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.

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.

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.

[Epidemiological features papillomatosis of the larynx in adults: a literature review]. / Epidemiologicheskie osobennosti papillomatoza gortani u vzroslykh (obzor literatury).

The literature review presents current data on the epidemiology, drug, and surgical treatment of laryngeal papillomatosis in adults. Possible prospects for further study of the prevalence and incidence of the disease and provoking factors of recurrence of the disease for the development of possible preventive measures are considered.

Is there any interplay between human gut microbiota and upper airway susceptibility to recurrent respiratory papillomatosis exacerbations?

INTRODUCTION: Recurrent respiratory papillomatosis is a long-term disease caused by HPV 6 and 11, but there is still noconsensus on the factors that may influence its course. AIM: The aim of the study is the analysis of the recurrent activity of respiratory papillomatosis measured by the number ofsurgeries and recent disease activity, as well as an interview regarding intestinal symptoms. MATERIAL AND METHODS: Our study involved 73 patients with confirmed papillomatosis (39 men, 34 women). The mainvariables of crucial importance for the severity of papilloma disease were: age of onset, number of operations, and currentdisease activity. Variables important for the analysis of the impact of intestinal dysbiosis on the course of papillomatosis wereas follows: intestinal symptoms and the number of antibiotic courses in the last year. The main outcome measure in this studywas the relationship between papilloma activity and indicators of intestinal microflora status. RESULTS: Our results showed that diet had a statistically significant effect on the last disease activity measured by the intervalrecurrence of RRP (P = 0.005). The remaining variables did not affect the number of surgeries performed during the patient'slifetime or the current RRP status. CONCLUSIONS: The acquired knowledge may contribute to further work on the discovery of the relationship between the stateof the intestinal microbiota and the course of recurrence of respiratory papillomatosis infection in patients with recurrentrespiratory papillomatosis.

Angiogenesis Inhibitor Drug-induced Benign Migratory Glossitis in a Patient of Juvenile-onset Recurrent Respiratory Papillomatosis under Maintenance Therapy.

Background: Benign migratory glossitis or geographic tongue is a chronic recurring inflammatory condition of the oral cavity. With its ephemeral characteristics, there has been reported literature showing its association with the administration of certain drugs including angiogenesis inhibitors. The antiangiogenic drugs act by selectively inhibiting the vascular endothelial growth factor (VEGF) signaling. It has been widely used as an adjunct and a maintenance agent for the treatment of various cancers. Aims: This study aims to report probable characteristic oral mucosal changes in a patient with juvenile-onset recurrent respiratory papillomatosis (JORRP) under maintenance therapy with an antiangiogenesis drug. Case description: The patient was presented with a burning sensation on having spicy food. This occurred after the completion of three cycles of bevacizumab infusion. It was associated with the appearance of migratory lesions over the tongue and evolved periods of remission and exacerbation. Clinical examination revealed lesions characteristic of the geographic tongue on the anterior two-thirds of the dorsal surface as well as the lateral surface of the tongue classified as type 2, according to Hume criteria. Oral examination revealed dental caries in relation to 52, 54, 62, 63, 74, and 85 teeth and grossly decayed 64. Topical lignocaine gel was instituted for symptomatic relief of the lesion. Full mouth rehabilitation with preventive and restorative therapeutic interventions was carried out. Clinical significance and conclusion: The documented literature along with this report put forth a probable association of geographic tongue with the use of bevacizumab drugs which requires further detailed studies. These lesions generally require symptomatic treatment with assurance only. The etiology is poorly understood. How to cite this article: Kalra N, Tyagi R, Khatri A, et al. Angiogenesis Inhibitor Drug-induced Benign Migratory Glossitis in a Patient of Juvenile-onset Recurrent Respiratory Papillomatosis under Maintenance Therapy. Int J Clin Pediatr Dent 2024;17(1):92-96.

Healthcare Spending and Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

OBJECTIVES: Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare, costly condition linked to human papillomavirus. Standard of care is serial surgical debridement. Many adjunctive therapies have been trialed, with recent success with systemic bevacizumab. This paper examines healthcare spending associated with systemic bevacizumab use for JoRRP and compares it to healthcare spending for surgical care alone to determine whether bevacizumab has a financial benefit. METHODS: Five patients treated with systemic bevacizumab for JoRRP were identified at a single institution. Spending data was derived from the electronic medical record. Sensitivity analysis was performed using variation in spending and frequency of treatments. RESULTS: Patients had an average of 4.2 treatments per year prior to bevacizumab (95% confidence interval [CI] 1.4-7.0) and 1.1 after (0.2-2.0). Patients underwent an average of 9.2 bevacizumab treatments in their first year after initiation, 4.0 in the second, and 4.5 in their third. Mean payment per debridement was $3198 ($2856-3539), with mean total surgical payment per year of $17,966 ($11,673-24,259) prior to initiating bevacizumab. Mean payment on a single bevacizumab infusion visit was $6508 ($6063-6952). Mean total surgical and bevacizumab spending per year after bevacizumab initiation were $83,951 ($12,938-154,964). CONCLUSIONS: Accounting for variations in the number of treatments per year with bevacizumab after initiation, healthcare spending after bevacizumab initiation is similar to spending on surgery alone for JoRRP in patients with severe disease.

Juvenile Papillomatosis of the Breast: a Report of Two Cases with Review of the literature.

Background: Juvenile papillomatosis (JP) of the breast is a rare and benign proliferative disorder affecting young women. The affected patients tend to have an increased risk of breast cancer development during follow-up. Objective: This article aims to highlight a rare entity of breast disease, that harbor risk of breast cancer. Case Presentation: Here, we present 2 cases of JP in young females; the first case is a 13 year-old presented with spontaneous nipple discharge, while the other patient is a 24 year-old presented with a right breast lump. Both patients had a total excision of the breast lesions, revealing JP at histology. Discussion: Juvenile Papillomatosis is considered a clinicopathological entity and is usually misdiagnosed as fibroadenoma clinically and radiologically, which requires histological correlation. The histologic findings are well-defined (hyperplasia, papillomatosis, and multiple cysts with foamy histiocytes).The controversy in management between surgery and observation is because of insufficient knowledge about the direct relationship between JP and subsequent cancer. Conclusion: Considering the risk of developing breast cancer in JP, enrolling patients and their families in a close follow-up and surveillance program is crucial.

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.

Juvenile onset recurrent respiratory papillomatosis: What do we know in 2024 ?

Juvenile onset recurrent respiratory papillomatosis is a lifelong benign squamous lesion associated with HPV infection, particularly HPV6 and HPV11 genotypes. These lesions are rare, but can lead to laryngeal obturations, which can cause disabling dyspnea, or transform into squamous cell carcinoma. The aim here is to provide an epidemiological, biological and clinical overview of this pathology, particularly in children, in order to understand the issues at stake in terms of research and the development of medical and therapeutic management tools.

Clinico-pathological Factors in Malignant Transformation of RRP.

Various clinico-pathological factors play role in the papilloma proliferation and pathogenesis of Recurrent respiratory papillomatosis (RRP). However, it is not known if they are directly responsible for malignant transformation of these papillomas or not. We did this study to elucidate any such association. The most recent debrided tissue of RRP in 20 patients was evaluated for p16 expression, VEGF estimation (tissue expression and serum levels), and tissue HPV DNA concentration. The final histopathology results were then correlated with these pathological factors and with clinical factors like duration of illness, age of onset of symptoms, extent of disease, etc. Squamous papilloma was seen in 60%, dysplasia in 25%, and squamous cell carcinoma (SCC) in 15% of the patients. Positive immunostaining for p16 (staining in ≥70% of tumor cells) was seen only in one case, which was SCC. There was no statistically significant difference between p16 expression, tissue VEGF expression, serum VEGF levels, and tissue HPV DNA in any of the histological groups. The mean age of disease onset was significantly higher in patients with SCC (p = 0.03). A significantly higher number of patients with dysplasia had tracheobronchial involvement (p = 0.022). We concluded that no single pathological factor is solely responsible for development of malignancy in RRP, whereas clinical factors like tracheobronchial involvement and age of onset may contribute to development of dysplasia or carcinoma.

Diode Laser for Juvenile Recurrent Respiratory Papillomatosis: A Case Series of 13 Patients.

Juvenile recurrent respiratory papillomatosis (JRRP) is the most common benign tumor in the larynx. It is uncommon; however, it is potentially life-threatening because it compromises the respiratory tract and required several surgeries to manage recurrences. Currently, the carbon dioxide laser is the treatment of choice. There are no studies about the role of the diode laser which is easy to use and has lower usage cost. This case series presentation reported on the therapeutic effects and recurrence rate of JRRP when using Diode laser. This is a case series presentation of 13 children, who were diagnosed with JRRP and operated for laryngeal papillomatosis with Diode laser in Otorhinolaryngology and Head and Nick Surgery Department et al. Mouwasat Hospital, Damascus, Syria between 2015 and 2022. 13 children required 56 surgeries at a rate of 1-2 surgeries/year, mean number of surgeries for each child was 4.31. That suggests that Diode laser might have a role in reducing the number of surgeries compared to a study used cold instrument and CO2 laser. The complications rate was 30.8%, which is considered a high rate compared to the other studies. In conclusion, we encourage using it when the CO2 laser device is not available. However, we suggest, reducing the power as low as possible and avoiding of two opposing raw surfaces, especially at the anterior commissure and deep excision. Further longitudinal studies are recommended to validate these results.

Cell proliferation and apoptosis in canine oral papillomatosis.

This study was aimed at the evaluation of cell proliferation, p53 level and apoptotic index by immunohistochemical methods in canine oral papillomatosis. The study material comprised of tumor tissue samples taken from six dogs being admitted to the Pathology Department of Faculty of Veterinary Medicine, Kafkas University, Kars, Türkiye. Choice of immunohistochemical staining was avidin-biotin peroxidase method. Cases of canine oral papillomatosis, determined to have been caused by canine papillomavirus-1, were found to have a rather high cell proliferation index. Furthermore, all cases were immunohisto-chemically demonstrated to carry a mutant p53 gene. Despite the mutation of p53 gene, the shift in the Bax/Bcl-2 ratio of dogs diagnosed with tumor was in favor of the pro-apoptotic Bax gene. The apoptotic mechanism was determined to occur through both the caspase-dependent and caspase-independent pathways. While the lesions occupied the entire oral cavity in some cases, histopathologically, malignant transformation was not detected in any of the six cases.

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.

Human papilloma virus (HPV) vaccination is associated with reduced number of surgical treatments, an observational study on recurrent respiratory papillomatosis in Northern Sweden.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a wart-like lesion mainly affecting the larynx, caused by human papillomavirus (HPV) genotypes 6 and 11. The disease affects both children and adults, and there is no cure. Surgery is the current symptom-relieving treatment; however, HPV vaccination is used as an adjuvant treatment. AIMS AND OBJECTIVES: The aims were to study effects of HPV vaccination in RRP cases and to compare juvenile-onset to adult-onset disease and high treatment frequency (TF) to low TF cases. MATERIAL AND METHODS: Medical records of RRP patients were studied from May 2006 to January 2023. Eighty-five RRP cases, tested for HPV genotypes with PapilloCheck®, were included. Vaccination- onset- and treatment analysis were performed. RESULTS: Twelve percent of the cases were vaccinated. The number of surgeries decreased from 2.0 to 0.8/year after HPV vaccination. Most cases had an adult-onset and less than one treatment per year. Juvenile-onset cases had a higher vaccination treatment ratio compared to adult-onset. CONCLUSIONS: HPV vaccination was associated with a lower number of treatments per year, supporting the use of vaccination as an adjuvant treatment. SIGNIFICANCE: Vaccination as adjuvant treatment to surgery may lead to increased quality of life for RRP patients and saved healthcare resources.

Quantification and Functional Studies of Neutrophilic Cells Identifies Distinct Papilloma Phenotypes.

OBJECTIVES: To characterize the distribution of immune cell subsets within laryngeal papillomas and to study the function of potentially immunosuppressive neutrophilic and regulatory T cells (Tregs). METHODS: Fresh clinical papilloma specimens were collected at the time of surgery and studied with multiparameter flow cytometry. Papilloma infiltrating neutrophilic cells and Tregs were sorted and studied functionally with ex vivo T cell suppression assays. RESULTS: Flow cytometric analysis of fresh laryngeal papillomas samples from 18 adult patients with recurrent respiratory papillomatosis revealed patterns in immune constituency between patients. Clearly divergent phenotypes based primarily on the degree of neutrophilic and T cell infiltration were identified. Relative neutrophilic cell enrichment and T cell depletion were observed in 50% of samples and neutrophilic cell depletion and T cell enrichment were observed in the others. Greater papilloma neutrophilic cell enrichment was positively associated with the number of clinically indicated interventions required in the 12 months prior to sample collection, linking papilloma neutrophil inflammation to disease severity. Functional assays revealed the ability of both papilloma infiltrating neutrophilic and Tregs to suppress T cell function at roughly equal magnitudes, but substantially increased infiltration of neutrophilic cells compared to Tregs across samples. CONCLUSION: Neutrophilic cells are an important contributor to immunosuppression within the respiratory papilloma microenvironment. Given these data and the association between greater neutrophilic cell infiltration and lack of clinical response to therapeutic vaccination, additional study of strategies aimed at limiting neutrophilic cell infiltration or function within papillomas is warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3238-3244, 2024.

Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Institution's Experience.

OBJECTIVES: Medical therapies to limit disease recurrence are critically needed for recurrent respiratory papillomatosis (RRP). Systemic bevacizumab is emerging as an exciting adjuvant therapy toward this end, but uptake has been poor due to the lack of experience and awareness of best prescribing practices. The objective of this study was to describe a single tertiary care academic medical center's experience using systemic bevacizumab for the treatment of RRP. METHODS: A retrospective review was performed to identify patients with RRP on systemic bevacizumab. Demographic and clinical characteristics, findings on imaging reports, and disease response at all anatomic subsites involved in papilloma were documented. RESULTS: Of the 17 RRP patients on systemic bevacizumab, 9 (52.9%) were male, and 12 (70.6%) were diagnosed with juvenile-onset RRP. The total lifetime number of surgeries was high, with more than half (n = 9; 52.9%) undergoing more than 50 surgeries. Following induction of systemic bevacizumab, a significant reduction in patients with laryngeal (n = 15; 94.1% vs. n = 7; 41.2%, p < 0.001) and tracheal (n = 11; 64.7% vs. n = 5; 29.4%, p = 0.04) RRP was noted. Surgical frequency was significantly lower following systemic bevacizumab (2.5 vs. 0.5 surgeries per year; p < 0.001). The most common complications were new-onset hypertension (n = 4; 23.5%) and proteinuria (n = 5; 29.4%). CONCLUSION: Systemic bevacizumab is effective in reducing the number of surgeries needed for RRP while exhibiting a relatively safe complication profile. Papillomas in the larynx and trachea are most responsive to systemic bevacizumab, while pulmonary RRP is most likely to exhibit a partial-to-stable response. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3253-3259, 2024.

Off-label drugs in otolaryngological practice against the background of legal conditions of Polish legislation.

<b><br>Introduction:</b> 'Off-label drug use' refers to the administration of drugs for unapproved indications or age groups, a different dosage or other form of administration. Considering the legal issues, there clearly exists a need to implement rules that would regulate the use of pharmaceuticals outside the scope of a marketing authorisation. The brevity and diversity of Polish laws in the field of health care leads to many interpretative doubts associated with particular legal acts.</br> <b><br>Aim:</b> We aimed to present clinical examples from everyday practice of off-label drug use from the medical and legal perspectives, and to support it with relevant legal acts.</br> <b><br>Material and method:</b> Off-label drug use in various otolaryngology subspecialties - otology (mesna), laryngology (bevacizumab, cidofovir and botulinum toxin) and head and neck surgery (botulinum toxin) - are presented and discussed in detail.</br> <b><br>Results:</b> Fourteen Polish legal acts regarding off-label drug use and 4 from EU legislation are commented on. The algorithm of cascade of decision-making processes in off-label drug use is shown.</br> <b><br>Conclusions:</b> Off-label use of medicinal products is not prohibited in Poland or the EU; nevertheless, it is undeniable that the unclear legal situation regarding the use of medicinal products for nonregistered indications creates difficulties. To minimise a doctor's liability risk, obtaining the informed consent from the patient for such treatment is advisable.</br>.

Clinical evaluation of pediatric patients with recurrent respiratory papillomatosis.: A longitudinal study at a Saudi Arabian tertiary care center.

OBJECTIVES: To study the clinical evaluation of recurrent respiratory papillomatosis (RRP) patients and the factors associated with the improvement in the Derkay's score as a measure of disease severity. METHODS: A retrospective cohort that included all juvenile RRP patients who were admitted to King Abdulaziz University Hospital, Riyadh, Saudi Arabia, between September 2015 and June 2022 and underwent surgical debulking. RESULTS: A total of 16 patients were eligible to join our study. Among them, 7 patients were males. Hoarseness of voice was the most frequent symptom. The median period of the follow-up was 56 months. Complete remission was achieved in 31.3%. The univariate linear regression model revealed that the cidofovir-treated patients had a significant reduction in the change value of Derkay's score compared to those without treatment (regression coefficient= -5.83, 95% confidence interval [CI]: [-11.5 to -0.143], p=0.045). Also, the increased first Derkay's score decreased the change value and subsequently increased the improvement chance of the disease (regression coefficient= -0.424, 95% CI: [-0.764 to -0.083], p=0.018). However, in the multivariate regression model, both variables showed non-significant results. CONCLUSION: cidofovir treatment and higher Derkay's scores affected the disease improvement.