Respiratory Papillomas Research Articles

Update on Pathologic Conditions, Imaging Findings, Prevention, and Management of Human Papillomavirus-related Neoplasms.

Human papillomavirus (HPV) is the most common sexually transmitted infection that proliferates in the squamous epithelium and is the most common source of viral-related neoplasms. Low-risk subtypes (HPV-6 and -11) cause respiratory papillomas (laryngeal, tracheal, and bronchial) and condyloma acuminata of the penis, anus, and perineal region (anogenital warts). High-risk subtypes (HPV-16, -18, -31, and -33) are responsible for oropharyngeal squamous cell carcinoma (SCC) that involves the tongue base, tonsils, posterior pharyngeal wall, and larynx and malignancies of the anogenital region (cancers of the cervix, vagina, vulva, penis, and anal canal). Recent studies have increasingly shown a favorable treatment response and substantial differences in the overall prognosis associated with HPV-associated oropharyngeal cancers. Given this fact, oropharyngeal, cervical, and penile SCCs are classified as HPV-associated and HPV-independent cancers in the current World Health Organization classification. Imaging is essential in the early detection, diagnosis, and staging of HPV-associated cancers. Imaging also helps assess treatment response and postoperative complications and is used for long-term surveillance. HPV-associated oropharyngeal SCCs have well-defined borders and solid and cystic nodal metastases at imaging. Updated screening and vaccination guidelines are currently available that have great potential to decrease the overall disease burden and help control this worldwide public health concern. Novel therapeutic strategies, such as immunotherapies, are being explored, and imaging biomarkers that can predict treatment response and prognosis are being investigated; radiologists play a pivotal role in these efforts. ©RSNA, 2024 Supplemental material is available for this article.

Advances in the use of bevacizumab for the treatment of respiratory papilloma

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

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

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). 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. 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. 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. 4 Laryngoscope, 134:3238-3244, 2024.

Recurrent Respiratory Papilloma of the Larynx

Recurrent respiratory papilloma (RRP) is a common benign neoplasm that most commonly affects the larynx. Caused primarily by human papilloma virus (HPV) types 6 and 11, RRP affects both children and adults; juvenile-onset RRP is thought to be related to HPV exposure during childbirth, whereas adult-onset disease has been hypothesized to be related to sexual contact.1Aaltonen L.M. Rihkanen H. Vaheri A. Human papillomavirus in larynx.Laryngoscope. 2002; 112: 700-707https://doi.org/10.1097/00005537-200204000-00020Crossref PubMed Scopus (83) Google Scholar Symptoms of RRP are typically voice or airway related. Adults tend to experience voice changes, primarily because of impairment of vocal fold vibration in the setting of papilloma along the membranous vocal folds. In children, in whom lesions tend to grow more quickly, airway narrowing may present with stridor in addition to voice changes. Direct or indirect laryngoscopy is standard work-up. Flexible fiberoptic or distal chip scopes may reveal heaped, irregular lesions of the glottis (Figure 1A) or supraglottis, and filters (eg, narrow-band imaging) (Figure 1B) may help to reveal intraepithelial capillary loops. Biopsy remains the criterion standard for diagnosis. Figure 2 illustrates typical findings, including a higher-power image of a cellular papillary frond with viral cytopathic effects and corresponding chromogenic in situ hybridization for low-risk HPV type 6/11.2Venkatesan N.N. Pine H.S. Underbrink M.P. Recurrent respiratory papillomatosis.Otolaryngol Clin North Am. 2012; 45 (671-94, viii-ix. https://doi.org/10.1016/j.otc.2012.03.006)Abstract Full Text Full Text PDF Scopus (89) Google Scholar Treatment includes excision or ablation with cold technique, photoangiolytic lasers, or microdebriders, with maximal conservation of the subepithelial vocal fold tissue. Recurrent respiratory papilloma routinely recurs, and so adjunct treatments with cidofovir and bevacizumab are advocated for recalcitrant cases.3Pogoda L. Ziylan F. Smeeing D.P.J. Dikkers F.G. Rinkel R.N.P.M. Bevacizumab as treatment option for recurrent respiratory papillomatosis: a systematic review.Eur Arch Otorhinolaryngol. 2022; 279: 4229-4240https://doi.org/10.1007/s00405-022-07388-6Crossref Scopus (3) Google Scholar Emerging evidence suggests that HPV vaccination, even in those already affected, may be beneficial in reducing the severity of disease.4Ponduri A, Azmy MC, Axler E, et al. The efficacy of human papillomavirus vaccination as an adjuvant therapy in recurrent respiratory papillomatosis. Laryngoscope. Published online January 18, 2023. https://doi.org/10.1002/lary.30560.Google Scholar The authors report no competing interests.

Cover Story: Eur. J. Immunol. 4'23

European Journal of ImmunologyVolume 53, Issue 4 2370041 Cover PictureFree Access Cover Story: Eur. J. Immunol. 4'23 First published: 10 April 2023 https://doi.org/10.1002/eji.202370041AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract Our cover image features immunostaining of classical and non-classical MHC class I molecules on HPV6/11 induced respiratory papilloma epithelia. HLA-A, B, and C are absent on these epithelial cells but are expressed in the papilloma stroma. However, non-classical MHC class I molecules, HLA-E and -G, are strongly expressed on papilloma epithelial cells and stroma. The image are from Israr et al. This is the strategy used by HPV6/11 infection to block NK activation and reduce HPV6/11 peptide presentation to T-cells. The authors also show that papilloma cells express increased amounts of PGE2 that directly inhibits NK cell function by signaling through the NK cell PGE2 receptors EP2 and EP4. The original image was digitally modified for the cover. Volume53, Issue4April 20232370041 RelatedInformation

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

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

Toll-like receptor agonists, poly(I:C) and flagellin, lead to IL-36γ induction with divergent release kinetics and differentially alter autophagy in primary human keratinocytes

IL-36γ, a pro-inflammatory member of the IL-1 cytokine superfamily, can be induced and secreted by normal human foreskin keratinocytes (HFKs) in response to pathogenic stimuli, however, the mechanisms underlying the secretion are unknown. In this study, we demonstrate that stimulation with the TLR3 agonist, poly (I:C), led to a delayed secretion of IL-36γ compared to stimulation with the TLR5 agonist, flagellin, despite equal levels of the cytokine (p = 0.006). IL-36γ was shown to be released from HFKs in its inactive, uncleaved form, based on western blotting. Moreover, recombinant IL-36γ in its activated, cleaved form induced endogenous IL-36γ 10-fold (p = 0.004) and CXCL8 five-fold (p = 0.003) over baseline levels compared to unactivated full-length recombinant IL-36γ. The ratio of LC3b-II/LC3b-I was significantly higher in poly(I:C)-treated cells compared to flagellin-treated and unstimulated controls without a change in SQSTM1/p62 after 24 hours of stimulation (p = 0.043). Under fluorescence microscopy, poly(I:C) led to a two-fold increase at eight hours and four-fold increase at 24 hours in accumulated autophagosomes post-stimulation (p = 0.032). In contrast, autophagosomes were unchanged relative to baseline in response to flagellin. Bafilomycin A1 treatment enhanced poly(I:C)-mediated IL-36γ secretion (p = 0.044) while rapamycin led to a noticeable, but non-significant, increase in flagellin-mediated IL-36γ secretion, indicating that interrupting autophagic flux can alter IL-3γ grelease from HFKs. Finally, we show that, compared to clinically normal laryngeal tissue, there were significantly higher levels of LC3b-II in HPV-infected respiratory papilloma tissue, indicating a higher number of autophagosomes; a signature of disrupted autophagic flux.

Clinical features of 19 cases of lower respiratory papillomatosis

Objective: To explore the clinical characteristics and prognosis of lower respiratory papilloma(LRP)and therefore to improve clinical diagnosis and treatment. Methods: We performed a retrospective analysis of patients who were diagnosed with LRP in our department from October 2008 to October 2020. Results: Nineteen patients were enrolled and 12 were male and 7 were female. The average age of the 7 adult patients was (41.3±17.5)years and that of the 12 pediatric patients was (5.5±3.5)years. Ten (83.3%)of the pediatric patients showed disease onset at an age of less than 5 years. The main symptoms were cough and sputum production (13/19), dyspnea (15/19), hoarseness (10/19) and signs of stridor or wheezing (7/19). Chest CT examination was performed in 9 patients, which showed nodules or masses (9/9), cystic thin-walled cavity (4/9), obstructive pneumonia (2/9), atelectasis (2/9), and spicule sign (1/9). The upper respiratory tract was affected in all the pediatric patients (12/12) and 3/7 of the adult patients. Eighteen cases (18/19) were diagnosed by bronchoscopy, 1 (1/9) by thoracoscopy. Eighteen cases (18/19) showed mulberry-like and papillary lesions under bronchoscopy. All the cases were histologically confirmed as squamous cell papilloma, with 17 cases(17/19)showing tissue HPV6/11(+), 2 negative (2/19). The positive rate of HPV6 was 36.8%, ant that of HPV11 was 21.1%, while the double positive rate of HPV6/11 was 31.6%, and HPV16/18 were negative in all the 19 cases. Isolated respiratory papillomatosis was found in 4 cases (4/19), and multiple papillomatosis in 15 cases (15/19). Seventeen cases (17/19) underwent endoscopic interventional therapy, and the result showed that 15 cases relapsed, and 2 cases had no recurrence. One patient was treated with thoracoscopic lobectomy, and died 4 months after surgery. One patient gave up treatment. Conclusions: LRP is a rare clinical disease with a chronic course, and isolated LRP is even rarer. Young patients often suffer from upper respiratory tract involvement, and the main symptoms are cough, sputum production, dyspnea and hoarseness. CT scanning showed nodules and masses, cystic thin-walled cavities or signs of airway obstruction. Bronchoscopy often demonstrates papillary lesions. The diagnosis depends on pathology, with squamous cell papilloma being the most common, and most tests are positive for HPV6/11. It is suggested that the incidence is associated with low-risk HPV infection. Endoscopic resection is the main treatment, which is prone to relapse. The treatment should take into account the pathological changes of upper respiratory tract, and the etiological treatment of HPV should be stressed.

Comprehensive multiomic characterization of human papillomavirus-driven recurrent respiratory papillomatosis reveals distinct molecular subtypes

Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.

Infectious Titres of Human Papillomaviruses (HPVs) in Patient Lesions, Methodological Considerations in Evaluating HPV Infectivity and Implications for the Efficacy of High-Level Disinfectants

Background: Recent publications from a single research group have suggested that aldehyde-based high-level disinfectants (HLDs), such as ortho-phthalaldehyde (OPA), are not effective at inactivating HPVs and that therefore, patients may be at risk of HPV infection from medical devices. These results could have significant public health consequences and therefore necessitated evaluation of their reproducibility and clinical relevance. Methods: We developed methods and used standardised controls to: (1) quantify the infectious levels of clinically-sourced HPVs from patient lesions and compare them to laboratory-derived HPVs, (2) evaluate experimental factors that should be controlled to ensure consistent and reproducible infectivity measurements of different HPV genotypes, and (3) determine the efficacy of select HLDs. Findings: A novel focus forming unit (FFU) infectivity assay demonstrated that exfoliates from patient anogenital lesions and respiratory papillomas yielded infectious HPV burdens up to 2·7x103 FFU; therefore, using 2·2x102 to 1·0x104 FFU of laboratory-derived HPVs in disinfection assays provides a relevant range for clinical exposures. RNase and neutralising antibody sensitivities were used to ensure valid infectivity measures of tissue-derived and recombinant HPV preparations. HPV infectivity was demonstrated over a dynamic range of 4 to 5 log10; and disinfection with OPA and hypochlorite was achieved over 3 to >4 log10 with multiple genotypes of tissue-derived and recombinant HPV isolates. Interpretation: This work, along with a companion publication from an independent lab in this issue, address a major public health question by showing that HPVs are susceptible to HLDs. Funding: Advanced Sterilization Products; US NIH (R01CA207368, U19AI084081, P30CA118100). Declaration of Interests: M.A.O. reports grants, personal fees and non-financial support from Advanced Sterilization Products, grants from U.S. National Institutes of Health, during the conduct of the study; In addition, Dr. Ozbun has a patent “Quantitative Methods for Assessing Papillomavirus Infections” pending. A.G.W. reports personal fees and non-financial support from ASCCP, non-financial support from ACOG, non-financial support from Loktal Medical Electronics, personal fees and non-financial support from CSCCP (Chinese Society for colposcopy and cervical pathology, personal fees and non- financial support from Henan People's Regional Hospital, personal fees from SouthCentral Foundation (Alaska Native Corp), non-financial support from FECOLSOG (Colombian colposcopy society), non- financial support from COMEGIC (Mexican colposcopy society), non-financial support from Doctors Hospital at Renaissance, non-financial support from MD Anderson, non-financial support from Univ Texas Rio Grande Valley, non-financial support from Global Coalition against Cervical Cancer, non-financial support from AIDS Malignancy Consortium, personal fees and non-financial support from Deaconess Beth Israel Hospital, personal fees and non-financial support from Texas Tech University, personal fees and non-financial support from ABPTGIC (Brazilian colposcopy society), outside the submitted work. V.B., N.A.P, R.T.S., E.C.B. and R.M. have nothing to disclose. A.S., J.Y. and M.R. are employees of Advanced Sterilization Products. G.E. is an employee and shareholder of Johnson & Johnson, which was the parent company for Advanced Sterilization Products and Janssen Pharmaceutica NV at the time the research was conducted. Ethics Approval Statement: The collection of clinical material used in this study complied with the Helsinki Declaration of 1975, as revised in 1983 and described previously and was approved by the University of New Mexico Health Sciences Center’s Human Research Protections Office (UNM HRPO #17-202 IRB Approved Protocol).

HEMOPTYSIS CAUSED BY NON-HUMAN PAPILLOMA VIRUS RESPIRATORY PAPILLOMA: A CASE REPORT

SESSION TITLE: Fellows Lung Pathology Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Solitary respiratory papillomas (SRP) are uncommon, often verrucated growths arising from the respiratory epithelium. They are associated with human papilloma virus infection and are predominantly found in the upper respiratory tract, but can rarely be found in the lower respiratory tract. CASE PRESENTATION: Patient is a 61 year old male that have presented with two months of cough and new hemoptysis. CT Thorax had shown an endobronchial lesion in the left mainstem and he had been referred to pulmonology for biopsy. On bronchoscopy at the distal left mainstem just proximal to the take off to the left lower lobe there was a verrucated vascular tumor arising from the posterior wall. This tumor was nearly obstructing the left lower lobe. Argon plasma coagulation was used, followed by complete resection using a rigid bronchoscopy. Pathology was consistent with a benign squamous papilloma. Further evaluation showed that the papilloma was negative for HPV. Social history was only significant for 25 pack years of smoking. DISCUSSION: SRP is a rare pulmonary phenomenon with an estimated incidence of 3-4/100,000 patient years with a 3:1 male predominance. Patient’s are commonly 50-60 years of age and present with a chronic cough, dyspnea and hemoptysis. Depending on the size and positioning of the tumor, a localized wheezing may be found on auscultation. SRP are more commonly found in the upper respiratory tract and can also be seen on the larynx, lesions more distally are less commonly seen. As with our patient, tumors of sufficient size may show up as an endobronchial lesion may been seen on CT. Bronchoscopic evaluation often shows a verrucated endobronchial lesion. On histopathology a squamous lesion is most common (65%), glandular (20%), or a mixed subtype (15%). Resection is curative, with resolution of symptoms. Recurrence of papilloma is very rare with an incidence of 2/100,000. Although a typically benign disease, malignant transformation has been seen in up to 15% of cases. SRP is commonly secondary to a human papilloma infection, and non-HPV papillomas are extremely rare and have been postulated to be secondary to a significant smoking history. There is evidence that exposure to irritants such as tobacco, gastric reflux disease may lead to the development of papillomas. CONCLUSIONS: Although traditionally associated with human papilloma virus, in addition to it’s other deleterious effects, tobacco usage may also lead to the development of SRP. Usually a benign lesion, papilloma secondary to tobacco usage can also indicate other potential malignancies Reference #1: Agrawal A, Alagusundaramoorthy S. Respiratory papillomas. Lung India. 2016;33(5):522. doi:10.4103/0970-2113.188973? Reference #2: Harada H, Miura K, Tsutsui Y, et al. Solitary squamous cell papilloma of the lung in a 40-year-old woman with recurrent laryngeal papillomatosis. Pathol Int. 2000;50(5):431-439. doi:10.1046/j.1440-1827.2000.01055.x DISCLOSURES: No relevant relationships by Christian Castaneda, source=Web Response No relevant relationships by Tarek Dammad, source=Web Response No relevant relationships by Albert Magh, source=Web Response No relevant relationships by Crystal Verdick, source=Web Response

An Experimental Model of Human Recurrent Respiratory Papillomatosis: A Bridge to Clinical Insights.

To investigate the growth pattern of recurrent respiratory papilloma (RRP) implants on chicken embryo chorioallantoic membranes (CAMs) and to evaluate possible associations between the clinical course of the disease and the behavior of experimentally implanted RRP tumors. Experimental study. Fresh 172 RRP tissue samples from 12 patients were implanted onto chick embryo CAMs. Morphological and morphometric analysis of the experimental CAM and chorionic epithelium was performed. The microvascular network of the CAM with the RRP implant was investigated under the effect of fluoresceinated anionic dextran. The peculiarities of the clinical course of the disease were evaluated. The implanted RRP tissue samples survived on CAMs in 86% of cases, retaining their essential morphologic characteristics and proliferative capacity of the original tumor. Implants induced thickening of both the CAM and the chorionic epithelium, but none of the RRP implants crossed the basement membrane of the hosting CAM. A "crawling film" of acellular material with newly formed papilloma sprouts located on the outer chorionic epithelium of the CAM was detected. Direct association between a recurrence rate of RRP and the number of newly formed papilloma sprouts around the implanted tumor on CAMs was revealed. The chicken embryo CAM-based model is appropriate for investigations of RRP and facilitates the understanding of tumor biology and the clinical course of the disease, thus providing the basis for further research and acceleration of the identification and development of new specific therapeutic compounds that limit the spread and recurrence of RRP. N/A Laryngoscope, 131:E914-E920, 2021.

Assessing the Efficacy of Human Papillomavirus Disinfection and the Risk of Transmission from Clinical Lesions

<h3>Background</h3> HPV genomes can be detected on medical devices following hospital disinfectant procedures. Recent reports concluded that oncogenic HPVs derived from laboratory tissue-based models are not susceptible to commonly used high-level disinfectants, intensifying concerns that medical instruments may provide transmission of nosocomial HPVs infections. Therefore, we determined the infectious load of HPVs from clinical lesions and investigated the effectiveness of disinfectants on HPV virions derived from laboratory model systems. <h3>Methods</h3> Infectious HPV virions were isolated from cell culture, organotypic epithelial tissue cultures, and mouse xenografts. Clinical samples from recurrent respiratory papillomas (RRPs) and anogenital warts were obtained under IRB approval. The infectivity of HPV virion stocks was measured by the detection of spliced viral E1^E4 mRNAs in infected keratinocytes. Infections were validated by time-dependent detection of E1^E4 mRNAs, resistance to ribonuclease treatment and susceptibility to antibody-mediated neutralization. Our infectivity assay demonstrated a dynamic range of >3-5 log10. Suspension-based disinfection assays employed diluted ortho-phthalaldehyde (OPA) and 0.825% hypochlorite. <h3>Results</h3> In contrast to prior reports, we found that validated HPV virions obtained from a variety of sources were susceptible to a 2.5 to 4 log10 reduction in infectious titer when exposed as directed to OPA or hypochlorite. Some HPV virion stocks failed to meet the infectivity criteria of time-dependent detection of E1^E4 mRNAs, resistance to ribonuclease and susceptibility to antibody-mediated neutralization. Such unvalidated virus stocks are likely to produce spurious results and lead to confounding conclusions. Assessment of HPV infectious titers from clinical lesions suggests that compared to common warts, clinical RRP and anogenital warts have lower levels of virions present at apical surfaces. <h3>Conclusions</h3> We conclude that laboratory sourced HPVs are susceptible to disinfection by OPA and hypochlorite. As the levels of infectious virions recovered from HPV-induced lesions fall below those used in our assays, proper cleaning and disinfection processing is likely to be effective

Altered Monocyte and Langerhans Cell Innate Immunity in Patients With Recurrent Respiratory Papillomatosis (RRP).

The micromilieu within respiratory papillomas supports persistent human papillomavirus (HPV) infection and disease recurrence in patients with recurrent respiratory papillomatosis (RRP). These patients show polarized (TH2-/Treg) adaptive immunity in papillomas and blood, enriched immature Langerhans cell (iLC) numbers, and overexpression of cyclooxygenase-2/prostaglandin E2 (PGE2) in the upper airway. Blood monocyte-derived, and tissue-derived iLCs from RRP patients and controls were now studied to more fully understand innate immune dysregulation in RRP. Patients' monocytes generated fewer iLCs than controls, due to a reduced fraction of classical monocytes that generated most but not all the iLCs. Prostaglandin E2, which was elevated in RRP plasma, reduced monocyte-iLC differentiation from controls to the levels of RRP patients, but had no effect on subsequent iLC maturation. Cytokine/chemokine responses by iLCs from papillomas, foreskin, and abdominal skin differed significantly. Freshly derived tissue iLCs expressed low CCL-1 and high CCL-20 mRNAs and were unresponsive to IL-36γ stimulation. Papilloma iLCs uniquely expressed IL-36γ at baseline and expressed CCL1 when cultured overnight outside their immunosuppressive microenvironment without additional stimulation. We conclude that monocyte/iLC innate immunity is impaired in RRP, in part due to increased PGE2 exposure in vivo. The immunosuppressive papilloma microenvironment likely alters iLC responses, and vice versa, supporting TH2-like/Treg HPV-specific adaptive immunity in RRP.

Correlation of Aggressivity Papilloma Recurrent Respiratory Tract With Human Papillomavirus Types 6 And 11

Background : Recurrent respiratory tract papilloma (PSPB) is a viral disease that correlated with an airway exophthalmia lesion. Papilloma is primarily caused by human papillomavirus (HPV) types 6 and 11 which are classified as low-risk HPV. Reports indicate that patients with the HPV-11 experience more aggressive course of the disease than HPV-6. Patients are often diagnosed at a younger age, the longer duration, require more frequent surgery and rare diseases of the disease when compared with those caused by HPV-6.Objectives : To investigate the correlation of aggressiveness of PSPB with HPV-6 and 11.Methods : Fifteen samples were conducted in the Outpatient Unit of Otorhinolaryngology and the Lotus Inpatient Installation of Dr. Soetomo General Hospital from December 2012 to March 2013 then determine the disease aggressiveness. PCR examination was done at the Tropical Disease Institute of Universitas Airlangga. Aggressive correlation of disease with HPV type was tested using Chi-Square.Results : Fifteen patients were enrolled that divided; the male was 10 and female was 5. The mean annual number of operations was 2.8 ± 1.27 and 9 patients reported more than 3 surgeries each year. 10 patients had distal papilloma and 11 patients had a history of tracheostomy. PSPB was found in 12 patients, HPV-11 was 9 patients and HPV-6 was 6 patients. Chi-square test results showed no significant results with p = 0.525.Conclusion : There was no correlation between PSPB aggression with HPV-6 and 11

Complicated tracheo-bronchial papillomatosis

Respiratory papillomas are rare benign lesions. They are characterized by the appearance of papillomatous lesions anywhere in the tracheobronchial tree. It affects children and young adults. Although the disease affects mainly the upper airways, it may be aggressive and extends distally to the lower respiratory tract and pulmonary parenchyma. The course of the disease is unpredictable. It may regress spontaneously, but in other instances, it may lead to serious complications ranging from airway obstruction up to malignant transformation. Surgical excision is the mainstay of definitive treatment to prevent recurrence and to exclude malignancy. We have reviewed the literature for this rare type of respiratory disease and present a thirty-five years old; male patient who had chronic cough and was referred to our unit with a CT-chest that revealed left main endo-bronchial lesion. Bronchoscopy and biopsy of the lesion were performed and revealed squamous papilloma. Final treatment introduced to the patient was endoscopic thermal ablation. However, the final pathology revealed complicated squamous bronchial papilloma with infection by aspergillosis and actinomycosis. Key words: HPV; Tracheo-bronchial papilmomatosis; endo-broncial lesion; bronchoscopy

Surgical Treatment for Recurrent Respiratory Papilloma: Strategy of our Department and the Value of Day Surgery

Surgical Treatment for Recurrent Respiratory Papilloma: Strategy of our Department and the Value of Day Surgery

Histologic effect of the potassium-titanyl phosphorous laser on laryngeal papilloma.

ObjectivesTissue effects occurring with potassium‐titanyl phosphorous (KTP) laser treatment are difficult to quantify due to the multiple variables that affect not only the fluence (energy delivered) but also the laser–tissue interaction. This histopathologic analysis of recurrent respiratory papilloma (RRP) removed after treatment with KTP laser therapy permits correlation of histologic effect with method of laser treatment.MethodsThe histopathology of RRP resected specimens in a single patient was compared following treatment with KTP laser in contact and non‐contact modes as documented with intraoperative photography and video imaging.ResultsEpithelial‐sparing injury selective to the microvasculature was identified on histopathologic assessment of a specimen treated with noncontact angiolysis. Highly cauterized papillomatous epithelium without identifiable vascular structures was identified on tissue removed after treatment with the KTP laser in contact mode.ConclusionThe histopathologic assessment of acute KTP laser effect on papilloma permits correlation between technique of application and tissue effect. Similar assessments may be helpful to modify dosimetry for individual patients requiring repeated treatment and may also assist in refining the development of existing KTP laser treatment classification systems.Level of Evidence4

Research status of human papillomavirus vaccine for prevention and treatment of respiratory papillomatosis

Recurrent respiratory papilloma (RRP) is closely related to human papillomavirus (HPV) infection and is the main pathogenic factor. At present, HPV vaccine injection is a new method to control RRP, and its efficacy has been confirmed by many clinical trials. The development and application of HPV vaccine is bound to bring new development to the treatment of RRP. This article reviews the status of HPV vaccine in clinical RRP treatment.

The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis.

Generation of an immunosuppressive microenvironment may enable a persistent human papillomavirus infection in the setting of an otherwise normal immune system. We hypothesized that expression of the T-lymphocyte co-inhibitory receptor programmed death 1 (PD-1) and its ligand PD-L1 would be increased in the recurrent respiratory papillomatosis (RRP) microenvironment compared to normal controls. Case-control study. Formalin-fixed paraffin-embedded respiratory papilloma and normal controls were obtained under institutional review board approval, stained for CD4, CD8, FoxP3, and PD-1, and scored by automated cell count. PD-L1 staining was scored by a blinded pathologist using an adjusted inflammation score that accounted for epithelial and immune infiltrate. Thirty-nine RRP cases and seven controls were studied. All immunologic markers demonstrated significantly increased staining in RRP specimens compared to normal controls (all P < .01). PD-1 correlated with both CD4 (P < .0001) and CD8 (P < .001) cell counts. Epithelial staining for PD-L1 (68%) and PD-L1+ infiltrating immune cells (76%) were observed in the majority of papilloma samples. The strongest staining for PD-L1 was usually observed in the basal papilloma layer adjacent to the immunologic infiltrate in the vascular core. Disease severity inversely correlated with CD8 cell counts (P = .01). A correlation between disease severity and other immunologic markers was not observed. Most RRP specimens demonstrate PD-1 T-lymphocyte infiltration and PD-L1 expression on both papilloma and infiltrating immune cells. This study suggests that this checkpoint pathway may be contributing to local immunosuppression in RRP, and opens the door for clinical trials utilizing PD-blocking monoclonal antibodies. NA Laryngoscope, 128:E27-E32, 2018.