Successful Bevacizumab Therapy in a 25-Year-Old Patient with Recurrent Respiratory Papillomatosis.

Background: Recurrent respiratory papillomatosis (RRP) is a chronic condition caused primarily by human papilloma virus (HPV) types 6 and 11, leading to recurrent growths in the respiratory tract. These types of papilloma can cause significant morbidity due to airway obstruction, often requiring frequent surgical interventions. Traditional treatments, including surgical removal and adjunctive therapies like antivirals and immune modulators, often fail to prevent recurrence, impacting the patient's quality of life. Case description: This report presents a 25-year-old female with a long-standing history of RRP, diagnosed at age 2. Despite numerous interventions, including CO2 laser ablations, interferon therapy, HPV vaccination, and a laryngotomy with tracheal reconstruction, the patient continued to experience severe airway obstruction requiring frequent surgeries. In 2023, intravenous therapy with bevacizumab, vascular endothelial growth factor inhibitor was introduced, leading to a significant reduction in the frequency of surgical interventions from 8 to 4 per year. This reduction improved the patient's respiratory function and quality of life, highlighting bevacizumab's therapeutic potential. Conclusion: The case underscores the debilitating nature of RRP and the challenges of its management. Bevacizumab, by targeting vascular endothelial growth factor (VEGF), has shown promise in reducing papilloma growth and the need for frequent surgeries. This case supports the inclusion of bevacizumab as an adjunctive therapy in RRP treatment, warranting further research to confirm its long-term efficacy and safety. LEARNING POINTS: Recurrent respiratory papillomatosis is a rare and complex disease that severely impacts patients' quality of life.This case report demonstrates that bevacizumab can significantly reduce surgical interventions in recurrent respiratory papillomatosis (RRP), offering a promising treatment that improves management of this chronic condition.Bevacizumab, already used in treating various diseases by targeting VEGF, shows promise in managing RRP as well, highlighting its potential across multiple conditions and expanding its therapeutic versatility.

Advances in Recurrent Respiratory Papillomatosis Treatment: Adjuvant Intralesional Bevacizumab's Impact, Potential and Insights from a Case Series Study.

Recurrent respiratory papillomatosis is an aggressive benign disease characterised by the repeated growth of multiple warts involving the larynx as well as other parts of the respiratory tract. Recurrent respiratory papillomatosis is most commonly caused by human papillomaviruses 6 and 11. It requires multiple surgical procedures for tumour debulking.Our study aims to evaluate the impact and potential of adjuvant intralesional bevacizumab in the treatment of recurrent respiratory papillomatosis while providing valuable insights based on a case series analysis.A prospective study of a total of 13 patients with Recurrent respiratory papillomatosis attending a tertiary care hospital with ages ranging from 3 to 30 years was conducted from February 2018 to February 2023 by intralesional bevacizumab 1 ml with a concentration of 2.5 mg/ml per dose, 3 injections, each once every 4 weeks by calculating the number of operative procedures per year, duration of time between procedures, calculating the Derkay score before 1 year of the first injection and after 1 year of the last dose injection of bevacizumab treatment. Inclusion criteria are ages between 3 and 30 years with recurrent respiratory papillomatosis who underwent at least 4 or more surgical procedures with no adjuvant therapies. In all our cases, the affected area was the larynx.Adjuvant therapy with intralesional bevacizumab increases the duration of time between surgical procedures and reduces the number of operative procedures each year with an overall improvement in the Derkay score. No adverse drug effects have been reported in our study.Intralesional Bevacizumab is an effective and safe adjuvant treatment option for recurrent respiratory papillomatosis. It increases the duration of time between surgical procedures and decreases the number of procedures per year with an overall improvement in the Derkay score.

Recurrent respiratory papillomatosis: comparing in-office and operating room treatments.

Objective: We report the management of recurrent respiratory papillomatosis (RRP) employing a protocol that includes both office-based (OB) and general anaesthesia (GA) procedures. Quality of life (QoL) outcomes in the OB cohort were compared to those obtained from an historical cohort treated only under GA. Methods: Patients affected by RRP from 2019 until 2023 ("new protocol") and from 2012 to 2019 ("historical protocol") were enrolled. In both groups the Derkay site score (DSS) was calculated. In patients adhering to the new protocol, questionnaires measuring QoL were prospectively administered (voice handicap hindex-10 [VHI-10] along with a specific questionnaire to measure the tolerance to the OB procedures). A cost analysis was also performed. Results: In all, 35 patients composed the new protocol cohort and 13 the historical. In the first group, patients underwent a median of 4 treatments. At 2 years, 68% of patients were treated exclusively in the office. Overall, for the new protocol, median DSS and VHI-10 after one year were both significantly lower than those at baseline [2 vs 4 and 3 vs 14, respectively; p < 0.001]. No differences were found between the new and the historical protocol cohorts considering DSS over time. Conclusions: Treatment of RRP may be conducted successfully in an office-based setting reducing healthcare costs.

[Epidemiological features of laryngeal papillomatosis in adults in Moscow]. / Epidemiologicheskie osobennosti papillomatoza gortani u vzroslykh v Moskve.

OBJECTIVE: To evaluate the incidence of laryngeal papillomatosis (LP) and LP recurrence in adults and to determine the risk factors for the development of LP recurrence in adults in Moscow. To solve the tasks set, a survey of patients carried out, including the collection of complaints and anamnesis, a standard examination of the ENT organs, an assessment of the condition of the larynx, and a histological examination. MATERIAL AND METHODS: We conducted a retrospective analysis of the case histories of 299 patients with LP observed and treated at the Sverzhevsky Research and Clinical Institute of Otorhinolaryngology in the period 2010-2020. RESULTS: On average, over the entire study period, the prevalence of PG was 17.80%. It was found that out of 299 patients, 69.6% (n=208) had a relapse of LP. Papilloma of the larynx were more often localized in the glottis. 275 (92%) patients had a widespread form of LP. LP recurrences were significantly more common in women and in patients with an existing cicatricle process in the larynx. The relapse rate was higher in non-smokers (73.5% vs 47.8%; p<0.001). Although the recurrence rate was higher in patients with non-voice occupations (70.6% vs. 52.9%), there was no statistically significant association between relapses and the vocal professions (p=0.125). CONCLUSION: As a result of the study, a number of risk factors for laryngeal papillomatosis recurrent have been identified, and their study should be continued.

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).

Mucosal Injection of the Silicon Phthalocyanine Pc 4 in a Rabbit Model-A Pilot Study.

OBJECTIVE: The silicon phthalocyanine Pc 4 is a photosensitizing agent previously shown to be a promising treatment for cutaneous neoplasms using photodynamic therapy (PDT). Based on prior preclinical studies, we believe Pc 4-PDT has potential as a targeted treatment of human recurrent respiratory papillomatosis or laryngeal leukoplakia by direct injection into mucosal surfaces. METHODS: This was a proof-of-concept pilot study assessing direct mucosal injection of Pc 4 into buccal and vocal fold mucosae in a rabbit model. Five New Zealand white rabbits underwent tattooing of bilateral buccal mucosae to delineate injection sites, followed by submucosal injections of control and Pc 4 solutions. Rabbits were monitored for post-injection tolerance. Punch biopsies were obtained from injected mucosa and assessed histopathologically. Once the buccal mucosa was found to be tolerant, vocal folds of three rabbits were injected. The rabbits were then sacrificed, and laryngeal tissue was assessed histopathologically. RESULTS: All rabbits tolerated injection of Pc 4 and control solutions into buccal mucosa with no evidence of gross visual inflammatory changes and no changes in behavior or masticatory function. Histopathologic analysis of Pc 4 injected buccal and control mucosal tissue revealed mild focal histological changes and no stigmata of diffuse inflammatory reactions. The histopathologic analysis of Pc 4 injected into laryngeal tissue revealed similar findings with addition of mild eosinophilia in one sample. CONCLUSION: Direct mucosal injection of Pc 4 in rabbit buccal and vocal fold mucosae appears to be well tolerated with no gross inflammatory changes, and only mild histopathologic inflammatory changes observed. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Quantifying Bevacizumab Efficacy in Recurrent Respiratory Papillomatosis.

OBJECTIVES: To develop and validate a novel method for quantifying the efficacy of Bevacizumab (Bev) in treating Recurrent Respiratory Papillomatosis (RRP), and to evaluate the clinical outcomes of a three-dose Bev induction therapy followed by surgical intervention. METHODS: Twenty-one RRP patients treated with a three-dose Bev regimen were included. A novel efficacy evaluation method using ImageJ software was developed to calculate the standardized lesion volume from laryngoscopic images. This was compared with the Derkay score. Clinical outcomes, including reduction rate, cumulative reduction rate, efficacy grading, recurrence, and adverse reactions, were analyzed. RESULTS: In the study cohort, the reduction rate was significantly higher after the first treatment compared with subsequent treatments. The overall response rate increased from 75% after the first treatment to 100% after the third. Among patients with localized lesions who underwent surgery, 76% experienced recurrence with a mean recurrence time of 114.23 days. Most recurrent lesions were smaller than at baseline. Adverse reactions included increased blood pressure in seven patients, which resolved without intervention. The new method showed a significant positive correlation with the Derkay score. CONCLUSION: In conclusion, based on the above findings, systemic Bev treatment for RRP is a safe and effective therapeutic approach, though further research is needed. Moreover, the new efficacy evaluation method we developed can significantly aid in studying the effectiveness of Bev treatment for RRP. LEVEL OF EVIDENCE: 2 Laryngoscope, 2024.

Cell-free DNA analysis for recurrent respiratory papillomatosis: A case report.

A 35-year-old male presented with recurrent respiratory papillomatosis. Human papillomavirus type 11 was detected from all sites of tumor tissue DNA by PCR. The pre-surgery cell-free DNA (cfDNA) viral load (3.33 × 103 copies/ng DNA) fell below the post-surgical detection limits on achieving remission, suggesting cfDNA's potential as a biomarker.

Idiopathic Eruptive Macular Pigmentation with Papillomatosis: A Common but Underdiagnosed Entity.

Idiopathic Eruptive Macular Pigmentation (IEMP) is an uncommon and possibly underdiagnosed dermatosis. It manifests as asymptomatic pigmented macules over the face, trunk and proximal extremities among children and adolescents. Degos et al. first documented this condition in 1978, unveiling its distinct characteristics. The macules, initially dark brown-black, naturally diminish over several months to years, with no lasting pigmentation or scarring. In this report, we highlight the case of a 14-year-old girl displaying all the distinctive traits of IEMP.

Recurrent Laryngeal Papillomatosis in Denmark from 1994 to 2021: A Nationwide Register Study.

OBJECTIVES: The aim of this study is to describe the incidence and demographics of laryngeal papillomatosis (LP) in Denmark, including sex and age distribution, recurrence rates, and HPV subtypes, using a new method of register identification. METHODS: The data were extracted from the Danish Pathology Data Bank using SNOMED codes instead of the usual method using ICD codes from the Danish National Health Register. The derived pathology records were manually verified by three medical doctors. The study period was 1994-2021. Patients were categorized according to age as either juvenile-onset RRP (JoRRP) if <18 years or adult-onset RRP (AoRRP) if 18 years or older. RESULTS: We identified 1819 RRP patients (JoRRP: 56; AoRRP:1763). The overall incidence per 100,000 inhabitants were 0.17 for JoRRP and 1.45 for AoRRP. The vast majority (72%) of the patients were male, but there was no significant difference in age at onset of RRP or recurrence rates between the sexes. Children below 3 years of age had the highest recurrence probability. Extracting data using SNOMED codes resulted in a positive predictive value of 99% regarding total number of biopsies and 98% regarding individuals. The incidence decreased throughout the study period. CONCLUSION: Comparable incidence and recurrence rates of RRP were found between Denmark and Norway. In this study, the Danish Pathology Register was found to be a highly valuable method for identifying LP patients. The effect of the nationwide HPV vaccination program can be evaluated using this method as the vaccinated cohort is starting to grow older and reproduce. LEVEL OF EVIDENCE: Retrospective registry-based national cohort study, level of evidence 3 Laryngoscope, 2024.

Forecasting Disease Burden with a Dynamic Transmission Model of Human Papillomavirus and Recurrent Respiratory Papillomatosis in the United States.

Juvenile- and adult-onset recurrent respiratory papillomatosis (JORRP and AORRP) are rare but serious conditions that are caused by oral human papillomavirus (HPV) infections. The proliferation of wart-like growths throughout the respiratory tract can result in medical problems, including death. The current treatment scheme is surgery, though prevention of HPV infection through vaccination is available. A previously developed model for JORRP and AORRP was adapted to the United States using data on disease burden and HPV infection. The model was validated against post-vaccination reductions in disease and used to forecast the future burden of JORRP and AORRP, estimating the impact that HPV vaccination will have on these diseases. Between 2007 (the beginning of HPV vaccination in the US) and 2021, this model estimates that approximately 1393 lives, 22,867 Quality-Adjusted-Life-Years, and over USD 672 million in treatment costs have been saved by HPV vaccination. There is also a substantial reduction in JORRP and AORRP burden, with a 95% reduction in incidence by 2040. Moreover, between 2040 and 2121, the model predicts 3-11 total cases of HPV6/11-related JORRP in the US, and 36-267 total cases of HPV6/11-related AORRP. HPV vaccination in the United States has driven, and will continue to drive, substantial reductions in the public health and economic burden of HPV6/11-related JORRP and AORRP.

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.

Adjuvant Intralesional Bevacizumab in Pediatric and Adult Populations With Recurrent Respiratory Papillomatosis: A Systematic Review.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is a rare disease of the airway for which there is no known cure. Treatment involves the surgical removal or destruction of these lesions. There has been a long-standing debate over the effectiveness of the adjuvant intralesional injection of the immune modifying agent bevacizumab. This study is a systematic review investigating the effect of adjuvant intralesional bevacizumab on patients with laryngeal papillomatosis. The main objective was to assess functional outcomes and efficacy. DATA SOURCES: Pubmed, Google Scholar, and Web of Science. REVIEW METHODS: Search words were "intralesional bevacizumab" AND "recurrent respiratory papillomatosis." Sources were systematically identified using inclusion and exclusion criteria (ie, study publication must post-date 2000, must be peer-reviewed, investigate patients with RRP, apply bevacizumab intralesionally, not systemically). Findings were then collected and analyzed. RESULTS: Ten studies were included for analysis. The majority of these studies found an increase in the surgical interval, voice outcomes, and a decrease in tumor burden in most patients. No studies reported side effects or lasting complications related to the bevacizumab injection. CONCLUSION: This systematic review provides further evidence for the safety of intralesional bevacizumab injections and their likely positive effect on disease control. Future research would benefit from the implementation of standardized documentation of RRP outcomes.

A Case Report of Juvenile-Onset Recurrent Respiratory Papillomatosis.

The most common benign laryngeal neoplasm in children is a papilloma. Laryngeal papillomatosis is a chronic disease and is rare in children. We report the case of a four-year-old Malay girl in whom chronic laryngeal papillomatosis, most likely acquired vertically during labor, was detected. She presented with hoarseness of voice for three years, and a flexible laryngoscopy examination revealed features of papilloma in the glottis area. The patient underwent direct laryngoscopy followed by excision of mass using the cold instrument. Surgical intervention is the primary treatment modality for laryngeal papillomatosis to maintain airway patency and voice quality.

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.

Intralesional cidofovir injections for the treatment of multifocal exophytic sinonasal papilloma.

KEY POINTS: Intralesional cidofovir injections in combination with surgery is an effective treatment for recurrent multifocal sinonasal exophytic papilloma. No malignant transformation has been observed in our experience. Anosmia is a potential side effect that patients should be aware of.

Global trends and hotspots on recurrent respiratory papillomatosis: A 20-year bibliometric analysis.

Objectives: Recurrent respiratory papillomatosis (RRP) is the most common benign laryngeal tumor in children. It can cause serious psychological and mental burden on patients since RRP requires repeated surgical treatment. This study aims to delineate the global trends and identify hotspots related to RRP over the past two decades. Methods: We systematically gathered research findings on RRP from 2004 to 2023, utilizing the Web of Science as our data source. Subsequently, we performed a comprehensive bibliometric analysis of the literature using Vosviewer, CiteSpace, and Bibliometrics online analysis platform. Results: A total of 839 publications were finally identified on RRP from 2004 to 2023. The United States has the largest number of publications (392), accounting for 46.7%. The Capital Medical University is the most productive organization (24), followed by the Centers for Disease Control and Prevention (18). The most productive journal was the Laryngoscope, with 86 publicatios. Comparatively, Vaccine is the most cited journal (2297). Craig S. Derkay ranked highest among all authors in publication (16). Burst detection shows onset, adjuvant therapy, management, juvenile-onset RRP, systemic bevacizumab, avastin, human papillomavirus vaccine are recent keywords of great interest to researchers. Conclusion: Research on RRP has progressed significantly over the past two decades, especially in terms of therapeutic strategies. We strongly believe that this article will provide new research directions for other researchers and may contribute to future breakthroughs in the field.

Fibroepithelial Neoplasm with Hybrid Features of Benign Phyllodes Tumor, Juvenile Papillomatosis, and Juvenile Fibroadenoma: A Case Report.

Phyllodes tumor is an uncommon breast fibroepithelial neoplasm mainly found in middle-aged patients, presenting a morphologic continuum from benign to malignant. Juvenile papillomatosis represents a rare benign proliferative breast tumor primarily affecting young individuals and carries a potential elevated risk of subsequent breast cancer development. Juvenile fibroadenoma is a well-circumscribed biphasic neoplasm that often occurs in adolescent girls, characterized by a pericanalicular growth pattern with usual-type epithelial hyperplasia and gynaecomastia-like micropapillary proliferation. Herein, we present an unusual example of a 26-year-old woman with a left breast outer lower quadrant palpable mass. Ultrasonography identified a 5.9 cm lobulated hypoechoic solid mass with scattered small cysts. The preoperative biopsy initially diagnosed a fibroepithelial lesion, considering giant cellular fibroadenoma and phyllodes tumor in the differential. Subsequent complete excision revealed areas of benign phyllodes tumor features closely admixed with distinctive elements such as prominent multiple cysts exhibiting apocrine and papillary apocrine metaplasia, duct papillomatosis, and duct stasis characteristic of juvenile papillomatosis, and hyperplastic ductal epithelium with micropapillary projections demonstrating a pericanalicular growth pattern indicative of juvenile fibroadenoma. The diagnosis was conclusively established as a fibroepithelial lesion with combined features of benign phyllodes tumor, juvenile papillomatosis, and juvenile fibroadenoma. Further investigation uncovered a family history of breast cancer. Molecular analysis revealed a pattern of unique and overlapping mutations within these distinct histopathological areas. This unusual presentation with hybrid features within a single tumor is described for the first time in the literature along with the molecular signature of the individual components.