Prevalence of males was observed in both the adult (81.3%) and the juvenile (56%) groups. Lesions in the larynx were more frequent in the glottis (46%). Genotyping analysis only revealed patients with HPV-6 (34.1%), HPV-11(17.1%), and co-infection HPV-6 and -11 (48.8%). RRP severity was significantly associated with the JoRRP (p < 0.001), with extralaryngeal disease and more surgeries. However, no significant association between RRP severity and HPV types was found. One co-infected patient in the JoRRP died due to the evolution of the disease with lung involvement.ConclusionThese results show the strong association of HPV-6 and/or HPV-11 types with RRP and could complement the diagnosis, prognosis, and therapies for these patients. In addition, the HPV vaccination should be encouraged to prevent the disease.     

Squamous cell carcinoma associated with intralesional injection of cidofovir for recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis is a common neoplasm of the larynx that may lead to severe, recurrent lesions. Intralesional injection of cidofovir has shown promise as an adjuvant therapy. There is concern for possible malignant transformation with its use but, to our knowledge, this has not been documented in the literature. We report a case of invasive squamous cell cancer arising from squamous papilloma in a patient treated with multiple injections of cidofovir. Although causation is not shown, we believe the association presented is a valuable addition to the literature and an important consideration in the use of cidofovir. Laryngoscope, 119:567–570, 2009     

Management of complex glottic stenosis in children with recurrent respiratory papillomatosis

Objectives

To describe our management of complex glottic stenosis in tracheotomy dependent children with severe recurrent respiratory papillomatosis.

Methods

Retrospective chart review at a tertiary care children's hospital.

Results

Three children with complex glottic stenosis secondary to severe recurrent respiratory papillomatosis were treated at our institution since 2011. Two patients had complete stenosis, and the third had near-complete stenosis. Two patients were managed using balloon dilation alone, and the third also underwent laryngotracheal reconstruction with posterior costal cartilage grafting. Two patients have been successfully decannulated and the third has been tolerating continuous tracheotomy capping for greater than twelve months. All three patients underwent aggressive debridement of papillomatosis and balloon dilation every 4–6 weeks until their burden of disease was controlled. In two patients, the glottic airway was patent, and the third continued to have complete restenosis between procedures and required laryngotracheoplasty with multiple post-operative dilation procedures to establish an adequate glottic airway.

Conclusions

Severe laryngeal stenosis is a well-described complication of recurrent respiratory papillomatosis, but its management is not well-defined. Aggressive management of papillomatosis with frequent debridement is critical in successfully managing laryngeal stenosis. Balloon dilation alone may be surprisingly effective in these patients, and laryngotracheoplasty can be used as an adjunct procedure in those patients who fail balloon dilation. Given the quality of life issues and concerns regarding distal spread of disease with tracheotomies in these patients, we feel that aggressive management and early decannulation is in the patient's best interest.     

Current advances in the basic research and clinical management of juvenile-onset recurrent respiratory papillomatosis

Juvenile-onset recurrent respiratory papillomatosis is a relatively uncommon disease that presents clinically with symptoms ranging from hoarseness to severe dyspnea. Human papilloma viruses type 6 and 11 are important in the etiology of the papillomata and are most probably transmitted from mother to child during childbirth. Although spontaneous remission is frequent, a rare fatal course because of pulmonary spread or malignant transformation has occurred. CO₂ laser evaporation of papillomas and adjuvant drug therapy using lymphoblastoid α-interferon are the most common treatment modalities at present. However, several other treatment modalities have been tried with varying success. Recent advances in basic research and different therapeutic approaches are reviewed. Received: 13 October 1999 / Accepted: 3 December 1999     

Lung involvement in juvenile onset recurrent respiratory papillomatosis: a systematic review of the literature

OBJECTIVES: Determine the exact incidence of pulmonary involvement in recurrent respiratory papillomatosis (RRP); explore available treatments and their effectiveness; determine the characteristics of cases that progress to lung cancer. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Library databases between 1966 and 2007; reference lists of retrieved publication. STUDY SELECTION: Studies investigating recurrent respiratory papillomatosis with lung involvement. Age limited to 20 years of age to qualify for the diagnosis of juvenile-onset RRP. DATA EXTRACTION: Data pertaining to study design, population demographics, risk factors, site of involvement, investigation including the determination of the human papillomavirus type, treatment, and outcomes including the development of cancer. DATA SYNTHESIS: No randomized control trials were retrieved. Hundred and one studies met our inclusion criteria (23 cohorts, 4 case series, 72 case reports, 2 open trials) with 161 cases of lung involvement identified. From the cohort studies we could estimate the incidence of lung involvement in RRP at 3.3%. The incidence of cancer in cases with lung involvement was 16%. We could not draw conclusions regarding treatment effectiveness in lung involvement, as that was not evaluated except in case studies. It would nevertheless appear that Interferon is not effective and the use of intravenous Cidofovir needs to be better evaluated. CONCLUSION: Well-designed, hypothesis-driven randomized control trials and prospective cohort studies are warranted to improve our understanding of the mechanisms underlying the development of lung involvement in RRP, the risks associated with different HPV types, the efficacy of potential therapeutic options as well as the risk of progression to cancer.     

Children and partners of patients with recurrent respiratory papillomatosis have no evidence of the disease during long-term observation

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm affecting the larynx and upper respiratory tract. The aim of our study was to investigate whether children and partners of patients with RRP develop the same disease and to determine whether there is an impact of pregnancy on the course of RRP. PATIENTS AND METHODS: Thirty-eight of 42 patients with RRP were accepted for a multicenter prospective study in Germany in 21.06.83-12.03.90. Mean follow-up duration was 15.3+/-1.8 years. The data of partners of patients with RRP was collected during the period of observation and then updated via interviews in January 2006. Twenty-nine children and four grandchildren were born to 14 patients with RRP. Fifteen of 448 cases of patients with RRP were treated in Saint Vladimir Moscow Children's Hospital in Russia in 1988-2003 and analyzed retrospectively. Sixteen children and one grandchild were born to 15 patients with RRP from Russia. In both studies, the virus type of patients with RRP was identified by nested PCR or Southern blot hybridization. Statistical analysis was performed using Fisher's exact test (probability value set at p<0.05). RESULTS: All children born to patients with RRP were healthy. RRP was not diagnosed in any of them on the basis of clinical or histological examination. Four of 45 children developed dysphonia, two of them had vocal cord nodules. None of the sexual partners of patients has developed RRP during the follow-up period. Pregnancy was accompanied by excessive growth of papillomas in all women (100%) with RRP associated with HPV type 11, and only in 16.7% of women with RRP associated with HPV type 6 (p=0.001). CONCLUSIONS: Patients with RRP are able to have healthy children regardless of the stage of the disease. Partners of RRP patients do not develop RRP during an observation period of 15 years. Pregnancy has a negative impact on the course of RRP and local laryngeal status in patients; it is more significant in HPV type 11 associated cases as it is manifested by more rapid papillomas growth and more frequent recurrence.     

The predictive value of serum interleukins in recurrent respiratory papillomatosis: a preliminary study

OBJECTIVE: IL-2 is the primary interleukin responsible for activation of the cell-mediated (Th1) arm of the immune response. Our objective was to determine whether a correlation existed between circulating levels of interleukin-2 as well as its soluble receptor (sIL-2R) and the clinical course of recurrent respiratory papillomatosis. METHODS AND MATERIALS: Fifteen children with a histological diagnosis of RRP were recruited. Age at the time of study, time since first diagnosis, and number of surgical interventions were recorded. The number of surgically treated recurrences per year was then calculated. We obtained serum samples from each of these 15 children and from 10 normal control subjects. We then performed in vitro determination of serum IL-2 and soluble IL-2 receptor levels using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: IL-2 was significantly lower (136.6 vs. 199.9 pg/mL, P =.035) in papilloma patients than in control subjects. IL-2R was also lower in papilloma patients (531.7 vs. 785.8 U/mL, P =.025). There was no statistical age difference between the papilloma and control groups. Among patients with papillomatosis, IL-2 and sIL-2R levels were significantly higher in those with aggressive disease (>4 surgically treated recurrences per year) versus non-aggressive disease (179.2 vs. 99.2 pg/mL, P =.024; and 697 vs. 387 U/mL, P =.022). Age was also significantly lower in the aggressive papilloma group (P =.002). CONCLUSIONS: Levels of interleukin-2 and IL-2 receptor were significantly lower in patients with recurrent respiratory papillomatosis compared with normal children. These data support the presence of an aberrant cell-mediated immune response in children with recurrent respiratory papillomatosis.     

Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: A systematic review

Objectives

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few develop JoRRP and the clinical course of the disease varies from one child to another. This systematic review seeks to provide an up-to-date understanding of the risk factors for acquisition and severity.

Methods

We conducted a comprehensive literature search in EMBASE, MEDLINE and EBMR databases using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also searched Google Scholar and the reference lists of eligible studies. Our search was limited to original studies published in French or English between 1995 and July 2012 and to patients under 20 years of age.

Results

Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32 studies meeting inclusion criteria. All were observational and together included 2296 JoRRP cases. Risk factors could be classified mainly as maternal and birth history, viral genotype, and host factors. A history of genital warts during pregnancy and delivery was strongly linked to the development of JoRRP. Depending on ethnicity, specific human leukocyte antigen class II alleles and immune response factors were important determinants of JoRRP acquisition and severity. HPV-11 genotype and younger age at onset of JoRRP were important predictors of severity.

Conclusions

Genetic and immunological profiles underlying the acquisition and clinical course are not readily modifiable. Thus, preventing condylomas in women of childbearing age could reduce the burden of this life-threatening disease.     

Protein expression of the tumor suppressors p16INK4A and p53 and disease progression in recurrent respiratory papillomatosis

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a benign condition that rarely metastasizes as invasive squamous cell carcinoma. Although this disease is associated with human papillomavirus, the role of this virus in tumorigenesis is unclear. OBJECTIVES: The aim of this study is to assess the involvement of the tumor suppressors P16INK4A and p53 in RRP tumor progression. DESIGN: Immunohistochemistry of p16INK4A and p53 was performed on biopsies of recurrent squamous papillomas and invasive lesions in nine patients. RESULTS: Twenty biopsies were graded as papillomas (RP), three as papillomas with high-grade dysplasia/carcinoma in situ (HGD/CIS), and two as invasive squamous cell carcinoma (SCCA). Forty-five percent of RP and 60% of HGD/CIS/SCCA expressed p16INK4A. Fifty percent of RP and 100% of HGD/CIS/SCCA expressed p53. The difference in the frequency of p53-positive staining between HGD/CIS and SCCA (100% of tissues examined) and RP (50% of tissues examined) approached statistical significance. Neither p16INK4A nor p53 was predictive of invasive transformation. CONCLUSIONS: Expression of p16INK4A, which is a surrogate for the tumor suppressor retinoblastoma (Rb), did not immediately lead to invasive disease. There is no correlation between disease severity of RRP and level of p16INK4A.     

CO2激光手术治疗复发性呼吸道乳头状瘤

复发性呼吸道乳头状瘤是呼吸道最常见的良性上皮性肿瘤,术后极易复发,频繁的手术干预,给患者及家属乃至整个社会带来了巨大的经济负担。目前手术仍为最主要的治疗方法,CO₂激光本身具有损伤小、术野出血少、精准度高、切割深度可控特点,有利于完整切除肿瘤;采取CO₂激光行黏膜下剥离实现完整切除复发性呼吸道乳头状瘤,其临床疗效显著,具有广阔的应用前景。     

Efficacy of cidofovir versus bevacizumab in recurrent respiratory papillomatosis: A randomized,double-blind,placebo-controlled pilot study

ObjectivesAfter surgical resection of papilloma, adjuvant therapy may be recommended for the control of recurrent respiratory papillomatosis (RRP). As the efficacy of adjuvant therapy remains unproven, the aim of this study was to compare the efficacy of cidofovir versus bevacizumab used as adjuvant therapies for the control of RRP.MethodsThis randomized, double-blind, placebo-controlled pilot study was performed in a national respiratory disease referral centre. Patients with RRP were recruited prospectively and were divided into juvenile or adult RRP. Participants were randomly assigned to receive adjuvant therapy with cidofovir, bevacizumab or placebo. The study drug or placebo was administered after direct microlaryngoscopy with papilloma resection using cold instruments. The Derkay severity score and the Voice Handicap Index (VHI) were assessed at 3–6-week intervals, for a total of 3 visits. Follow-up included VHI and Derkay score assessments at 2-month intervals over the course of one year. Annual rates before and after surgical treatment were compared.ResultsFive children and 11 adults were enrolled in the study. After one year, the group treated with cidofovir had a significant decrease in Derkay score (p = .027). No difference between treatment arms was observed in the annual surgery rate. There was a significant decrease in the VHI score in all treatment groups (p < .001), and no significant difference was observed between groups (p = .32).ConclusionWhile we observed a significant decrease in RRP severity with intralesional cidofovir, we were unable to provide proof of efficacy of intralesional bevacizumab.Clinicaltrials.gov Identifier: NCT02555800.     

Efficacy of microsurgery in combined with topical-PDT in treating recurrent respiratory papillomatosis: compare JORRP with AORRP

Abstract

Background: Recurrent respiratory papillomatosis (RRP) remains a challenging and frustrating disease to treat.

Objective: To explore the efficacy of microsurgery in combined with Topical-PDT in treating recurrent respiratory papillomatosis.

Materials and methods: Fifty patients with RRP were treated with microsurgery in combined with Topical-PDT. Medical document of each patient was retrospectively reviewed. Detailed clinical information, metrics of clinical course, and current results were evaluated.

Results: Juvenile onset RRP (JORRP) might experience a more aggressive course than AORRP (adult onset RRP) with higher Derkay score (p?<?.01) and higher operation frequency per year (p?<?.01). Microsurgical excision combined with Topical-PDT every 25?days achieved “remission” of disease in 78% of patients, “clearance” of disease in 52%, and “Cured” in two patients. Each patient who achieved “remission” of disease, performed 6.82?±?3.39 operations, and continued 8.93?±?7.03?months of treatment duration. No statistically differences were found in these two aspects between JORRP and AORRP. A negative correlation between tracheotomy and the efficacy of microsurgery in combined with Topical-PDT was found (p?=?.025, Pearson’s r = –0.3).

Conclusions and significance: Microsurgery in combined with Topical-PDT might be a powerful method to treat RRP. Tracheotomy is a negative factor for this therapy.     

Severity of juvenile onset recurrent respiratory papillomatosis is not associated with socioeconomic status in a setting of universal health care

BACKGROUND: Juvenile onset recurrent respiratory papillomatosis (JORRP) results from HPV transmission. Cervical cancer, also transmitted via HPV, is known to be correlated with socioeconomic status (SES). This study aims to determine if an association exists between SES and severity of JORRP. METHODS: Cross-sectional study of all active JORRP patients at the Hospital for Sick Children in Toronto in 2005. SES information from Hollingshead surveys, Postal walk Census data, and Low Income Cutoff Data were compared with Derkay-Wiatrak disease severity scores, peak annual surgical frequency, and age of diagnosis. Statistical analysis was performed using Spearman, Mann-Whitney, and linear regression analyses. RESULTS: Twenty-one patients were surveyed. Hollingshead results were as follows: two patients (10%) were class I (major business and professional); 11 patients (52%) were class II (medium business, minor professional, technical); 4 patients (19%) were class III (skilled craftsmen, clerical, sales workers); 4 patients (19%) were class IV (machine operators, semiskilled workers); 0% were from class V (unskilled laborers, menial service workers). Interestingly, based on postal code data nine patients (45%) were below the low income cutoff as compared to the Toronto (metropolitan) and Ontario (provincial) rates of low income (17% and 14%, respectively). There was significant correlation between each of the SES measures and between disease severity measures. However, analysis of the SES measures versus disease severity measures did not demonstrate any significant relationship. CONCLUSIONS: Though almost half the patients lived below the low income cutoff, this study did not demonstrate a significant correlation between socioeconomic status and severity of disease in JORRP. One possible explanation is that universal access to the Canadian health care system is able to provide support despite a large proportion of patients being socioeconomically vulnerable. A national level study is underway to further detect any relationship between SES and JORRP severity in the general population.     

Clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosis

The aim of the study was to assess the clinical efficiency of quadrivalent HPV (types 6/11/16/18) vaccine in patients with recurrent respiratory papillomatosis (RRP). This was a prospective study of patients with RRP treated from January 2009 to July 2012 at the Ear, Nose and Throat Department of the Emergency County Hospital of Cluj-Napoca, Romania. Demographic characteristics, onset of RRP, HPV typing, use and number of cidofovir injections, number of surgeries for RRP per year, and use of human papillomavirus vaccine (types 6, 11, 16, 18) (recombinant, adsorbed)/Silgard^® were considered from all the patients included in the study. Charts were reviewed for follow-up after diagnosis, after cidofovir, and after Silgard; all the statistical tests were applied at a significance level of 5 %. The recurrences were observed within 27.53 ± 11.24 days after intralesional cidofovir injection. Thirteen patients with recurrence after cidofovir agreed and received Silgard^® vaccine. 85 % [54.44–99.41] of patients had no recurrences during 1-year follow-up. The recurrence of papillomas was observed in two patients (15 %, 95 % CI [0.59–45.56]), one with adult-onset RRP and one with juvenile-onset RRP. Both recurrences appeared after the first Silgard dose; one month after the third vaccine dose each patient underwent a new surgery for remaining papillomas with no recurrences at 1-year follow-up visit. Silgard^® vaccination had a good effect and proved to be efficient in the treatment of our patients with RRR without appearance of recurrence in 85 % of the patients during 1-year follow-up.     

Effectiveness of the human papillomavirus (types 6, 11, 16, and 18) vaccine in the treatment of children with recurrent respiratory papillomatosis

ObjectiveTo evaluate whether the quadrivalent human papillomavirus (HPV) (types 6, 11, 16, and 18) vaccine influences the clinical course of juvenile-onset recurrent respiratory papillomatosis (RRP) when administered to a group of patients with this condition.MethodsUncontrolled intervention study of patients with juvenile-onset RRP examined at the Pediatric Otorhinolaryngology Clinic, Federal University of São Paulo, where nine patients between the ages of nine and 17 received three doses of the prophylactic quadrivalent HPV vaccine (Gardasil^®) and were followed for one year. Disease staging, intervals between relapses, intervals between surgeries, and the number of surgeries during the year prior to vaccination and during the first year after vaccination were compared.ResultsEight patients were infected with HPV-6 and one with HPV-11. There were no statistically significant differences in the clinical scores (p = 0.083), anatomical scores (p = 0.257), intervals between relapses (p = 0.062), intervals between surgeries (p = 0.357), or the numbers of surgeries (p = 0.180) when the years before and after vaccination were compared. All patients had relapses following vaccination.ConclusionPatients with juvenile-onset RRP experienced a similar clinical course in the year after versus the year before vaccination with Gardasil^®.