Initial Experience Treating HPV-Related Laryngeal Diseases with Oral Brincidofovir: A Pilot Study.

OBJECTIVE: To determine if brincidofovir, an oral analog of cidofovir that achieves high tissue levels of the active metabolite with low systemic toxicity, has an observable effect on HPV-related disease of the larynx. METHODS: Two patients with laryngeal recurrent respiratory papillomatosis (one each of genotypes 6 and 11) and 1 with recurring aryepiglottic fold carcinoma in situ (genotype 16) received oral brincidofovir according to protocol. Close-range videoendoscopic examinations were done during and after the study period to observe disease behavior in the absence of other interventions, and after subsequent surgical intervention. Disease character and magnitude of recurrence for each patient were compared to their patterns prior to brincidofovir. RESULTS: Brincidofovir reduced papilloma burden in 1 patient and markedly attenuated the rate and magnitude of recurrence in both. After surgical intervention, Patient 1 remains disease-free at 10 years (7 years from last intervention) and Patient 2 has no symptoms at 8 years. Patient 3 with recurring carcinoma in situ has required less frequent resections and specimens show reduced degrees of dysplasia present only in islands amid normal mucosa at 8 years (currently no evidence of disease at 21 months from last intervention). CONCLUSION: Brincidofovir appears to attenuate HPV disease of the larynx in this small pilot study, though further investigation is required because of the highly variable nature of the disease and potential confounding factors.

HPV infection and clinical profiles in laryngeal diseases. A preliminary study.

PURPOSE: The study analysed the presence of HPV in samples tissue from laryngeal chronic hyperplastic inflammation, with and without pre-neoplastic potential, and from squamous cell carcinoma of the larynx. The aim of this analysis was to evaluate the presence/absence of different types of HPV and their relationship to the clinical profile of the patients studied (habit of smoking and drinking). METHODS: Sixty cases were randomly selected from patients undergoing surgical treatment of the larynx for inflammatory/ neoplastic lesions and of neck nodes. Patients underwent standard clinical workup, comprising medical history and physical examination, panendoscopy, whole-body CT scan (in cancer patients), diagnostic or therapeutic microlaryngoscopy with laryngeal biopsy, and HPV evaluation. RESULTS: The HPV analysis showed an increased risk for heavy smokers of HPV positivity, as well as precancer lesions and cancer. Type 6 and 16 seem to be prevalent in all types of laryngeal mucosa disease, but pre-neoplastic conditions versus cancer seem to show a wider variety of HPV infections while cancer patients are invariably affected by types 6 and 66. Heavy smoking is related to HPV infection likewise alcohol in association with smoking. Advanced T is more associated with HPV positivity. CONCLUSIONS: These data impose a closer follow-up of smokers and pre-neoplastic cases and the utility of the broadspectrum polymerase chain reaction assay in laryngeal dysplastic and cancer lesions. This study may allow to develop biomarkers for early detection or recurrence surveillance, to identify therapeutic targets, and to begin individualization of treatment based on the biology of these tumours. KEY WORDS: HPV infection, Larynx, Laryngeal chronic hyperplastic inflammation, Squamous cell carcinoma.

Safety and clinical activity of PD-L1 blockade in patients with aggressive recurrent respiratory papillomatosis.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV)-driven disorder that causes substantial morbidity and can lead to fatal distal airway obstruction and post-obstructive pneumonias. Patients require frequent surgical debridement of disease, and no approved systemic adjuvant therapies exist. METHODS: A phase II study was conducted to investigate the clinical activity and safety of programmed death-ligand 1 (PD-L1) blockade with avelumab in patients with RRP. RESULTS: Twelve patients were treated. All patients with laryngeal RRP displayed improvement in disease burden, and 5 of 9 (56%) displayed partial responses. None of 4 patients with pulmonary RRP displayed a response. Using each patient's surgical history as their own control, patients required fewer surgical interventions after avelumab treatment (p = 0.008). A subset of partial responders developed HPV-specific reactivity in papilloma-infiltrating T-cells that correlated with reduced HPV viral load and an increased Tissue Inflammation Signature. CONCLUSIONS: Avelumab demonstrated safety and clinical activity in patients with laryngeal RRP. Further study of immune checkpoint blockade for RRP, possibly with longer treatment duration or in combination with other immunotherapies aimed at activating antiviral immunity, is warranted. TRIAL REGISTRATION: NCT, number NCT02859454 , registered August 9, 2016.

Postoperative Systemic Acyclovir in Juvenile-Onset Recurrent Respiratory Papillomatosis: The Outcome.

A prospective observational study was conducted consisting of 21 patients of Juvenile-onset recurrent respiratory papillomatosis, attending the Department of Otorhinolaryngology and Head Neck Surgery at our institution, who underwent surgical excision of the papillomas followed by oral acyclovir postoperatively. The study was aimed to observe the effect of systemic acyclovir on postoperative outcomes in children having recurrent respiratory papillomatosis undergoing primary surgical excision. It was observed that the mean interval between surgeries as well as the number of surgical interventions required was significantly lesser when acyclovir was used as a postoperative adjuvant than when surgery was done alone. Hence, the interval between successive surgeries, or in other words, the time interval between relapse of the disease could be prolonged significantly with the use of postoperative systemic acyclovir. Thus, the disease could be controlled for longer periods and repeated surgeries avoided.

Human papillomavirus types causing recurrent respiratory papillomatosis in Zimbabwe.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) caused by human papillomavirus (HPV) is preventable through vaccination. This study was motivated by the recent thrust of the Zimbabwean government to reduce incidence of HPV related cervical cancer in Zimbabwe through vaccination against HPV. We therefore set out to type HPV genotypes causing RRP in Zimbabwe. We also describe for the first time, the demographics of Zimbabwean RRP patients, the characteristics of patients with different HPV types and possible risk factors of HPV infection in our setting. METHODS: We conducted a prospective, hospital based study were patients were recruited from two national otorhinolaryngology hospitals in Zimbabwe. All patients diagnosed with RRP during a twenty four month period were included in the study. A questionnaire was administered per patient to collect both demographic and clinical variables. HPV DNA was extracted from formalin fixed paraffin embedded laryngeal tissue. The extracted HPV DNA was amplified using polymerase chain reaction and next generation sequencing was used to genotype the HPV types. RESULTS: A total of 52 patients all aged 14 years and under were recruited into the study. Only Juvenile onset RRP cases were observed over the two year period and 64% of the patients were HPV positive. HPV types 6 and 11 were the dominant types observed constituting 85% of all HPV types. The remaining 15% constituted of HPV 16 and HPV 18. 27% of the patients had coinfection with at least two different HPV types. There were no statistically significant differences between the characteristics of HPV positive and HPV negative patients. No statistically significant risk factors were observed. CONCLUSION: HPV types 6 and 11 were the predominant genotypes causing RRP in Zimbabwe. Thus the use of quadrivalent or even nonavalent HPV vaccines may play an important role in the prevention and management of RRP in Zimbabwe.

[Prevalencia y genotipos del virus del papiloma humano en muestras de tejido laríngeo de pacientes con cáncer de laringe del noreste de México]. / Prevalence and genotypes of the human papillomavirus in laryngeal tissue samples of patients with laryngeal cancer from Northeastern Mexico.

ANTECEDENTES: El cáncer de laringe representa el 21.7% de las neoplasias malignas de vías aerodigestivas superiores. La prevalencia del virus del papiloma humano (VPH) en el cáncer de laringe oscila entre el 0 y el 80%. MÉTODO: Se incluyeron 112 muestras de tejido laríngeo de pacientes con cáncer de laringe. Se amplificó el ADN y se analizó la presencia y el genotipo del VPH mediante hibridación reversa (INNO-LiPA®). Se realizaron pruebas de ji cuadrada, Fisher y t de Student no pareada. RESULTADOS: Se incluyeron muestras de 107 hombres (95.5%) y 5 mujeres (4.5%), con una edad de 65.3 ± 10.1 años, con antecedente de tabaquismo 108 (96.4%), alcoholismo 9 (8.0%) y carcinoma epidermoide moderadamente diferenciado queratinizante 96 (85.7%). Se identificó VPH en 60 (53.5%), VPH-11 en 51 (45.5%), VPH-52 en 27 (24.1%), VPH-16 en 9 (8.0%), VPH-45 en 3 (2.6%) y coinfección por más de un genotipo en 31 (27.6%). No hubo diferencia entre pacientes con y sin infección por VPH en cuanto a edad, sexo, localización, diagnóstico histopatológico, tabaquismo ni alcoholismo (p > 0.05). CONCLUSIONES: La prevalencia de infección por VPH en el cáncer de laringe fue del 53.5%, con coinfección por más de un genotipo en el 27.6%. El genotipo más frecuente fue el VPH-11, tipo de bajo riesgo, seguido por el VPH-52, de alto riesgo oncogénico. BACKGROUND: Laryngeal cancer represents 21.7% of malignancies of the upper aerodigestive tract. The prevalence of the Human Papillomavirus (HPV) in laryngeal cancer ranges 0 to 80%. METHODS: We included 112 laryngeal tissue samples obtained from patients with laryngeal cancer. DNA was extracted and amplified by PCR. HPV presence and genotype were analyzed by the reverse hybridization INNO-LiPA® assay. Chi-square, Fisher's and unpaired Student t tests were used. RESULTS: Samples from 107 male (95.5%) and 5 female patients (4.5%) were evaluated, aged 65.3±10.1 years, 108 with smoking history (96.4%), 9 with alcoholism history (8.0%), and in 96 the histological diagnosis was moderately differentiated keratinizing squamous cell carcinoma (85.7%). HPV was detected in 60 samples (53.5%), HPV-11 in 51 (45.5%), HPV-52 in 27 (24.1%), HPV-16 in 9 (8.0%), HPV-45 in 3 (2.6%), and coinfection by more than one genotype in 31 (27.6%). There was no difference between patients with and without HPV infection with respect to age, sex, tumor location and histology, smoking and alcoholism history (p>0.05). CONCLUSIONS: The prevalence of HPV infection in laryngeal cancer was 53.5% with coinfection with more than one genotype in 27.6%. The most frequent genotype was HPV-11, an oncogenic low-risk genotype, followed by HPV-52, a high-risk genotype.

Prevalence of human papillomavirus in benign and malignant laryngeal lesions in Egyptian patients: Cross-sectional study.

OBJECTIVE: To assess the prevalence of human papillomavirus (HPV) in benign and malignant laryngeal lesions among Egyptian patients. DESIGN: Observational analytical cross-sectional study. SETTING: Ain Shams University hospital, Otorhinolaryngology department PARTICIPANTS: Formalin-fixed paraffin-embedded specimens of 126 patients (70 benign laryngeal lesions and 56 squamous cell carcinoma lesions) were assessed for the presence of HPV DNA using MY09/11 PCR-based DNA detection. MAIN OUTCOME MEASURES: Percentage of positive samples was calculated. RESULTS: All 70 benign laryngeal lesion specimens were negative for the HPV DNA, while 2 of the 56 squamous cell carcinoma lesions (3.6%) were positive. CONCLUSIONS: The presence of HPV DNA in only two specimens in our study suggests that the proportion of laryngeal squamous cell carcinomas attributable to infection by HPV seems to be very low in Egypt.

Gardasil Vaccination for Recurrent Laryngeal Papillomatosis in Adult Men Second Report: Negative Conversion of HPV in Laryngeal Secretions.

BACKGROUND: In our first report on antibody levels in middle-aged and older men with recurrent laryngeal papillomatosis (RLP), we reported increases in human papillomavirus (HPV) antibody levels similar to those seen in adult women and young men. We posited that HPV antibodies produced in laryngeal mucus by Gardasil would prevent postoperative reinfection in patients with RLP. STUDY DESIGN: This is a case series study. PURPOSE: The purpose of this study was to examine whether Gardasil injection effectively inhibits recurrence of RLP. Specifically, in this second report, whether HPV antibodies produced in laryngeal secretions by Gardasil are capable of causing negative conversion of HPV-DNA (deoxyribonucleic acid) in laryngeal mucosa was investigated. METHODS: A total of 11 patients for whom antibodies were measured in the first report were studied. Before vaccination and after 1 year Post-vaccination, HPV screening tests were performed on laryngeal secretions, and whether HPV-DNA negative conversion had occurred was evaluated. At the time of collection of laryngeal secretions, the presence or absence of laryngeal papillomas was examined. RESULTS: Before vaccination, all patients were HPV low-risk positive on laryngeal secretion screening tests. After vaccination, three patients were positive. Laryngeal papillomas remained in five patients. CONCLUSIONS: The HPV-DNA test showed negative conversion in eight of 11 (72.7%) patients after vaccination. Residual laryngeal papillomas were found in five of 11 (45.5%) patients. The serum HPV antibody titer did not differ significantly between the group in which laryngeal secretions showed HPV negative conversion and the group in which conversion did not occur. The serum antibody titer did not differ significantly as a function of whether there were residual tumors.

Low prevalence of human papillomavirus in head and neck squamous cell carcinoma in the northwest region of the Philippines.

BACKGROUND: Geographic heterogeneity of human papillomavirus (HPV) involvement in head and neck squamous cell carcinoma (HNSCC) has been observed over the last few years. This trend has not been evaluated in the Philippines. Hence, this study aims to provide for the first time a data on the prevalence of HPV in HNSCC in the northwestern region of the Philippines. METHODS: Two hundred one (201) biopsy samples (179 formalin fixed paraffin embedded and 22 fresh frozen) from 163 Filipino HNSCC cases (oral cavity = 88; larynx = 60; oropharynx = 15) diagnosed between 2003 to 2013 were initially included in this study. HPV DNA was detected by two methods: (1) BSGP5+/6+-PCR/ multiplex human papillomavirus genotyping and (2) TaqMan probes-based real-time qPCR. Presence of HPV type-specific transcripts were also analyzed by reverse transcription-PCR with subsequent hybridization to oligonucleotide probes coupled to Luminex beads. Co-amplification of the ß-globin and ubiquitin C genes served as internal positive controls for DNA and RNA analyses, respectively. RESULTS AND CONCLUSIONS: Of the 163, 82 (50.3%) cases had at least one tissue sample that was valid for molecular analysis. Only two of the DNA valid cases (2.4%) were HPV DNA-positive (HPV11 and HPV33). All HPV mRNA assays rendered negative results except for HPV11 transcripts. Results of this study may indicate that there is probably very low prevalence of HPV-associated HNSCC among Filipino adults living in a rural region of the Philippines. This study could serve as a benchmark for designing follow-up studies that would assess possible changes in trends of HNSCC among Filipinos in different ethnic regions of the country, especially urban areas in which the population is expected to adapt Western style sexual behavior. A prospective sampling of fresh frozen tissue is also highly recommended to ensure better molecular analyses.

Cell Type- and Tissue Context-dependent Nuclear Distribution of Human Ago2.

Argonaute-2 protein (Ago2), a major component of RNA-induced silencing complex (RISC), has been viewed as a cytoplasmic protein. In this study, we demonstrated by immunofluorescence confocal microscopy that Ago2 is distributed mainly as a nuclear protein in primary human foreskin keratinocytes in monolayer cultures and their derived organotypic (raft) cultures, although it exhibits only a minimal level of nuclear distribution in continuous cell lines such as HeLa and HaCaT cells. Oncogenic human papillomavirus type 16 (HPV16) or type 18 (HPV18) infection of the keratinocytes does not affect the nuclear Ago2 distribution. Examination of human tissues reveals that Ago2 exhibits primarily as a nuclear protein in skin, normal cervix, and cervical cancer tissues, but not in larynx. Together, our data provide the first convincing evidence that the subcellular distribution of Ago2 occurs in a cell type- and tissue context-dependent manner and may correlate with its various functions in regulation of gene expression.

Laryngeal papillomatosis associated dysplasia in the adult population: an update on prevalence and HPV subtyping.

OBJECTIVES: The objectives were to determine the prevalence of laryngeal dysplasia and associated human papilloma virus (HPV) subtypes in adult patients, 18 years or older, suffering from laryngeal papillomatosis at a tertiary care institution. STUDY DESIGN: Retrospective cohort study. METHODS: Patients with biopsy proven laryngeal papillomatosis were identified via chart review. All available pathology specimens were reviewed by a dedicated head and neck pathologist to confirm/refute the diagnosis of laryngeal dysplasia, and grade the level of dysplasia. Interrater agreement was compared using cross-tabulation methods. Specimens identified to be positive for dysplasia underwent further testing via in situ hybridization for low-risk (6/11) or high-risk (16/18) HPV subtypes. RESULTS: Of the 85 subjects identified to have laryngeal papillomatosis, 24(28%) demonstrated laryngeal dysplasia. There was good interrater agreement on the presence of dysplasia; however, there was only fair agreement on the grade of dysplasia. Of the pathology specimens tested for HPV subtype, the majority of patients (62%) were positive for HPV 6/11, including all high-grade dysplasia patients. Three (12%) dysplasia specimens were negative for both high- and low-risk HPV subtypes. CONCLUSIONS: We found a 28% prevalence of dysplasia in our patient population with the majority of patients positive for low-risk HPV subtypes indicating that high-risk HPV subtypes do not predispose laryngeal papilloma patients to dysplasia.

Characterization of genotype IX Newcastle disease virus strains isolated from wild birds in the northern Qinling Mountains, China.

This study was conducted to evaluate the virulence and evolution of genotype IX Newcastle disease virus (NDV) isolates obtained from wild birds in the northern Qinling Mountains of China. Five isolates were obtained from 374 larynx and cloacae swabs, which were collected from multiple asymptomatic wild bird species from August 2008 to July 2011, and were subsequently characterized by pathotype and genotype. Deduced amino acid sequences revealed that all five NDV isolates exhibited velogenic fusion protein cleavage sites motif (112)R-R-Q-R-R-F(117), shared as high as 99.8-99.9 % homology with each other, and varied in pathotype by intracerebral pathogenicity indices (ICPI) of 0.425-1.638. Phylogenetic analysis showed that all five isolates were clustered to genotype IX NDV. This is the first study to confirm multiple asymptomatic wild bird species as natural carriers of virulent genotype IX NDV. A novel NDV isolate from the Spotted-necked Dove (family Columbidae) exhibited discordance between its lentogenic ICPI and its virulent proteolytic cleavage site motif (112)R-R-Q-R-R-F(117). Although the five isolates underwent several amino acid mutations in the fusion protein, evidence of continuous evolutionary divergence did exist in the genotype IX NDV, which was always regarded as a conservative genotype.

Recommendations for the diagnosis of human papilloma virus (HPV) high and low risk in the prevention and treatment of diseases of the oral cavity, pharynx and larynx. Guide of experts PTORL and KIDL.

The role of human papilloma viruses (HPV) in malignant and nonmalignant ENT diseases and the corresponding epidemiological burden has been widely described. International head and neck oncology community discussed growing evidence that oral HPV infection contributes to the risk of oro-pharyngeal carcinoma (OPC) and recommended HPV testing as a part of the work up for patients with OPC. Polish Society of ENT Head Neck Surgery and National Chamber of Laboratory Diagnosticians have worked together to define the minimum requirements for assigning a diagnosis of HPV-related conditions and testing strategy that include HPV specific tests in our country. This paper briefly frames the literature information concerning low risk (LR) and high risk (HR) HPV, reviews the epidemiology, general guidance on the most appropriate biomarkers for clinical assessment of HPV. The definition of HPV-related cancer was presented. The article is aiming to highlight some of major issues for the clinician dealing with patients with HPV-related morbidities and to introduce the diagnostic algorithm in Poland.

Human papilloma virus prevalence in a multiethnic screening population.

OBJECTIVE: The goal was to determine the prevalence of high-risk HPV16 using saliva in a screening population in Detroit, Michigan. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction was applied to detect HPV16 in saliva DNA from 349 screening subjects without head and neck cancer (HNC), 156 with HNC, and 19 controls. Cut points for human papilloma virus (HPV) positivity were >0 and >0.001 copy/cell. Proportions were compared between groups using exact χ(2) or Fisher exact tests (P < .05). RESULTS: At a cut point >0, each group had an overall HPV prevalence of more than 5%, with a higher prevalence of 30.8% in the HNC patient group. At a cut point >0.001, the prevalence was lower: 0% in the control, 1.2% in the screening, and 16.7% in the HNC group. In the latter, for both cut points, HPV prevalence was different across sites (<0.001) and significantly higher in the oropharynx than larynx or site as other after Hochberg's adjustment. At >0, women in the screening group had a higher prevalence of HPV than did men (P = .010), and at >0.001, the prevalence was higher for men in the HNC group than for women (P = .035). In the screening group, at >0, only African Americans had a higher prevalence than Caucasian Americans (P = .025). CONCLUSIONS: In the screening group, a 6.9% and 1.2% screening rate was noted at cut points >0 and >0.001, respectively. The results provide data to inform public health considerations of the feasibility of saliva as a screening tool in at-risk populations with the long-term goal of prophylactic vaccination against oral HPV.

[Cycloferon in complex therapy management of chronic laryngitis].

The clinical course of various forms of chronic laryngitis, including contact granulomas not only persistant and relapsing, but also inclined to oncologic pathology due to hyperplastic changes in the larynx resulting in malignization was described. Inhibition of the leukocyte interferon-synthesizing activity was observed in more than 88.1% of the subjects. Pathogenic viruses were isolated from 48.2% of the patients, EBV and mycoplasma prevailing. High direct correlation between chronic laryngitis and Herpes viruses was shown. The presence of three-component virus associations in the larynx mucosa was likely indicative of the bening process malignancy. The use of the interferon inductor cycloferon in the complex surgical and medicamentous management of chronic laryngitis was shown valid. The rate of the relapses lowered to 1.7 episodes a year.

Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx.

Although a strong etiologic relationship between human papillomavirus (HPV) and a majority of oropharyngeal squamous cell carcinomas has been established, the role of HPV in non-oropharyngeal head and neck carcinomas is much less clear. Here, we investigated the prevalence and clinicopathologic significance of HPV and its reported biomarkers, CDKN2A(p16) and CDKN1A(p21), in laryngeal squamous cell carcinomas in patients treated either with primary surgery and postoperative radiation or with definitive radiation-based therapy. Nearly all of 76 tumors were keratinizing and none displayed the nonkeratinizing morphology that is typically associated with HPV infection in the oropharynx. However, CDKN2A(p16) immunohistochemistry was positive in 21 cases (28%) and CDKN1A(p21) in 34 (45%). CDKN2A(p16) and CDKN1A(p21) status strongly correlated with each other (P=0.0038). Yet, only four cases were HPV positive by DNA in situ hybridization or by reverse transcriptase PCR E6/E7 mRNA (all four were CDKN2A(p16) and CDKN1A(p21) positive). Unexpectedly, 9 additional tumors out of 20 CDKN2A(p16) positive cases harbored high-risk HPV DNA by PCR. For further investigation of this unexpected result, in situ hybridization for E6/E7 mRNA was performed on these nine cases and all were negative, confirming the absence of transcriptionally active virus. Patients with CDKN1A(p21)-positive tumors did have better overall survival (69% at 3 years) than those with CDKN1A(p21)-negative tumors (51% at 3 years) (P=0.045). There was also a strong trend towards better overall survival in the CDKN2A(p16)-positive group (P=0.058). Thus, it appears that the role of HPV is more complex in the larynx than in the oropharynx, and that CDKN2A(p16) and CDKN1A(p21) expression may not reflect HPV-driven tumors in most cases. Because of this, CDKN2A(p16) should not be used as a definitive surrogate marker of HPV-driven tumors in the larynx.

Risk factors of juvenile onset recurrent respiratory papillomatosis in the lower respiratory tract.

BACKGROUND: Juvenile onset recurrent respiratory papillomatosis (JORRP) is a relatively rare disease. It affects the larynx in most cases. Because reports on JORRP to the lower respiratory tract (LRT) are few, we investigated clinical features of patients with a history of JORRP to analyze the risk factors of this disease. METHODS: Data from 208 JORRP patients admitted to Beijing Tongren Hospital from January 2008 to December 2010 were reviewed. Gender, age at onset of symptoms, age at first surgery, duration of symptoms before the first surgical procedure, the number of surgical procedures, mean interval between surgical interventions, and the number of tracheotomies in patients with and without LRT spread of JORRP were analyzed. The data from patients with and without tracheotomy were recorded and compared. Two cases of primary tracheal papillomatosis were reviewed. RESULTS: Papillomas extension down to the LRT was observed in 46 children (22.1%). Patients with LRT papillomatosis had a shorter time from the onset of the symptoms until the first surgery, required significantly more surgical procedures, and had a shorter mean surgical interval. Tracheotomy was performed in 13/162 (8.0%) children with laryngeal papillomatosis vs. 36/46 (78.3%) children with LRT papillomatosis. After tracheotomy, 36/49 (73.5%) children developed LRT papillomatosis and 10/157 (6.4%) children who did not have a tracheotomy developed LRT papillomatosis. Patients with tracheotomy required a significantly higher number of surgical procedures. The younger the patient had a tracheotomy, the longer the duration of cannulation was. CONCLUSIONS: JORRP patients with LRT spread are prone to develop more aggressive disease. Tracheotomy resulted in a significant increase of LRT involvement.