Respiratory Papillomas Research Articles

Nasopharyngeal papillomas treated with CO2 laser and human papillomavirus vaccination

This case report describes the use of CO2 laser and quadrivalent human papillomavirus (HPV) vaccination in two patients with nasopharyngeal HPV11-positive recurrent respiratory papillomas (RRP). These patients initially underwent CO2 laser excision but developed recurrent lesions and underwent HPV vaccination as adjunct therapy. The recurrent lesions shrank after vaccination and were again excised with CO2 laser. Subsequently, these patients had no recurrence of lesions on long-term follow-up at 33 months or 6 years after surgery. Thus, in patients with nasopharyngeal RRP, resection with CO2 laser, and HPV vaccination as adjunct therapy should be considered in HPV11-associated cases. Laryngoscope, 127:2279-2281, 2017.

Três médicos e uma mãe

A papilomatose laríngea, doença rara potencialmente fatal, carateriza-se pela proliferação de papilomas no trato respiratório, múltiplos, recorrentes, cuja etiologia é a infeção por papilomavírus humano (HPV). Menina, 21 meses, filha de mãe com serologia positiva para vírus da imunodeficiência humana (VIH) e HPV. Em acompanhamento nas consultas de Pediatria do Desenvolvimento do Hospital, Pediatra Particular e Médico de Família (MF). Aos 18 meses, na consulta de acompanhamento do MF, a mãe preocupada salienta a fala sussurrada e choro rouco da filha com diagnóstico frequente de laringite aguda no Pediatra e MF nos últimos 3 meses, motivando a referenciação à Otorrinolaringologia e posterior diagnóstico de papilomatose laríngea. A abordagem da disfonia na criança evita o uso inapropriado de corticoides, inibidores da bomba de prótons e antibioticoterapia. Neste relato sobressai a desvantagem associada ao seguimento por múltiplos médicos, sendo o MF fundamental para reunir e integrar a informação clínica, permitindo a continuidade de cuidados.

Economic impact of recurrent respiratory papillomas in a UK adult population

To calculate the financial burden of recurrent respiratory papilloma. This study is UK-based, where up until now no financial estimates have been calculated for this group of patients. Recurrent respiratory papilloma is caused by the human papilloma virus (subtypes 6 and 11). The burden for the patient and the healthcare system is significant given the recurrent nature of the disease. Data were collected, using a questionnaire completed during routine clinical follow up, from a single centre managing recurrent respiratory papilloma in Glasgow, Scotland. Cost information was sourced from the Scottish Government's Information Services Division. Fourteen patients with active recurrent respiratory papilloma between 2013 and 2014 were identified. The direct measurable cost to NHS Greater Glasgow and Clyde amounted to £107 478. Recurrent respiratory papilloma is a benign condition, but the financial implications of diagnosis are significant. Recurrent respiratory papilloma has a natural history of relapse and remission, and patients may require healthcare input over a period of several years.

OR Management of Recurrent Respiratory Papilloma

Surgical management of recurrent respiratory papillomatosis has depended upon surgical removal and debulking of disease to maintain a patent airway and preserve vocal function. Over time, this has evolved from cold instrumentation alone to microscope-guided laser ablation. Powered instrumentation in the form of microdebriders has also come to serve an important role for the rapid removal of exophytic, airway obstructive disease. With this evolving technologic sophistication, the surgical paradigm has progressed from maintaining a patent airway to maintaining vocal function. This chapter will discuss the evolution of surgical management, the considerations for airway management and operative anesthesia, and will finally discuss current adjuvant medical therapies and imaging modalities that seek to limit disease recurrence and enhance detection and surgical management.

Office-based Management of Recurrent Respiratory Papilloma.

This review will highlight the indications and benefits of office-based therapy for recurrent respiratory papillomatosis (RRP) and discuss the utilization of photo-dynamic lasers and adjuvant medical therapy in office-based settings. Office-based management of RRP allows for more timely interventions, is preferred by the majority of patients, and negates the risk of general anesthesia. Current literature argues for the utilization of KTP laser over CO2 laser for office-based treatment of RRP. Medical therapies for RRP are limited, but agents such as bevacizumab are promising and have been shown to reduce disease burden. Medical therapies that can induce disease remission are still needed. Office-based procedures save time and healthcare expenses compared to like procedures in the operating room. However, the increased frequency for office-based procedures predicts similar overall healthcare costs for office-based and OR laser excision of RRP. Office-based management of RRP is a feasible and well-tolerated strategy in appropriately selected patients with adequate local anesthesia.

Respiratory papillomas

Papillomas are known to occur in the lower respiratory tract. They are however, rare compared to their occurrence in the upper respiratory tract. These are generally exophytic tumors in the more proximal upper airways however cases with more distal location with an inverted growth pattern have also been described in the literature. These can be solitary or multiple and multifocality associated with multiple papillomas in the upper respiratory/aerodigestive tract. The four major types of respiratory papillomas are (1) Recurrent respiratory papillomas, (2) solitary squamous papillomas, (3) solitary glandular papillomas, (4) mixed papillomas. We review the incidence, etiopathology, diagnosis, and possible treatment modalities and algorithms for these respiratory papillomas.

Immune Dysregulation in Patients Persistently Infected with Human Papillomaviruses 6 and 11.

Human Papillomaviruses (HPVs) 6 and 11 are part of a large family of small DNA viruses, some of which are commensal. Although much of the population can contain or clear infection with these viruses, there is a subset of individuals who develop persistent infection that can cause significant morbidity and on occasion mortality. Depending on the site of infection, patients chronically infected with these viruses develop either recurrent, and on occasion, severe genital warts or recurrent respiratory papillomas that can obstruct the upper airway. The HPV-induced diseases described are likely the result of a complex and localized immune suppressive milieu that is characteristic of patients with persistent HPV infection. We review data that documents impaired Langerhans cell responses and maturation, describes the polarized adaptive T-cell immune responses made to these viruses, and the expression of class select II MHC and KIR genes that associate with severe HPV6 and 11 induced disease. Finally, we review evidence that documents the polarization of functional TH2 and T-regulatory T-cells in tissues persistently infected with HPV6 and 11, and we review evidence that there is suppression of natural killer cell function. Together, these altered innate and adaptive immune responses contribute to the cellular and humoral microenvironment that supports HPV 6 and 11-induced disease.

The Use of the Quadrivalent Human Papillomavirus Vaccine (Gardasil) as Adjuvant Therapy in the Treatment of Recurrent Respiratory Papilloma

To examine the effect of the quadrivalent human papillomavirus vaccine, Gardasil, on the disease course of patients with recurrent respiratory papillomatosis (RRP). A retrospective chart review of patients with RRP was conducted and 20 patients were selected who had received the Gardasil vaccine as part of their treatment. Efficacy was assessed by calculating the intersurgical interval (ISI) before and after receiving the vaccine, as well as number of complete and partial remissions. Analysis of all patients found a significant increase in the ISI of 3.1 months (95% confidence interval [CI]: 1.02-5.19, P=0.0061). Male patients experienced an increase in the ISI of 4.2 months (95% CI: 1.6-6.7, P=0.0048). Female patients had a nonsignificant increase in ISI of 1.2 months (95% CI: 3.1-5.4, P=0.51). Eight patients (40%; six male and two female) experienced complete remission. Five patients (25%) overall (three male and two female) experienced partial remission. In total, complete or partial remission was achieved in a total of 13 (65%) patients (nine male and four female). The Gardasil vaccine can modulate the severity of RRP and induce remission in some patients. The effect was much greater in males and in females in low estrogen states.

Decreased Langerhans cell responses to IL-36γ: altered innate immunity in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36γ, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain TH1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of TH2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36γ protein, and that human keratinocytes transduced with HPV11 have reduced IL-36γ secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36γ by expressing inflammatory cytokines and chemokines. When stimulated with IL-36γ, iLCs from patients with RRP had lower expression levels of the TH2-like chemokine CCL-20 as compared with controls. Patients' iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of TH1- and a TH2-like chemokines by iLCs from patients could have consequences in the priming of IFN-γ expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36γ. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, TH1-like and/or Tc1-like adaptive response, thus resulting in the predominant TH2-like and/or Treg micromilieu present in papillomas.

Glottic Papilloma in Pregnancy

ABSTRACT Respiratory papilloma (RP) is the most common benign neoplasm of the larynx, both in children and in adult. The etiology of recurrent respiratory papilloma is human papilloma virus (HPV), which has propensity to lay in normal epithelium, hence the high rate of recurrence. We report a case of an adult onset large glottic papilloma seen in a female with 3rd trimester pregnancy, which was excised under microscope under local anesthesia. The effect of pregnancy and latest modalities of treatment are discussed in this article. How to cite this article Mittal R, Verma H, Mathur N, Bhuie HS. Glottic Papilloma in Pregnancy. Int J Phonosurg Laryngol 2014;4(1):43-44.

Evaluation of the chicken embryo chorioallantoic membrane model for laryngeal tumor transplantation

The laryngeal squamous cell carcinoma is the second common malignant tumor of the respiratory tract and together with recurrent respiratory papillomas represents the most common tumors of the larynx. Many experimental models are used to study the morphology of malignant tumors. The chicken chorioallantoic membrane (CAM) model is one of them. The CAM has all the nutrition needed for the piece of the transplanted tumor to survive. The aim of this study was to investigate whether the laryngeal papilloma and the laryngeal squamous cell carcinoma tissues transplanted on the chick CAM survive with their main histological features, and to determine the morphological changes of the CAM with different transplants. For the preparation of the CAM, fertilized hen eggs were put into an incubator for 3 days. Then the windows in the shell were opened. The fresh samples of tumors were transplanted on the CAM on the 7th day of incubation. After 3 days after transplantation the CAM with onplants were excised and fixed in the 10% formalin solution. Morphological changes in the control CAM and in the CAM with tumor onplants were observed using the digital camera on the OLYMPUS microscope. The results showed that the CAM with the laryngeal squamous cell carcinoma onplant was distinctly thicker than that of the control group and than the CAM with the papilloma onplant; the chorionic epithelium was thickened and appeared stratified of up to 5–6 layers and in some locations squamous keratinized; the mesenchymal cells were densely arranged under the tumor transplants. We observed that morphological changes in the thickness of the CAM and the chorionic epithelium were more obvious in the CAM under the carcinoma transplants. After 72 hours of the tumor tissue transfer onto the membrane, the tumor cells retained their vitality and also their influence on the CAM tissues could be observed.

Peri-operative management on juvenile recurrent respiratory papillomatosis

To investigate the safety of peri-operative management on children with juvenile recurrent respiratory papilloma (JORRP). A retrospective analysis was conducted on preoperative assessment, anesthesia methods and options, operative procedure, and postoperative airway maintenance in 28 JORRP children aged from ten months to seven years old. A total of 148 times of surgery was performed on these 28 children. One hundred and nine JORRP children graded one and two-degree dyspnea underwent surgery within 24 hours and were intubated successfully in the first attempt after intravenous induction. Thirty-nine emergency operations were performed in the children graded three and four-degree dyspnea, 35 of them were intubated successfully in the first attempt after inhalation induction and 4 succeeded in the second attempt. No complications occurred in 129 JORRP children postoperatively, 17 children suffered from mild dyspnea and relieved after oxygen inhalation, 2 children were intubated and sent to intensive care unit because of postoperative hypoxemia. All JORRP children got through the peri-operative period safely. The quality of pronunciation in 101 children improved markedly and 35 suffered from slight hoarseness on the 1st postoperative day. Three children had the tracheal tube of tracheostomy removed after receiving five, four and three operations respectively. Nineteen children were followed up for 2 - 5 years. Among them, one child did not relapse 3 years after surgical management.One child suffered from laryngostenosis postoperatively. No death occurred. Complete preoperative preparation, rational anesthesia methods, careful operative procedure and airway maintenance after surgery could increase the safety for children with recurrent respiratory papilloma.

Immune Suppression in Premalignant Respiratory Papillomas: Enriched Functional CD4+Foxp3+ Regulatory T Cells and PD-1/PD-L1/L2 Expression

Respiratory papillomas, caused by human papillomaviruses types 6 and 11 (HPV6/11), are premalignant lesions with potential for malignant conversion. The cytokine and chemokine micromilieu of papillomas is T(H)2-like with a marked absence of IFN-γ expression. To illuminate why patients with recurrent respiratory papillomatosis (RRP) fail to effectively control their disease, we further investigated the suppressive cellular microenvironment in papillomas. CD4(+)CD25(+)CD127(low/-)Foxp3(+) regulatory T cells (Treg) and CD4(+)CD25(-)CD127(low/-)Foxp3(-) T cells within papillomas were characterized and isolated. Their suppressor function was measured by inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Expression of PD-1, CD69, and Helios was identified on these T cells. PD-L1, PD-L2, CCL17, and CCL22 mRNA was also identified in papillomas by quantitative PCR. Functional Tregs were markedly enriched in papillomas and strongly inhibited anti-CD3 and anti-CD28 antibody activated PBMC proliferation. The natural Treg marker Helios was reduced on Tregs from papillomas, indicating that the majority of Tregs in papillomas are adaptive. The majority of the papilloma-derived CD4(+) T cells expressed the CD4(+)CD25(-)CD127(low/-)Foxp3(-)PD1(+)CD69(+) phenotype and failed to suppress PBMC proliferation, suggesting that they are chronically activated and exhausted. The Treg-attracting chemokine CCL22 was equally expressed by all laryngeal tissues examined. However, CCL17 was robustly expressed by papillomas compared with unaffected laryngeal tissues from RRP patients and individuals without RRP. PD-L1 was elevated in papillomas compared with control laryngeal tissues. Papilloma CD4(+) T cells are enriched with functional Tregs, and the adaptive Helios(-) Treg fraction was increased within the T(H)2-like papilloma micromilieu. CD4(+)CD25(-)CD127(low/-)Foxp3(-) T-cells failed to suppress PBMC proliferation and may be exhausted. The PD-1/PDL-1 pathway may represent an additional immunosuppressive mechanism that contributes to defective HPV6/11 clearance in RRP.

Solitary Papillomas of the Lower Airways: Epidemiological, Clinical, and Therapeutic Data during a 22-Year Period and Review of the Literature

Solitary respiratory papillomas (SRPs) are considered uncommon yet benign neoplasms of the lower respiratory tract. Most of our understanding stems from single case reports or limited case series. To determine the incidence of solitary SRPs and more accurately describe the localization, distribution of subtypes of solitary SRPs, clinical features, and the risk of malignant transformation. This retrospective report is based on data collected in a busy single-center bronchoscopy practice during a 22-year period. Among 36,780 patients who underwent bronchoscopic procedures between 1986 and 2008, we identified 32 patients with SRPs. This patient group was compared with 69 patients with SRPs described in the English literature as case reports, case series, or diagnostic dilemmas. Twenty-three patients were men (male/female ratio of 3:1), and 21 patients were former smokers (65.6%). The mean age of initial presentation in men and women was 56.9 ± 14.3 versus 53.3 ± 14.4 years, respectively. The presenting symptoms included cough in 18 patients (40.6%), hemoptysis in 11 (25%), dyspnea in seven (21.8%), and fever in five patients (15.7%). Two patients with papillomas in the subglottic region had wheezing and were on aerosolized bronchodilator therapy. In one patient, the papilloma was incidentally discovered on a chest computed tomography scan. The histologic analysis of lesions revealed squamous papillomas in 65.6%, a glandular subtype in 18.75%, and a mixed subtype in 15.6%. Malignant transformation was observed in five patients (15.7%). The malignancies consisted of squamous cell carcinoma in two patients, and single cases of small cell lung carcinoma, glandular carcinoma, and low-grade carcinoma. In our experience, the estimated incidence of SRPs is 3.95 cases/100,000 patients/yr. SRPs occur more commonly in men (ratio 3:1). Squamous papillomas occur commonly during the fifth decade of life, glandular papillomas predominate in the sixth decade, and the distribution of mixed type papillomas is from the third to the sixth decade of life. Malignant transformation was observed in a minority of patients.

Current Management of Adult HPV: From Papilloma to Cancer

Program Description: Human papilloma virus (HPV) infection is a major cause of disease. It is causal in respiratory papillomatosis and cervical cancer and is etiologically associated with cancers of the oropharynx as well as additional anogenital sites. Our knowledge of the role of HPV in these diseases is evolving and there are yet many unanswered questions. Furthermore, the epidemiology of these diseases may change with trends in increasing promiscuity and the advent of widespread HPV vaccination. Patients have often read extensively about their diagnosis on the internet and may present with incomplete/incorrect knowledge and difficult questions about disease transmission, progression, treatment and transformation. This miniseminar brings together experts that specialize in different manifestations of HPV disease: adult and pediatric clinicians that treat recurrent respiratory papilloma (RRP), a head and neck surgeon that treats oropharyngeal carcinoma and actively researches vaccines targeting HPV related malignancy, and a guest clinician from gynecology to give insights on the treatment of HPV from a different perspective. The format will focus on case presentations to highlight the specific topics selected for discussion to include: basic biology of HPV infection and oncogenesis, treatment strategies for RRP, adjuvant treatments for RRP, counseling regarding contacts of patients with HPV related disease, HPV vaccine indications, and current concepts regarding the role of HPV in oropharyngeal cancer. There will be opportunity for the audience to ask questions throughout the presentation. Educational Objectives: 1) Understand current RRP management strategies including surgical techniques, adjuvant medications and nutritional supplements. 2) Be able to counsel patients on etiology of RRP, transmission, cancer risk, and vaccination. 3) Understand how RRP fits in the spectrum of HPV-related disease.

Expression of matrix metalloproteinases (MMP-2 and MMP-9) in recurrent respiratory papillomas and laryngeal carcinoma: clinical and morphological parallels

The task of the present study was to investigate the expression of MMP-2 and MMP-9 in recurrent respiratory papillomas (RRP) and accomplish a comparative analysis with those in laryngeal squamous cell carcinoma (LSCC). The immunohistochemical expression of MMP-2 and MMP-9 was investigated in specimens taken from RRP (n = 38) and LSCC (n = 39) patient groups, and the normal tissue of vocal fold (n = 12, control group). The expression of MMP-2 and MMP-9, both in epithelium and stroma cells, was graded on a semiquantitative scale, ranging from 0 (no expression) to 18 points (high expression). Statistically significant differences in the expression of MMP-2 and MMP-9, both in epithelium and stroma among the RRP, LSCC patients and control group (epithelium) with the LSCC group having the highest MMPs expression scores were revealed. However, no statistically significant correlations among expression of MMPs and clinical and/or morphological features were found in the group of RRP patients. The MMP-2 stroma value of 10.4 points was determined as the optimum point (limiting value) for separating RRP and LSCC patient groups. Results of the present study indicate that the expression of both MMP-2 and MMP-9 are up-regulated early in development of laryngeal papillomas, when the benign neoplastic lesion begins and the next determinant step is concerned with the occurrence of malignization. These results seem promising, as they may improve our understanding of the molecular events leading to the papilloma formation and development, however, further research is needed.

Flexible CO2Laser Fiber in the Pediatric Airway

Objective. Our institution has been using a novel flexible laser fiber in pediatric surgical airway procedures, which has been quite successful. The purpose of this paper is to present our preliminary experience in the treatment of pediatric airway lesions using this laser technique.Methods.A case series reviewing 40 patients undergoing 95 laser procedures is reported. Indications included removal of suprastomal granulation tissue, removal of granulation after laryngotracheal reconstruction, subglottic and supraglottic stenoses, recurrent respiratory papillomas, subglottic hemangioma, laryngeal cleft, and left main stem bronchus stenosis. Procedures were performed via microdirect laryngoscopy and bronchoscopy.Results. No complications including postoperative glottic webs, concentric scar formation, or airway fires occurred in any of the patients (after the series was completed, we did experience an airway fire. It was a flash flame that was self-limited and caused no long-term tissue injury).Conclusions. The endoscopic application of a new flexible carbon dioxide laser fiber for management of pediatric airways lesions provides good outcomes in selected patients. Distal respiratory papillomas, subglottic stenosis, and granulation tissue are, in our experience, appropriate indications.

A Case of Multiple Squamous Cell Papillomas of the Trachea

We report a case of 68-year-old woman suffering from breathlessness on exertion with stridor. A chest computed tomography showed a tumor arising from the posterior wall of the trachea. The diagnosis was squamous cell papilloma of the surgically removed tumor, which had caused the asphyxiation. After removal of the tumor, the patient received radical therapy: semiconductor laser transpiration. Polymerase chain reaction (PCR) detected human papilloma virus (HPV) type 6, thought to be the cause of the respiratory papilloma.

Pak1 and Pak2 are activated in recurrent respiratory papillomas, contributing to one pathway of Rac1‐mediated COX‐2 expression

Recurrent respiratory papillomas are premalignant tumors of the airway caused by human papillomaviruses (HPVs), primarily Types 6 and 11. We had reported that respiratory papillomas overexpress the epidermal growth factor receptor (EGFR), the small GTPase Rac1 and cyclooxygenase-2 (COX-2), and have enhanced nuclear factor-kappaB (NFkappaB) activation with decreased levels of IkappaB-beta but not IkappaB-alpha. We also showed that EGFR-activated Rac1 mediates expression of COX-2 through activation of p38 mitogen-activated protein kinase. We have now asked whether the p21-activated kinases Pak1 or Pak2 mediate activation of p38 by Rac1 in papilloma cells. Pak1 and Pak2 were constitutively activated in vivo in papilloma tissue compared with normal epithelium, and Rac1 siRNA reduced the level of both phospho-Pak1 and phospho-Pak2 in cultured papilloma cells. Reduction in Pak1 and Pak2 with siRNA decreased the COX-2 expression in papilloma cells, increased the levels of IkappaB-beta and reduced the nuclear localization of NF-kappaB, but had no effect on p38 phosphorylation. Our studies suggest that Rac1 --> Pak1/Pak2 --> NFkappaB is a separate pathway that contributes to the expression of COX-2 in HPV-induced papillomas, independently of the previously described Rac1 --> p38 --> COX-2 pathway.

Use of 532-nm Pulsed Potassium Titanyl Phosphate Laser and Adjuvant Intralesional Bevacizumab for Aggressive Respiratory Papillomatosis in Children

To describe the initial pediatric experience with intralesional bevacizumab (Avastin) treatment for children with severe, recurrent respiratory papilloma (RRP). Retrospective medical chart review. Tertiary care multidisciplinary aerodigestive center. Three children, aged 3 to 6 years, with severe RRP requiring more than 4 operative interventions in 1 year whose parents (or legal guardians) consented to adjuvant treatment with intralesional bevacizumab. All 3 children were treated as follows: surgical debridement with a microdebrider, pulsed potassium titanyl phosphate laser treatments, and adjuvant intralesional injections with bevacizumab (1.25 mg total). Time interval between operative interventions, Derkay severity scale for RRP, and pediatric voice-related quality of life (PVRQOL) scores. All 3 children demonstrated increased time between operative interventions. Two children had a substantial decrease in their Derkay score and improved PVRQOL scores. One child, although time between operative interventions improved, did not have any change in Derkay score and required further adjuvant therapy. Injectable bevacizumab appears to show some efficacy in prolonging the time between treatments and therefore reducing the number of treatments per year in children with severe RRP. However, before any meaningful conclusions can be drawn, further studies must be conducted in the form of head-to-head trials looking specifically at the issues of time between treatment intervals, efficacy of one adjunct over another, vocal outcomes, and whether several adjunctive treatments confer advantage over 1 treatment. In-depth and careful informed consent is mandatory for these studies so that parents are aware of the risks and benefits (known and unknown) before such individualized decisions are made.