VEGF as a Key Actor in Recurrent Respiratory Papillomatosis: A Narrative Review.

Recurrent respiratory papillomatosis (RRP) is a benign disease of the upper aerodigestive tract caused by human papillomavirus (HPV) types 6 and 11. The clinical course is unpredictable and some patients, especially younger children, experience a high rate of recurrence with a significant impact on their quality of life. The molecular mechanisms of HPV infection in keratinocytes have been extensively studied throughout the years, with particular regard to its role in causing malignant tumors, like cervical cancer and head and neck carcinomas. A minor but not negligible amount of the literature has investigated the molecular landscape of RRP patients, and some papers have studied the role of angiogenesis (the growth of blood vessels from pre-existing vasculature) in this disease. A central role in this process is played by vascular endothelial growth factor (VEGF), which activates different signaling cascades on multiple levels. The increased knowledge has led to the introduction of the VEGF inhibitor bevacizumab in recent years as an adjuvant treatment in some patients, with good results. This review summarizes the current evidence about the role of VEGF in the pathophysiology of RRP, the molecular pathways activated by binding with its receptors, and the current and future roles of anti-angiogenic treatment.

PGE2 expression by HPV6/11-induced respiratory papillomas blocks NK cell activation in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP), a rare chronic disease caused primarily by human papillomavirus types 6 and 11, consists of repeated growth of premalignant papillomas in the airway. RRP is characterized by multiple abnormalities in innate and adaptive immunity. Natural killer (NK) cells play important roles in immune surveillance and are part of the innate immune responses that help prevent tumor growth. We identified that papillomas lack classical class I MHC and retain nonclassical class I MHC expression. Moreover, in this study, we have identified and characterized the mechanism that blocks NK cell targeting of papilloma cells. Here, we show for the first time that the PGE2 secreted by papilloma cells directly inhibits NK cells activation/degranulation principally through the PGE2 receptor EP2, and to a lesser extent through EP4 signaling. Thus, papilloma cells have a potent mechanism to block NK cell function that likely supports papilloma cell growth.

Effectiveness of surgery combined with photodynamic therapy for recurrent respiratory papillomatosis.

OBJECTIVE: This study aims to analyze the safety and effectiveness of a new model of surgery combined with Photodynamic therapy for treating Recurrent Respiratory Papillomatosis (RRP). METHODS: Review the case data of patients with RRP who opted for comprehensive surgery combined with Photodynamic therapy at the Nanjing BenQ Medical Center, from January 2021 to May 2023. The efficacy of this program was evaluated by comparing the annual number of surgeries and Derkay scores before and after the surgery. RESULTS: A total of 23 RRP patients were included in the study. After treatment, the recurrence rate was 65.2 % (15/23), with an average recurrence time of 94.3 ± 50.8 days. The average Derkay score at the time of recurrence was significantly lower than the average pre-treatment Derkay score (P < 0.001). The average annual recurrence rate before treatment was 2.2 ± 1.3, compared to 1.5 ± 1.5 after treatment, with no significant difference (P = 0.16). However, subgroup analysis revealed a significant decrease in the annual recurrence rate of adult-onset RRP after treatment (P = 0.01). The most common adverse reaction was mild pharyngeal pain (11/23). There were 3 cases of new-onset vocal cord adhesions. No patients experienced serious respiratory-related adverse reactions, anesthesia-related adverse reactions, or systemic phototoxic reactions. CONCLUSION: In conclusion, this study indicates that surgery combined with Photodynamic therapy (PDT) might be a safe and effective option for treating RRP, especially in patients with Adult-Onset Recurrent Respiratory Papillomatosis (AORRP).

A pilot study on salivary HPV DNA detection to monitor active disease from patients with recurrent respiratory papillomatosis.

PURPOSE: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-related disease affecting the upper airway and saliva could be an important non-invasive sampling source for viral screening and clinical monitoring. We investigated whether HPV DNA could be detected in saliva (cellular pellets and supernatant) from RRP patients and influence on clinical manifestation of the disease. MATERIALS AND METHODS: In this pilot study, saliva samples from 14 RRP patients were obtained in preoperative condition (n = 7) and in disease-free interval (DFI; n = 7). Healthy donors (n = 14) were also included. HPV DNA was investigated by polymerase chain reaction (PCR)-based assays. RESULTS: From cellular pellets, HPV-positive saliva was only detected from preoperative collections (5/7; 71.4 %) and showed a mean cycle threshold (Ct) value of 24.33 (±1.25), whereas all patients in DFI were HPV-negative (Ct ≥ 32.16), revealing significant difference between these two clinical moments (p = 0.021). Patients in DFI and healthy donors showed similar Ct values. From saliva supernatant, detectable HPV cell-free DNA (cfDNA) occurred in 42.9 % (3/7) and 57.1 % (4/7) of preoperative collections using the commercial cfDNA kits from Norgen and Qiagen, respectively. Salivary cfDNA size distribution obtained by TapeStation analysis showed a predominant size range of 150 to 400 bp in both patients and healthy controls, corresponding to mononucleosomal and dinucleosomal fragments. CONCLUSIONS: In conclusion, HPV DNA screening in saliva (both cellular pellets and cfDNA) may have clinical utility to monitor active disease of RRP patients.

Intralesional cidofovir vs. bevacizumab for recurrent respiratory papillomatosis: a systematic review and indirect meta-analysis.

BACKGROUND: Specific HPV types cause recurrent respiratory papillomatosis (R.R.P.). When administered intralesionally, cidofovir, an antiviral agent, has shown favorable outcomes in reducing papilloma. Bevacizumab, an angiogenesis inhibitor, has demonstrated improved R.R.P. However, both treatments lack FDA approval for R.R.P. Our study aims to evaluate the efficacy and safety of intralesional Cidofovir and Bevacizumab for R.R.P. and compare the two interventions. METHODS: We searched five electronic databases to find relevant studies. After the screening, data were extracted from the included studies. Pooled ratios with 95% confidence intervals (CIs) were used for categorical outcomes, and mean difference (MD) was used for continuous outcomes. Statistical heterogeneity was evaluated using the chi-squared test for I2 statistics. The Cochrane Risk of Bias assessment tool was used to assess the methodological quality of randomized controlled trials (RCTs), while the National Institutes of Health's tool was used for observational studies. Analysis was done by Review Manager software. RESULTS: In our comprehensive meta-analysis of 35 articles involving 836 patients, cidofovir demonstrated an overall remission ratio of (0.90 [95% CI: 0.83, 0.98], p = 0.01), while bevacizumab (0.92 [95% CI: 0.79, 1.07]), p = 0.3). The complete remission ratio for cidofovir was (0.66 [95% CI: 0.57, 0.75], p > 0.0001), while bevacizumab was (0.29 [95% CI: 0.12, 0.71], p = 0.07). In partial remission, Bevacizumab showed a higher ratio than Cidofovir 0.74 [0.55, 0.99] vs. 0.40 [0.30, 0.54]. Bevacizumab had a pooled ratio of 0.07 [95% CI: 0.02, 0.30] in terms of no remission, indicating better outcomes compared to Cidofovir with a ratio of 0.28 [95% CI: 0.16, 0.51]. Additionally, Cidofovir showed a favorable decrease in the Derkay Severity Score (DSS) with a mean difference (MD) of 1.98 [95% CI: 1.44, 2.52]. CONCLUSION: Cidofovir had a higher impact on complete remission compared to Bevacizumab. Both showed partial remission, with Bevacizumab having a higher ratio. Moreover, Cidofovir showed a significant decrease in DSS. Bevacizumab had lower rates of no remission and recurrence and fewer adverse events compared to Cidofovir. However, the difference between the two treatments was not significant, except for partial remission.

Cimetidine for recurrent respiratory papillomatosis in pregnancy as an alternative adjuvant treatment.

BACKGROUND: We report the first case of cimetidine as an alternative adjuvant therapy in a pregnant woman with recurrent respiratory papillomatosis (RRP). A 40 year old woman at 19 week gestation presented with progressive hoarseness and shortness of breath for 1 month. Flexible nasopharyngolaryngoscopy revealed multiple papillomatous lesions over both vocal cords and subglottic area obstructing 60% of her airway. She had previously been diagnosed with juvenile onset RRP at the age of 5 and underwent endoscopic clearance regularly every 6 months. METHOD: The patient was started on a trial of oral cimetidine at a dose of 30 mg/kg and responded well, eventually requiring endoscopic excision only after 2 years. Subsequently, she underwent in vitro fertilisation treatment and stopped taking her cimetidine. After undergoing endoscopic clearance of her papillomata under general anaesthesia, she restarted on cimetidine during her 2nd and 3rd trimester. RESULTS: Ensuing follow-up demonstrated stable minimal papillomata lesions on her right inferior surface of her vocal cord with no recurrence on her left vocal cord and subglottic area. CONCLUSION: Cimetidine is generally safe and not known to be associated with any major teratogenic risks during pregnancy. RRP is postulated to worsen in pregnant women due to the increase in oestrogen levels during pregnancy. Hence, adjuvant therapy was imperative for our patient to reduce recurrent papillomata formation during her pregnancy. Larger scale studies are warranted to assess the use of long-term high-dose cimetidine in terms of efficacy and safety in pregnancy.

Systemic bevacizumab for treatment of recurrent respiratory papillomatosis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Effectiveness of combined approach to recurrent respiratory papillomatosis (RRP).

PURPOSE: Recent approaches for recurrent respiratory papillomatosis including local injection of bevacizumab and HPV vaccination show promise in reducing the need for frequent surgeries. In this study we propose a new combined approach of surgery, intralesional injection of 25 mg bevacizumab and HPV vaccine that can lead to resolution of RRP. MATERIAL AND METHODS: Our study involved 5 patients treated with a combination of transoral microsurgery, intralesional injection of 25 mg bevacizumab, and HPV vaccination with Gardasil 9 between April 2020 and May 2023. Standard video laryngoscopy was performed to assess the presence of papilloma and Derkay score was used to assess the severity of disease. RESULTS: All 5 patients completed the study successfully and a complete response was achieved by all. The follow-up ranged from 8 to 45 months. The mean total Derkay score before treatment was 41 (range 25 to 52) and after the combined approach was 0 both anatomically and clinically in all patients. CONCLUSIONS: This study demonstrates the effectiveness of a combined treatment approach for RRP involving surgical intervention, intralesional injection of bevacizumab, and HPV vaccination.

[Update on HPV-associated head and neck cancers-highlights of the 2024 ASCO Annual Meeting]. / Update zu HPV-assoziierten Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2024.

BACKGROUND: Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is becoming increasingly important in head and neck oncology. At this year's conference of the American Society of Clinical Oncology (ASCO), a large number of papers were presented on the topic of HPV-associated HNSCC, particularly with regard to neoadjuvant treatment approaches, radiation de-escalation strategies, therapeutic vaccines, and treatment monitoring. In this context, study results on the treatment of HPV-related recurrent respiratory papillomatosis (RRP) were also presented. OBJECTIVE: Based on contributions to the 2024 ASCO Annual Meeting, an insight into the latest developments in HPV-associated diseases of the head and neck is provided. METHODS: The papers were reviewed for clinical relevance and contextualized based on current therapeutic concepts. RESULTS AND CONCLUSION: A large number of studies on liquid biopsies (LB) were presented. It was shown that although the methods for analyzing LBs for HPV-positive patients are well developed and can be used for diagnostics, risk classification, treatment management, or tumor follow-up, the methods vary considerably, and their clinical application has not yet been sufficiently validated. With regard to therapeutic HPV vaccination, three large studies were presented for the treatment of recurrent/metastatic HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The only randomized study was on the vaccine ISA101b (peltopepimut-S) and did not reach its primary endpoint; however, the vaccine seemed to be highly effective in patients with a combined positive score (CPS) ≥ 20. Furthermore, data from a phase I study on PRGN2012, an adenovirus-based immunotherapy used therapeutically for the treatment of recurrent respiratory papillomatosis (RRP), were presented. PRGN2012 led to a reduction in surgical interventions for RRP, and the US Food and Drug Administration (FDA) designated PRGN2012 as a breakthrough therapy and orphan drug. However, the vaccine is not yet approved for the treatment of RRP.

Quality of Life in Recurrent Respiratory Papillomatosis Patients after Vocal Fold Surgery: An In-Depth Exploration.

INTRODUCTION: This study explores the quality of life among patients with recurrent respiratory papillomatosis (RRP) after vocal fold surgery as measured by the outcome scores of the Voice Handicap Index (VHI) and the Distress Thermometer and Problem List in Patients with Recurrent Respiratory Papillomatosis (DT&PL). Differences in quality of life were explored within the independent variables age, surgical frequency, weeks since last vocal fold operation, gender, HPV type, surgical location, vaccination with Gardasil©, and a patient's request to speak with a speech-language pathologist. METHODS: A single-center, observational cohort study was conducted using VHI and DT&PL scores and demographic and clinical data obtained from patient files. Inclusion criteria were a confirmed HPV type, age 18 years or older, the ability to fill in both questionnaires in Dutch, and having undergone at least one surgical procedure to remove laryngeal papilloma. Relationships of the independent variables with VHI and Distress Thermometer (DT) scores were explored using univariable and multivariable regressions and linear regression models. RESULTS: Of 271 RRP patients, 100 met the inclusion criteria and responded to requests to fill in both questionnaires with a minimum of 12 weeks after their last operation. Our study showed a statistically significant negative relationship between age and VHI scores (p = 0.02) in the univariable, and multiple linear regressions (p = 0.01), indicating that patients experienced fewer self-perceived functional voice disabilities with each increase in age. A parallel negative relationship is seen between the variables age (p = 0.03) and DT scores. Our results showed a statistically significant positive relationship between the number of vocal fold surgeries and DT scores (p = 0.03). CONCLUSION: The results of this study show a significant relationship between age, surgical frequency, and quality of life in patients with RRP. Older patients have lower Voice Handicap Index (VHI) and Distress Thermometer (DT) scores, indicating fewer self-perceived voice and disease-related quality of life problems. Conversely, a rise in surgical frequency is significantly associated with higher DT scores, reflecting greater disease-related distress.

Role of chemokines in HPV-induced cancers.

Human papillomaviruses (HPVs) cause cancers of the uterine cervix, oropharynx, anus, and vulvovaginal tract. Low-risk HPVs, such as HPV6 and 11, can also cause benign mucosal lesions including genital warts, and in patients with recurrent respiratory papillomatosis, lesions in the larynx, and on occasion, in the lungs. However, both high and less tumorigenic HPVs share a striking commonality in manipulating both innate and adaptive immune responses in HPV- infected keratinocytes, the natural host for HPV infection. In addition, immune/inflammatory cell infiltration into the tumor microenvironment influences cancer growth and prognosis, and this process is tightly regulated by different chemokines. Chemokines are small proteins and exert their biological effects by binding with G protein-coupled chemokine receptors (GPCRs) that are found on the surfaces of select target cells. Chemokines are not only involved in the establishment of a pro-tumorigenic microenvironment and organ-directed metastases but also involved in disease progression through enhancing tumor cell growth and proliferation. Therefore, having a solid grasp on chemokines and immune checkpoint modulators can help in the treatment of these cancers. In this review, we discuss the recent advances on the expression patterns and regulation of the main chemokines found in HPV-induced cancers, and their effects on both immune and non-immune cells in these lesions. Importantly, we also present the current knowledge of therapeutic interventions on the expression of specific chemokine and their receptors that have been shown to influence the development and progression of HPV-induced cancers.

Transcriptomic Landscape of Gene Expression Profiles and Pathways in Juvenile-Onset Recurrent Respiratory Papillomatosis Tumor Tissues and Human Papillomavirus 6 and 11 E6- and E7-Overexpressing Head and Neck Squamous Cell Carcinoma Cell Lines.

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is the most common benign laryngeal neoplasm in children and is considered to be primarily caused by human papillomavirus (HPV) types 6 and 11. In the present study, we performed RNA sequencing (RNA-seq) of 8 tumors and 4 adjacent nontumor tissues to explore the transcriptional profiles of JORRP tumors. A total of 1,151 upregulated genes involved in the interleukin-17 (IL-17) signaling pathway and 1,620 downregulated genes involved in dysregulated inflammatory responses were reported. Immunohistochemistry (IHC) assays confirmed the upregulation of IL-17C in JORRP tumors compared with paired adjacent nontumor tissues. Real-time PCR (RT-PCR) assays showed positive correlations between CXCL1 (CXC chemokine ligands 1) and CXCL8 and the Derkay Clinic Score of JORRP patients. We further overexpressed the HPV6 or HPV11 E6 and E7 oncogenes in SNU-1076 head and neck squamous cell carcinoma (HNSCC) cell lines and carried out RNA-seq. We found that HPV6-E6-E7 gene overexpression resulted in only 16 upregulated genes and 1 downregulated gene; however, HPV11-E6-E7 gene overexpression resulted in 1,776 upregulated genes and 461 downregulated genes compared with the control cell lines. The differentially expressed genes (DEGs) of HPV11-E6-E7 gene overexpression were positively enriched in the DNA replication-related terms by Gene Ontology (GO) analysis and the IL-17 signaling pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Taken together, our present findings revealed IL-17 signaling pathway-related gene profiles that might contribute to disease pathogenesis and that the HPV11 E6 and E7 oncogenes promote disease progression by enhancing tumor growth and activating the IL-17 signaling pathway in JORRP patients. IMPORTANCE Juvenile-onset recurrent respiratory papillomatosis (JORRP) is primarily caused by human papillomavirus 6 (HPV6) and HPV11 infection; however, the gene signatures of tumors are currently less understood. In the present study, we performed RNA sequencing and found upregulated genes associated with the IL-17 signaling pathway and downregulated genes associated with inflammatory-related pathways. Further RNA sequencing was performed in HPV6-E6-E7- or HPV11-E6-E7-overexpressing SNU-1076 HNSCC cells lines to explore the potential pathogenic molecular mechanisms of HPV virus. We found that HPV11-E6-E7 overexpression resulted in gene expression related to DNA replication and the IL-17 signaling pathway. Our results suggested enriched that the IL-17 signaling pathway resulting from HPV11 infection might contribute to JORRP pathogenesis.

Analysis of lesion location and disease characteristics of pharyngeal and laryngeal papilloma in adult.

OBJECTIVES: Papilloma is a common benign epithelial tumor of the respiratory tract in adults. Its histological structure and immune environment vary from site to site. This study investigated the disease characteristics and prognostic differences of papillomas at various primary locations. METHODS: Clinical data was collected from patients with adult glossal root and hypopharyngeal papilloma admitted to our tertiary referral center between January 2010 and December 2020, and compared with patients with laryngeal papilloma. Differences in age, sex, smoking, alcohol consumption, single or multiple lesions, surgical methods, immunohistochemical indexes, Ki-67 and p16, were analyzed in patients with different primary papilloma sites. RESULTS: A total of 84 cases of glossal root papilloma, 51 cases of hypopharyngeal papilloma, and 51 cases of laryngeal papilloma were included. Differential analysis between groups showed that there were statistically significant differences in age, sex, smoking, single and multiple lesions, and surgical methods in the different primary sites. Ki-67 expression in laryngeal papilloma was higher than that in glossal root and hypopharyngeal papilloma. There was no significant difference in p16 expression in the three groups. In terms of prognosis, laryngeal papilloma is more likely to relapse than glossal root or hypopharyngeal papilloma, and the recurrence time is shorter. CONCLUSIONS: As the largest clinical study of papilloma in different primary locations, this study found that the clinical characteristics and postoperative recurrence of papilloma of the glossal root and hypopharynx differ from those of papilloma of the larynx. This finding supports the current clinical experience in treating papillomas in different locations and facilitates the development of clinical treatment plans.

Molecular Mechanisms of Carcinogenesis in Pediatric Airways Tumors.

Primary tumors of the airways in the pediatric population are very rare entities. For this reason, little is known about the pathogenesis of these neoplasms. Understanding the biology has different practical implications: for example, it could help in the differential diagnosis, have a prognostic significance, or may lead to the development of a targeted therapy. The aim of this article is to present the current knowledge about pediatric airways tumors, focusing on the molecular mechanisms that cause the onset and progression of these neoplasms. After a brief introduction of epidemiology and clinical presentation, the tumorigenesis of the most frequent pediatric airways tumors will be described: Juvenile-onset recurrent respiratory papillomatosis (JORRP), Subglottic Hemangiona (SH), Rhabdomyosarcoma (RMS), and Mucoepidermoid carcinoma (MEC).

Safety of different surgical modalities for recurrent respiratory papillomatosis resection: A systematic review and meta-analysis.

BACKGROUND: Currently, the most common surgical modalities used for recurrent respiratory papillomatosis (RRP) resection are microdebrider, carbon dioxide (CO2 ) laser and potassium-titanyl-phosphate (KTP) laser. However, complication rates vary among different surgical modalities and have been controversial in different studies. OBJECTIVE OF REVIEW: This study systematically reviews the available studies which reported intra-operative and post-operative complications, aiming to compare the safety of microdebrider, CO2 laser and KTP laser. TYPE OF REVIEW: Meta-analysis. SEARCH STRATEGY: Seven electronic databases (PubMed/MEDLINE, EMBASE[Ovid], Scopus, Cochrane Library and Web of Science) were searched from inception through 28 April 2022. Randomised controlled, prospective or retrospective observational studies that recorded the complications of three different surgical modalities for RRP resection were included in the meta-analysis. EVALUATION METHOD: Outcomes of interest were intra-operative and post-operative complications, and complication rate was calculated to evaluate the safety of surgical methods. RESULTS: Twenty different studies were included in quantitative synthesis. Only one study compared outcomes of those three kinds of treatment modalities simultaneously, two studies compared microdebrider and CO2 laser, and the remaining studies focussed on only one of three treatments. The weighted average complication rate for microdebrider was 0.03 (95% confidence interval [CI] 0.00-0.21), n = 6, for CO2 laser treatment was 0.16 (95% CI 0.09-0.25), n = 14 and for KTP laser treatment was 0.04 (95% CI 0.00-0.14), n = 4. CONCLUSION: The limited evidence demonstrated that CO2 lasers in the surgical treatment of RRP may lead to more surgical complications, and microdebrider and KTP lasers may be safer. However, the heterogeneous data limit any strong comparison of outcomes of different treatment of laryngeal papillomas. Future randomised controlled trials that directly compare the safety of different surgical modalities are needed.

Role Of CO2 Laser & Microdebrider In The Treatment Of Juvenile Onset Recurrent Respiratory Papillomatosi.

OBJECTIVE: To compare the efficacy of two main treatment modalities of microdebrider and carbon dioxide laser excision for juvenile onset recurrent respiratory papillomatosis. Methods: The retrospective study was conducted in May 2021 at the Combined Military Hospital, Kharian, Pakistan, and comprised data from July 1, 2007, to January 31, 2020, of patients of either gender aged 2-12 years who were treated for juvenile onset recurrent respiratory papillomatosis either with microdebrider excision in group A or carbon dioxide laser excision in group B. Extent and severity of disease was documented as per the Derkay-Coltrera grading system. Data was analysed using SPSS 20. RESULTS: Of the 39 patients, 23(59%) were girls and 16(41%) were boys. The overall mean age at the time of procedure was 6.62±2.06 years. Group A had 22(56.4%) subjects; 15(68.2%) girls and 7(31.8%) boys, while group B had 17(43.6%) cases; 8(47%) girls and 9(53%) boys. The mean operative time for group A was 40.91±11.50 minutes and for group B it was 60.59±19.51 minutes. Postoperative breathing and oedema status was better for group A (p<0.05), while there was no significant difference regarding postoperative pain, residual disease and repeat surgeries (p>0.05). CONCLUSIONS: Microdebrider was found to be superior to carbon dioxide laser excision in the treatment of juvenile onset recurrent respiratory papillomatosis.

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis.

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

The predominant site of pharyngeal lesions in patients with recurrent respiratory papillomatosis.

PURPOSE: Recurrent respiratory papillomatosis (RRP) is a disorder characterized by the frequent recurrence of benign neoplasms in the respiratory tract. Some patients with RRP develop laryngeal papilloma, while others present with extralaryngeal lesions in the nose, pharynx, and trachea. The present study aimed to determine the pharyngeal sites where RRP-related lesions develop more frequently. METHODS: We retrospectively reviewed the medical records of 127 patients treated at our department between January 2015 and December 2020. We compared the human papilloma virus (HPV) infection status and differences in tumor location between 41 patients with RRP and 86 patients with pharyngeal papilloma (PP). RESULTS: In the RRP group, extralaryngeal papillomata were observed in 10 patients, eight (19.5%) of whom presented with lesions in the inferior wall of the nasopharynx (IWoN). On the contrary, only one patient with PP (1.1%) developed papillomata in this region. IWoN papilloma was significantly more likely to arise in the RRP group than in the PP group (p = 0.0004). CONCLUSION: In RRP, pharyngeal lesions frequently arise in the IWoN, while this region remains largely unaffected in patients with PP.

High recurrence rate in patients with juvenile-onset respiratory papillomatosis and its risk factors.

PURPOSE: To identify the recurrence rate and risk factors for recurrence in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). METHODS: A retrospective review was performed for all JORRP patients who underwent surgery between 2002 and 2019 at our institution. The demographic characteristics and clinical parameters were recorded. Kaplan-Meier estimates and Cox proportional hazards models were used to analyze the rate of recurrence and its risk factors. RESULTS: Our study included 721 patients. The cumulative recurrence rates at 1, 5, and 10 postoperative years following initial surgery were 74.2%, 90.0%, and 94.3%, respectively. Age at diagnosis younger than 4.5 years (HR = 2.380, 95% CI [1.169-4.846], P = 0.017), high Derkay anatomical score (HR = 1.136, 95% CI [1.043-1.236], P = 0.003) and HPV type 11 infection (HR = 2.947, 95% CI [1.326-6.551], P = 0.008) were independent risk factors for recurrence. Adjuvant therapy with interferon was less likely to recur (HR = 0.237, 95% CI [0.091-0.616], P = 0.003). Additionally, gender, tracheotomy, mode of delivery, parity, expression of Ki-67, HPV vaccination, and surgical treatment method were not independently associated with recurrence (P > 0.05). CONCLUSION: Age at diagnosis younger than 4.5 years, high Derkay anatomical score and HPV type 11 infection were associated with an increased risk for recurrence in patients with JORRP. Adjuvant therapy with interferon may reduce the risk of recurrence.

Bevacizumab as treatment option for recurrent respiratory papillomatosis: a systematic review.

PURPOSE: To this day, there is no cure for recurrent respiratory papillomatosis (RRP). Multiple surgical procedures are performed to achieve symptom relief and prevention of airway obstruction. A promising drug for RRP is the vascular endothelial growth factor (VEGF) binding antibody bevacizumab. This chemotherapeutic agent has an angiogenesis-inhibiting effect which inhibits tumor growth. The objective of this review was to investigate the efficacy of bevacizumab as treatment option for RRP, and to explore the difference of its effects between intralesional and systemic treatment. METHODS: A systematic search was conducted in Cochrane, PubMed, and Embase. Articles were included if bevacizumab treatment was given intralesionally and/or systemically. The methodological quality of the studies was assessed using the CAse REport (CARE) guidelines. RESULTS: Of 585 unique articles screened by title and abstract, 15 studies were included, yielding a total of 64 patients. In 95% of the patients treated with systemic bevacizumab, the post-bevacizumab surgical interval was considerably prolonged. More than half of them did not need any surgical intervention during mean follow-up of 21.6 months. Treatment with intralesional bevacizumab showed a lower efficacy: in 62% of the patients, the post-bevacizumab surgical interval (mean, 1.8 months follow-up) was extended when compared to the interval before the treatment. CONCLUSION: Systemically and intralesionally administered bevacizumab are effective treatment options for severe RRP. A systemic administration might be the treatment of first choice. Further prospective research with long term follow-up is advocated to elucidate this important topic.