Adult-onset Recurrent Respiratory Papillomatosis Research Articles

Pulmonary Involvement in Recurrent Respiratory Papillomatosis: A Systematic Review.

Recurrent respiratory papillomatosis (RRP) is a non-malignant disease, characterized by the production of wart-like growths in the respiratory tract, affecting both young people and adults (juvenile-onset recurrent respiratory papillomatosis, JORRP, and adult-onset recurrent respiratory papillomatosis, AORRP, respectively). Infection caused by human papillomavirus (HPV) is known as the main factor involved in RRP development. Complications of RRP may rarely occur, including lung involvement and malignant transformation. The present systematic review aimed to evaluate the prevalence of severe complications, such as lung involvement and lung tumor in JORRP and AORRP patients, and assess the role of HPV genotypes in the progression of disease severity following the guideline for reporting systematic reviews and meta-analysis (PRISMA Statement). A total of 378 studies were found on PubMed and Scopus using the following MESH terms: "recurrent respiratory papillomatosis and lung tumor" and "pulmonary tumor and recurrent respiratory papillomatosis". Basing on inclusion and exclusion criteria, a total of 11 studies were included in the systematic review. We found a pooled prevalence of 8% (95% CI: 4-14%; I2: 87.5%) for lung involvement in RRP patients. In addition, we found a pooled risk difference of 5% in lung involvement between JORRP and AORRP (95% CI: -7-18%; I2: 85.6%, p-value: 0.41). Among patients with lung involvement, we observed a pooled prevalence of lung tumor of 4% (95% CI:1-7%; I2: 67.1%) and a pooled prevalence mortality for this group of 4% (95% CI:2-6%; I2: 0%). Overall, the positivity rate for HPV-6 and -11 in patients with RRP was 91%. Considering only cases with pulmonary involvement, the pooled prevalence for HPV-11 was 21% (95% CI: 5-45%; I2: 77.2%). Our results evidenced a low/middle risk of pulmonary involvement and lung tumor in JORRP and AORRP patients, with an increased risk for HPV-11-positive patients. Further studies should be performed to improve knowledge and adopt preventive measures to contrast the progression to severe diseases in RRP patients.

Systemic bevacizumab for treatment of recurrent respiratory papillomatosis.

To characterize treatment response of recurrent respiratory papillomatosis (RRP) including adult-onset RRP (AORRP) and juvenile-onset RRP (JORRP) to systemic bevacizumab (bev), and share our treatment regimen experience. Patients were enrolled in bev treatment based on a pathologically confirmed diagnosis of squamous papilloma. According to lesion characteristics and medical history, systemic bev was used as preoperative adjuvant therapy, postoperative adjuvant therapy, or primary therapy. The assessment of treatment response relied on the morphological changes of lesions. Vocalization and voice-related quality of life were evaluated using the voice handicap index-30 (VHI-30) for adults and the pediatric VHI (pVHI) for children. Adverse effect was monitored through patient self-reported symptoms and regular follow-ups. This study included 24 patients, comprising nine AORRP and 15 JORRP cases. In AORRP, all patients (100%) exhibited various degrees of response to systemic bev, with 5 (55.56%) achieving complete response (CR). Among JORRP patients, 14 (93.33%) showed a response to systemic bev, with 8 (53.33%) achieving CR and currently being followed up. No instances of aggravation were observed during systemic bev treatment. A total of 21 patients (21/24, 87.50%) reported voice improvement, accompanied by reduced VHI-30 or pVHI scores across all aspects, including total, functional, physical, and emotional dimensions. No grade 3 or higher adverse events occurred. The most common adverse events were grade 1 gum bleeding (n = 4, 16.67%) and grade 1 proteinuria (n = 4, 16.67%). Systemic bev can be used as a powerful therapy for both AORRP and JORRP. The findings provide a reference to the systemic bev treatment for RRP.

Intralesional Cidofovir: A Systematic Review of Administration Protocols and Long-term Recurrence Rates in Adult and Juvenile Recurrent Respiratory Papillomatosis

This is a systematic review aimed to explore Cidofovir administration protocols, recurrence rates, and long-term effectiveness for severe cases of recurrent respiratory papillomatosis (RRP). The primary goal was to identify current practices, determine the preferred protocol, and assess the adjuvant therapy's ability to prevent long-term papilloma recurrence in juvenile and adult-onset disease. The following databases were searched: Pubmed, Google Scholar (pages 1-10), EMBASE, Scopus, ISI (clarivate), Cochrane Library, and Journal Storage from 1996 to June 2022. Articles that reported the use of intralesional Cidofovir in RRP and reported remission/recurrence rates with follow-up were included in the review. The systematic review was registered through PROSPERO and contains the detailed protocol for the conduction of the review. A total of 389 records were identified, 126 titles and abstracts screened, 45 studies fully read, and 30 studies met the inclusion criteria. Two hundred and fourteen adult-onset RRP (AORRP) and 126 juvenile-onset RRP (JORRP) cases were treated with Cidofovir across the included studies. There was no universal protocol for administering Cidofovir, with variations in concentration, treatment period, number and interval of injections, and follow-up duration. Most lesions showed human papilloma virus types 6 and 11. Recurrence rates varied, and other outcomes reported included remission rates, lesion reduction, surgical intervals, and side effects. Some studies demonstrated significant improvements in disease severity and extended intervals between recurrences after Cidofovir administration. The analysis of 30 studies reveals the need for greater consistency in reporting treatment parameters and outcomes. The use of recurrence-free period as an outcome measure and the potential benefits of a concentration of 7.5mg/mL are identified. Additionally, the importance of viral typing within papilloma lesions is emphasized. To further enhance understanding and establish optimal protocols, future research should focus on uniform reporting, including severity, dosage, interval, treatment duration, functional outcome, and related procedures. PROSPERO CRD42022299549.

Recurrent laryngeal papillomatosis: multimodal therapeutic strategies. Literature review and multicentre retrospective study.

Recurrent respiratory papillomatosis (RRP) is a benign, rare disease caused by Human Papilloma Virus (HPV) that can be divided into juvenile and adult forms. The course of the disease is variable, but is usually more aggressive in the juvenile form. The standard surgical treatment is represented by CO2 laser resection, although photoangiolytic lasers represent a valid alternative. Adjuvant therapies have been proposed for disease control in case of frequent surgical resections or spreading into the lower airways. In recent years, the development of immunotherapy led to the use of bevacizumab either intratumorally or intravenously, but the most promising therapeutic development is represented by HPV vaccination. This paper aims to present a narrative review of the literature and the experience of three different University Centres in the treatment of RRP. A retrospective analysis of the clinical charts of all patients affected by laryngeal papillomatosis and treated in three different University Centres between 2002 and 2022 was performed. The following parameters were collected: sex, age at first evaluation, sites of larynx involved, HPV type, type of first surgical treatment, presence and number of recurrences, surgical treatment of recurrences, adjuvant therapies, side effects and status at last follow-up. Seventy-eight patients were available for evaluation. Of these, 88% had adult onset RRP (Ao-RRP) and 12% juvenile onset RRP (Jo-RRP). The glottis was the most frequently involved subsite; all patients were submitted to surgical resection with CO2 laser under general anaesthesia. Recurrences appeared in 79% of the patients, the patients who did not recur were all adults. The mean number of recurrences was 9 (range 1-110). Recurrences were more frequent in children (M = 20; range 2-110) than adults (M = 5; range 1-21). Thirty-two (52%) of the 62 patients who recurred were re-treated with CO2 laser under general anaesthesia, while office-based treatment with a photoangiolytic laser was preferred in the remaining 30 (48%) patients. Adjuvant treatments were applied in 26 patients. The analysis of the course of the disease showed that in the 9 patients with Jo-RRP, 6 (67%) were free of lesions at the last follow-up, while the other 3 (33%) had papillomas. Of the 69 patients with Ao-RRP, 53 (77%) were alive and free of disease at the last visit, 14 (21%) were alive with disease, 1 (1%) was lost at follow-up and 1 (1%) died for other disease. Severe side effects were not observed except for 2 patients, who developed posterior glottic stenosis. Our results confirmed the literature review. RRP is a potentially aggressive disease, especially in juvenile onset. Surgical resection is still first-line treatment, but in case of multiple recurrences the use of adjuvant therapies must be taken into consideration.

Surgical outcome of different surgical modalities for adult recurrent respiratory papillomatosis

Background Surgical debulking remains the mainstay of treatment of adult-onset recurrent respiratory papillomatosis (AO-RRP). But there are no guidelines for decision-making of surgical modality. Objectives This retrospective study aims to obtain a better understanding of AO-RRP, and select the best surgical modality for RRP among microdebrider, CO2 laser, and KTP laser. Material and methods Medical records of 72 AO-RRP patients were reviewed, with at least a 6-month follow-up. We focused on demographic data, the median treatment intervals (MTI) (Days), the survival curves, and treatment-related complications. Results Seventy-two AO-RRP and a total of 172 surgical procedures were included, with either the microdebrider (n = 46), CO2 laser (n = 102), or KTP laser (n = 24). The MTI of all patients was 230.0[132.0, 455.0] (median[P25-P75]), with microdebrider group (267.50[152.5, 449.5]), CO2 laser group (247.5[145.5, 474.7]), and KTP laser group (107.5[68.3, 330.5]), and there were no significant differences among three surgical modalities on MTI or survival curves (p > .05). The duration of surgery was 44.9[25.6] in the microdebriders group, 48.4 [29.5] in the CO2 laser group, and 51.3[18.4] in the KTP laser group, but there was no significant difference in the operation duration among the three groups (p > .05). Postoperative glottic webs and scar formations were found in 4.3% of patients in microdebrider group, 16.7% of patients in CO2 laser group, and 8.3% of patients in KTP group. Conclusion and Significance Microdebrider surgery for RRP took the shortest time and had the lowest rate of postoperative complications. However, different surgical modalities are equally effective in controlling recurrence after RRP surgery.

Recurrent Respiratory Papillomatosis: Quality of Life Data from an International Patient Registry.

Quality of life studies in recurrent respiratory papillomatosis (RRP) have traditionally relied upon clinician-designed survey instruments. This study's objective is to report quality of life outcomes from a patient-designed questionnaire. Patients who provided health information and completed a quality of life questionnaire were identified from the RRPF-CoRDS patient registry. Demographic, clinical, and quality of life measures were collected. Means and standard deviationswere calculated for continuous data, and frequencies and percentages were calculated for categorical data. Outcomes for patients with juvenile-onset RRP (JORRP) and adult-onset RRP (AORRP) were compared using Student's t-tests for continuous data and χ2 analyses for categorical data. Seventy-three patients with RRP were identified (JORRP: 32; AORRP: 41). Common clinical symptoms included raspy voice (78.1%) and dyspnea (61.6%). The majority (97.3%) of patients reported feeling debilitated by their diagnosis, and 94.5% of patients reported avoiding participation in career and/or social activities due to their voice quality. Due to their RRP, 65.7% reported missing at least five work days each month. Social anxiety was reported in 79.5% of patients, though only 28.8% of the cohort reported utilizing mental health services. The median (range) lifetime number of surgeries received was 20 (1 - 3). Most patients (57.5%) reported paying at least 5% of their annual income towards RRP-related medical care. RRP presents high mental and fiscal burden. Our results highlight data from a quality of life questionnaire designed by RRP patients, and may help to elucidate potential disconnects between what clinicians and RRP patients consider most impactful. 4 Laryngoscope, 2022.

Metformin for the Treatment of Recurrent Respiratory Papillomatosis.

Metformin is an oral agent used for the management of type 2 diabetes. As a result of its ability to alter cellular metabolic requirements, metformin also possesses antiproliferative properties. Metformin has been shown to reduce mutagenesis in several malignancies, however has never been described as a treatment option for recurrent respiratory papillomatosis (RRP). The aim of this study is to present a case series of non-diabetic patients with adult-onset RRP who were treated with metformin. Case series. Five patients (age 48 ± 17.82, range 35-68, 4 males, 1 female) were identified with a history of laryngeal RRP who were treated with 500 mg of metformin twice daily. Follow-up time ranged from 11 to 105 months. Two patients had spontaneous regression of RRP lesions within months of starting metformin. Four patients had reduced time intervals between surgical procedures after starting metformin. All patients tolerated metformin well with only minor side effects of self-limiting light-headedness, facial flushing or gastrointestinal upset. Metformin is a low-risk medication that was used to reduce progression and burden of disease in 5 patients with RRP. Further studies should investigate the sole or adjunct use of metformin for treatment of RRP.

Adult-onset Recurrent Respiratory Papillomatosis at a South African Referral Hospital.

The aim of this study was to describe the clinical presentation and outcome of patients with adult-onset recurrent respiratory papillomatosis (AoRRP) in a developing country with the challenges of poor health care access and high prevalence of HIV infection. This was a retrospective study of patients diagnosed with AoRRP who were managed in the Department of Otorhinolaryngology at Universitas Academic Hospital in Bloemfontein, South Africa over a 10 year period. There were a total of 41 patients, of which 26 (63.4%) were male. The age at diagnosis ranged between 16.4 and 67.4 years (mean 39.4 ± 14.9 years). All patients presented with a hoarse voice, with three patients also having upper airway obstruction. Eight (19.5%) patients were HIV positive. HPV typing was performed in 29 patients; 14 had HPV11 disease, 12 had HPV6 disease and in 3 patients HPV DNA was not detected. There was no significant difference in initial presentation or outcome between HIV negative and HIV positive patients, or between patients with HPV6 and HPV11 disease. Two patients had malignant transformation of the papillomas. In both these patients, HPV was not detected in the papillomas. HPV type and HIV infection did not appear to influence the clinical presentation and outcome in patients with AoRRP. There is a risk of malignant transformation in patients in which HPV is not detected in the papillomas.

Adjuvant therapy for recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP) is a relatively rare disease with potentially devastating consequences for the patient. Its course is unpredictable, ranging from mild disease and spontaneous remission to aggressive disease with pulmonary dissemination and the need for frequent surgery. It can also have a chronic clinical course and cause potentially life-threatening airway damage. A number of alternative medical therapies to standard surgical treatment have been investigated in recent decades, but the results of these studies remain moderate. Recent years have brought significant changes in the incidence of the disease due to breakthroughs in vaccination and prevention of human papillomavirus (HPV) or related pathology. In Poland and many other countries, RRP is not a notifiable disease, hence current data is very limited. It has been accepted to refer to RRP as Juvenile-onset papillomatosis (JoRRP) when the disease occurs in childhood, otherwise it is Adult-onset RRP (AoRRP). This review will present the most promising directions in the fight and prevention of this disease.

Surgery and Adjuvant Therapy Improve Derkay Scores in Adult and Pediatric Respiratory Papillomatosis.

Comparing Derkay anatomical score at time of procedure, disease characteristics, and mean treatment interval among adult and pediatric patients with recurrent respiratory papillomatosis (RRP). Restrospective study. Retrospective review of juvenile-onset (JO) and adult-onset (AO) RRP patients treated longitudinally at pediatric and adult institutions from 1999 to 2019. Patients were included if they had a tissue diagnosis of papilloma and had at least a 12-month follow-up. One hundred and twelve patients met inclusion criteria (68 JO-RRP and 44 AO-RRP). All patients were stratified into either potassium titanyl phosphate (KTP) (n=42), CO2 (n=21), or microdebrider (n=49) treatment groups. The Derkay score improved between first and last procedure in the KTP group (mean difference, 3.5; P < .001), CO2 group (mean difference, 4.4; P < .001), and microdebrider group (mean difference, 4.1; P < .001), but overall improvement did not differ across groups (P=.73). Baseline mean to last mean Derkay score improved for nine patients during bevacizumab treatments (mean difference, 3.0; P=.01) but did not improve for these same patients during an interval prior to receiving bevacizumab treatments. Baseline mean to last mean Derkay score improved for 19 patients during cidofovir treatments (mean difference, 3.84; P < .001) but did not improve for these same patients during the interval prior to receiving cidofovir treatments. The AO-RRP population had more patients with dysplasia (50%) compared to JO-RRP population (10%) (P < .001). Various surgical modalities appear to be equally effective treatments for RRP. Adult and pediatric patients have decreased recurrent disease burden when receiving bevacizumab or cidofovir. AO-RRP patients have more concomitant dysplasia. 3 Laryngoscope, 132:2420-2426, 2022.

Epstein-Barr virus may contribute to the pathogenesis of adult-onset recurrent respiratory papillomatosis: A preliminary study.

Human papillomavirus (HPV) causes adult-onset recurrent respiratory papillomatosis (AORRP), but AORPP prevalence is much lower than HPV prevalence. Thus, HPV infection is necessary, but not sufficient, to cause AORRP and other factors likely contribute to its pathogenesis. The present study aimed to investigate whether co-infection with herpetic viruses may contribute to the pathogenesis of AORRP. Prospective case-control study conducted from January 2018 to November 2019. Tertiary referral centre. Eighteen consecutive patients with AORRP and 18 adults with healthy laryngeal mucosa (control group) undergoing surgery. Cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex viruses 1 and 2, human herpesvirus 6, varicella zoster virus and HPV (including genotyping) were detected in biopsies of papilloma or healthy mucosa using real-time polymerase chain reaction and reverse line blot. Dysplasia and Ki67 levels were determined in papilloma specimens. EBV was present in 6 (33.3%) AORRP patients and no control patients (P=.019). Presence was not dependent on tobacco exposure (P=.413) or HPV genotype or concentration (P>.999). EBV presence was strongly related to increased cell proliferation (P=.005) and number of previous surgeries (P=.039), but not dysplasia (P>.999). Human herpesvirus 6 was found in 3 (16.7%) AORRP biopsies, with one false positive. No other herpetic virus was found. Unlike other herpetic viruses, EBV seems to interact with HPV, enhancing cell proliferation and contributing to the pathogenesis and progression of AORRP. Further research is required to elucidate specific interactions and their role in the pathogenesis of AORRP.

Use of intralesional cidofovir in the recurrent respiratory papillomatosis: a review of the literature.

Recurrent respiratory papillomatosis (RRP) is characterized by exophytic, benign, and papillary lesions infected by the virus in the epithelium of the upper aerodigestive tract. RRP is caused by persistent infection of the respiratory epithelium by human papillomavirus (HPV) HPV6 and-11. The clinical course of RRP is unpredictable, frequently relapsing, and may be lifelong. The aim of this study is to evaluate the efficacy and safety of the use of intralesional Cidofovir in the treatment of RRP. We have selected articles on the use of cidofovir as adjuvant therapy in laryngeal papillomatosis. We reviewed 20 reports that enrolled 185 patients with "adult onset recurrent respiratory papillomatosis" (AORRP) and 85 patients with "juvenile onset recurrent respiratory papillomatosis" (JORRP). We evaluated concentration of cidofovir, number of injections, injection interval, therapeutic response, side effects, and progression to dysplasia. The mean concentration of cidofovir was 7.5 mg/ml at injection. The mean number of injections per patient is 6 with 26 days between injections. The percentage of patients with dysplasia after use of cidofovir is 1.48%. The AORRP response to cidofovir is better with a 74% complete response rate, compared to 56.5% of the JORRP. Intralesion use of cidofovir has a good adjuvant action in RRP increasing the complete remission of the disease. The treatment does not increase the risk of laryngeal dysplasia.

Características clínicas y epidemiológicas de la papilomatosis laríngea recurrente. Estudio retrospectivo del periodo 2012 a 2017

Introducción y objetivo: La papilomatosis laríngea representa la neoplasia benigna de laringe más común, siendo la papilomatosis respiratoria recurrente (PRR) su presentación clínica más compleja. Esta entidad, de baja prevalencia mundial, se asocia a un importante impacto económico y en la calidad de vida de los pacientes. Existen limitados datos sobre su perfil epidemiológico en latinoamérica. Los objetivos del estudio son identificar las características clínicas, epidemiológicas, de tratamiento y seguimiento propios de esta entidad y específicos para nuestra región. Método: Estudio observacional retrospectivo que describe a los pacientes con PRR atendidos en el servicio de Otorrinolaringología del Hospital de Especialidades Teodoro Maldonado Carbo (Guayaquil-Ecuador), en un periodo de 5 años. Resultados: Se identificaron 34 pacientes con PRR. El 88,24% fue de inicio en el adulto. La relación hombre/mujer fue 2,09:1. La edad de diagnóstico varió entre 3-75 años con promedio de 45,41 años. El síntoma predominante fue la disfonía con 97,06%. El principal sitio anatómico de lesión fue las cuerdas vocales en el 85,29%. 23 pacientes fueron intervenidos en el hospital (67,65%). 15 pacientes presentaron papiloma escamoso sin displasia (65,21%). Se identificaron 5 pacientes en remisión, 5 con persistencias y 13 con recurrencias postquirúrgica. Discusión: La frecuencia anual de PRR fue mayor que lo reportado en la bibliografía internacional. Existieron variaciones con respecto a la distribución según edad y sexo, y porcentaje de displasia y malignización. No se observó diferencias en la frecuencia de los síntomas, tiempo de evolución, localización anatómica, número de cirugías previas o recurrencias post quirúrgicas. Conclusiones: La PRR de inicio en el adulto fue la presentación más frecuente con predilección por el sexo masculino y distribución etaria bimodal. El principal síntoma al diagnóstico fue la disfonía, asociada a evolución crónica y compromiso de las cuerdas vocales. La edad de diagnóstico fue inversamente proporcional al número de cirugías previas, pero no se relacionó con la severidad prequirúrgica o diagnóstico histopatológico. La prevalencia de recurrencias postquirúrgicas dominó en ambos grupos denotando la agresividad de la infección, así como la limitación del tratamiento unimodal.

Mitochondrial somatic mutations and the lack of viral genomic variation in recurrent respiratory papillomatosis

Recurrent Respiratory Papillomatosis (RRP) is a rare disease of the aerodigestive tract caused by the Human Papilloma Virus (HPV) that manifests as profoundly altered phonatory and upper respiratory anatomy. Current therapies are primarily symptomatic; enhanced insight regarding disease-specific biology of RRP is critical to improved therapeutics for this challenging population. Multiplex PCR was performed on oral rinses collected from twenty-three patients with adult-onset RRP every three months for one year. Twenty-two (95.6%) subjects had an initial HPV positive oral rinse. Of those subjects, 77.2% had an additional positive oral rinse over 12 months. A subset of rinses were then compared to tissue samples in the same patient employing HPViewer to determine HPV subtype concordance. Multiple HPV copies (60–787 per human cell) were detected in RRP tissue in each patient, but a single dominant HPV was found in individual samples. These data confirm persistent oral HPV infection in the majority of patients with RRP. In addition, three novel HPV6 isolates were found and identical HPV strains, at very low levels, were identified in oral rinses in two patients suggesting potential HPV subtype concordance. Finally, somatic heteroplasmic mtDNA mutations were observed in RRP tissue with 1.8 mutations per sample and two nonsynonymous variants. These data provide foundational insight into both the underlying pathophysiology of RRP, but also potential targets for intervention in this challenging patient cohort.

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

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.

Cost of treating recurrent respiratory papillomavirus in commercially insured and medicaid patients

The study objective was to estimate the first 2 years' direct costs of treating new cases of juvenile-onset and adult-onset recurrent respiratory papillomatosis (RRP) and determine the predictors of treatment costs. Cases were patients diagnosed with RRP in commercial insurance claims in 2011-2014 and Texas Medicaid in 2008-2012 for treatment of RRP. Controls were patients without a diagnosis of HPV-related cancer or RRP, matched with cases by age, sex, geographic area, date of diagnosis of RRP, and propensity score. Total health care costs in the first 2 years after diagnosis were obtained from cases and matched controls. A generalized linear model was created to identify predictors of monthly costs. In commercially insured patients, a total of 122 cases of juvenile-onset (<18 years old) and 1824 cases of adult-onset (≥18 years old) RRP were identified. The mean first 2 years' cost difference between cases and controls was $58,733 for juvenile-onset disease and $11,185 for adult-onset disease after model adjustments. In the Texas Medicaid population, 73 cases of juvenile-onset and 96 cases of adult-onset RRP were identified. The mean first 2 years' cost difference between cases and controls was $76,115 for juvenile-onset disease and $4,633 for adult-onset disease after model adjustments. The first 2 years' medical costs difference of juvenile-onset and adult-onset RRP among commercially insured and Medicaid population were approximately $60,000 to $70,000 and $5,000 to $11,000, respectively, and should be considered in HPV vaccination promotion investment decisions. N/A Laryngoscope, 130:1186-1194, 2020.

A phase II study of pembrolizumab for HPV-associated papilloma patients with laryngeal, tracheal, and/or pulmonary involvement.

2502 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 &amp; 11. RRP proliferates in the respiratory tract impacting breathing, swallowing, and voice and carries a 1-4% risk of malignant transformation. There is no curative therapy for RRP. Given the tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts &gt; 12 years of age were treated with pembro 200mg every 3 weeks. Adjuvant surgical debridement of RRP was permitted for airway obstruction but not dysphonia. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease in response out of 21 (assuming &gt; 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). Serial biopsies (up to 8 biopsies/patient over the 24 months of treatment) to identify biomarkers of response and mechanisms of immune resistance (PD-L1 expression, mutations in HLA class I antigen presentation machinery, and tumor mutational burden) are underway. Results: Accrual is complete (n = 21 pts accrued between May 2016 and Jan 2019). Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. As of February 1, 2019, ORR is 43% (9/21) (.95 two-stage CI: 22%-66%) (4 of 11 with juvenile-onset RRP and 5 of 10 with adult-onset RRP disease responded). No complete responses have been observed. Fatigue was the most frequent treatment related adverse event (TRAEs); Grade 3 TRAEs included uveitis and hypophysitis, both were reversible upon pembro discontinuation. The frequency of surgical interventions was reduced in all pts undergoing surgery for airway palliation prior to study entry. Conclusions: Pembro reduces the need for routine surgical interventions based on the response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.

Laryngopharyngeal Reflux Is a Potential Risk Factor for Juvenile-Onset Recurrent Respiratory Papillomatosis.

Introduction Human papillomavirus (HPV) causes juvenile-onset recurrent respiratory papillomatosis (JORRP). Although HPV is common in children, the prevalence of JORRP is low. It is likely that other factors contribute to the pathogenesis of JORRP, during either activation or reactivation of a latent HPV infection. There is evidence that laryngopharyngeal reflux (LPR) might be such a risk factor for adult-onset recurrent respiratory papillomatosis. This study investigated if LPR might also be a risk factor for JORRP. Materials and Methods Children with JORRP of the larynx that required microlaryngoscopy at a tertiary referral hospital were included in this prospective case-series study from November 2015 to November 2017. Using immunohistochemistry, HPV infection and pepsin associated with LPR were diagnosed from laryngeal biopsies. Results Eleven children (aged 4-14 years) were analyzed. No patient had a history of immunodeficiency or tobacco smoke exposure. All patients underwent at least three previous surgeries due to JORRP and had been vaccinated against HPV in the past. Five children were treated using antivirotics and immunomodulators. The only known maternal risk factor was that three mothers were primiparous. All 11 samples were infected with HPV (type 6 or 11). Pathologic LPR was diagnosed in 5/11 children (45.5%). Conclusion LPR may be a risk factor for JORRP, contributing to its development by activating or reactivating a latent HPV infection. Results are in accordance with those from our previous study in adults.

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.

FROM BAD TO WORSE: A CASE OF MALIGNANT TRANSFORMATION OF RESPIRATORY PAPILLOMATOSIS TO SQUAMOUS CELL CANCER OF THE LUNG IN AN HIV-POSITIVE PATIENT

SESSION TITLE: Lung Pathology 1 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Recurrent respiratory papillomatosis (RRP) is a rare disease manifested by the presence of numerous papillomas within the larynx and tracheobronchial tree. Etiologically derived from human papilloma virus (HPV), primarily from serotypes 6 and 11, RRP has a course with a wide spectrum of possibilities including spontaneous regression to malignant transformation. CASE PRESENTATION: A 57-year-old African American male with a 30 pack-year smoking history and medical history of HIV (on ARVs) and tracheobronchial papillomatosis presented as a walk-in to the pulmonary clinic for complaints of hemoptysis, weight loss and fatigue. The physical exam was significant for coarse breath sounds and inspiratory crackles over the right middle and lower lobe. He was not in respiratory distress. He did not have any evidence of oral, sinonasal, laryngeal, anal, or genital papillomatosis. Bronchoscopic tissue sampling 3 months previously confirmed benign papillomatosis. The chest X-ray demonstrated new confluent mass-like consolidation in the right lower lobe and a new medial left lower lobe consolidation. A previous CT of the chest demonstrated collapse of the bilateral lower lobe bronchioles, numerous scattered nodules, and increased consolidative nodularity in the right greater than left lower lobe. He underwent bronchoscopy with biopsy, which demonstrated squamous papilloma with high-grade dysplasia and small cell carcinoma without definite invasion. A PET CT scan demonstrated multiple bilateral nodular densities with intense FDG uptake and no evidence of metastasis. He was referred to oncology and is currently receiving chemotherapy with Carboplatin and Paclitaxel. DISCUSSION: Adult-onset RRP is rare, most commonly occurring in the juvenile age group. Rarer is extension into the lung parenchyma, occurring in less than 1% of patients. Malignant transformation is most rare in this usually benign disease, though active smoking and HIV infection increases the risk of this occurring. In fact, it is known that malignant transformation to squamous cell carcinoma of the anus, also associated with HPV-related papillomatosis, is one of the most frequent non-AIDS defining illnesses in HIV patients. It is thus reasonable to extrapolate from this information that an increased risk for malignant transformation from HPV-related papillomatosis occurs in the lungs as well. To our knowledge, this is the first report of malignant transformation to squamous cell carcinoma of the lung in an HIV-infected individual with adult-onset RRP. CONCLUSIONS: RRP ranges from benign disease to risk for malignant transformation. Behavior modification with smoking cessation and close follow-up are strongly encouraged. Hammoud D, Haddad BE. Squamous cell carcinoma of the lungs arising in recurrent respiratory papillomatosis. Respiratory Medicine CME. 2010;3(4):270-272. https://doi.org/10.1016/j.rmedc.2009.09.021. Reference #1: Xiao Y, Wang J, Han D, Ma L. A Case of the Intrapulmonary Spread of Recurrent Respiratory Papillomatosis With Malignant Transformation. Lopez FA, ed. The American Journal of the Medical Sciences. 2015;350(1):55-57. https://doi.org/10.1097/MAJ.0000000000000370. Reference #2: Moanna A, Flenaugh EL, Lennox JL, Moss M, Vuchetich A. Severe Recurrent Respiratory Papillomatosis in an HIV-infected Adult on Highly Active Antiretroviral Therapy. Journal of Bronchology. 2005;12(4):210-213. https://doi.org/10.1097/01.lab.0000174647.08643.cc.Hidalgo-Tenorio Reference #3: C, Gil-Anguita C, Ramírez-Taboada J, et al. Risk factors for infection by oncogenic human papillomaviruses in HIV-positive MSM patients in the ART era (2010–2016). Maatouk. I, ed. Medicine. 2017;96(39):e8109. https://doi.org/10.1097/MD.0000000000008109. DISCLOSURES: No relevant relationships by Aarti Duggal, source=Web Response No relevant relationships by Eric Flenaugh, source=Web Response No relevant relationships by Marilyn Foreman, source=Web Response No relevant relationships by Marina Mosunjac, source=Web Response No relevant relationships by Snigdha Nutalapati, source=Web Response No relevant relationships by Dana Thomas, source=Web Response