Respiratory Papillomas Research Articles

Clinical analysis of microdebrider removal of recurrent respiratory papilloma: A report of 33 cases

OBJECTIVE To investigate the advantages of applying microdebrider removal of juvenile-onset recurrent respiratory papillary epithelioma (JO-RRP), using an endoscopy-assisted prop-up laryngoscope. METHODS The degree of severity of the neoplasms was divided into 3 scores (i.e. 1 point for a slight degree, 2 points for a moderate and 3 points for a severe degree). The involvement of 22 respiratory and digestive sub-areas was evaluated and the total accumulative scoring and the scores for the lesions in the vocal area were calculated and sub-grouped. All the papillary epitheliomas were excised using a laryngeal micro-debrider or the micro laryngeal forceps under endoscopy-assisted suspension laryngoscopy. The differences between applications of the two modes of treatment for the cases of the groups with same scoring were compared as follows: the operation time, interval of operation, recent vocal quality after operation, postoperative scarring and incision of the trachea, as well as the distribution of tumors in a re-operation. RESULTS The 142 operative procedures were performed in 33 pediatric patients, with application of a laryngeal microdebrider in 14 cases and excision in 19. Compared to the excision group (EG), the laryngeal microdebrider group (MDG) displayed many superior features, such as a short operation time, long interval between operations, obvious improvement in vocal quality soon after operation, and a low frequency of subsequent tumors. There was a significant difference between these modes of the operation. A postoperative incision of the trachea was required in 2 cases of EG, whereas no post-operation was needed in the MDG. CONCLUSION There are many advantages in using laryngeal micro-debrider removal of JO-RRP. The procedure is simple and convenient, having a distinct operating field, precise incision, minor wounds, fewer complications and better vocal quality soon after operation, as well as quicker rehabilitation and longer intervals between operations, etc.

High level expression of human epithelial β-defensins (hBD-1, 2 and 3) in papillomavirus induced lesions

BackgroundEpithelial defensins including human β-defensins (hBDs) and α-defensins (HDs) are antimicrobial peptides that play important roles in the mucosal defense system. However, the role of defensins in papillomavirus induced epithelial lesions is unknown.ResultsPapilloma tissues were prospectively collected from 15 patients with recurrent respiratory papillomatosis (RRP) and analyzed for defensins and chemokine IL-8 expression by quantitative, reverse-transcriptase polymerase chain reaction (RT-PCR) assays. HBD-1, -2 and -3 mRNAs were detectable in papilloma samples from all RRP patients and the levels were higher than in normal oral mucosal tissues from healthy individuals. Immunohistochemical analysis showed that both hBD-1 and 2 were localized in the upper epithelial layers of papilloma tissues. Expression of hBD-2 and hBD-3 appeared to be correlated as indicated by scatter plot analysis (r = 0.837, p < 0.01) suggesting that they were co-inducible in papillomavirus induced lesions. Unlike hBDs, only low levels of HD5 and HD6 were detectable in papillomas and in oral mucosa.ConclusionHuman β-defensins are upregulated in respiratory papillomas. This novel finding suggests that hBDs might contribute to innate and adaptive immune responses targeted against papillomavirus-induced epithelial lesions.

The detection of human papilloma virus in infant respiratory tract papillomas

The detection of human papilloma virus in infant respiratory tract papillomas

Epidermal Growth Factor–Induced Cyclooxygenase-2 Expression Is Mediated through Phosphatidylinositol-3 Kinase, Not Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase, in Recurrent Respiratory Papillomas

Recurrent respiratory papillomas, caused by human papillomaviruses, are premalignant tumors that overexpress the epidermal growth factor receptor (EGFR). The goals of this study were as follows: (a) to evaluate the expression of cyclooxygenase-2 (COX-2) in papillomas, (b) to investigate the role of EGFR signaling in COX-2 expression, and (c) to determine whether COX-2 activity is important for the growth of papilloma cells. Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Explant cultures of both normal laryngeal and papilloma cells were used to define the signaling pathways that regulate COX-2 expression and investigate the potential of targeting COX-2 as a strategy to suppress papilloma growth. COX-2 levels were markedly increased in papillomas. In vitro studies suggested that overexpression in papillomas reflected activation of EGFR-->phosphatidylinositol 3-kinase signaling. Treatment with prostaglandin E2 (PGE2) induced COX-2, whereas celecoxib, a selective COX-2 inhibitor, suppressed levels of COX-2, suggesting a positive feedback loop. Moreover, treatment with PGE2 stimulated papilloma cell growth, whereas celecoxib suppressed proliferation and induced apoptosis. Overexpression of COX-2 in papillomas seems to be a consequence of enhanced EGFR-->phosphatidylinositol 3-kinase signaling. We propose a positive feedback loop for COX-2 expression, with induction of COX-2 resulting in enhanced PGE2 synthesis and further expression of COX-2 that contributes to the growth of papillomas in vivo. These data strengthen the rationale for evaluating whether nonsteroidal anti-inflammatory drugs, prototypic COX inhibitors, will be useful in the management of respiratory papillomas.

Delivery of Cidofovir to Respiratory Papillomas of the Distal Trachea

Delivery of Cidofovir to Respiratory Papillomas of the Distal Trachea

Extraesophageal acid reflux and recurrent respiratory papilloma in children

Recurrent respiratory papillomatosis (RRP) is a benign infectious disease which is caused by the human papilloma virus (HPV). When it infects the larynx, hoarseness and airway obstruction are often the presenting symptoms. Latent virus is found in the laryngeal mucosa of many more patients than exhibit the disease. The factors which lead to virus activation have not been identified, however, extra-esophageal acid reflux disease (EERD) has been suggested as one of these factors. This is a case series of four patients with RRP who had increase in severity of their disease with the recognition of concurrent extra-esophageal acid reflux. The clinical course of the papillomatosis and the diagnosis and treatment of reflux are compared over time. In all four cases, with identification and treatment of the EERD, control of the RRP improved, and in at least two patients, was complete with resolution of the EERD. Lapses in compliance with medications or behavioral and dietary recommendations in three out of four patients led to a rebound in symptoms and signs of RRP, including worsening of vocal quality and the endoscopic appearance of the larynx. The clinical course of these patients suggests a link between the presence of EERD and RRP. The inflammation induced by chronic acid exposure may result in the expression of HPV in susceptible tissues. Prompt diagnosis and effective treatment of EERD should be considered in all patients with difficult to control RRP or with clinical presentation or endoscopic signs of EERD.

PHOSPHATIDYLINOSITOL 3-KINASE REGULATES EARLY DIFFERENTIATION IN HUMAN LARYNGEAL KERATINOCYTES

Epidermal growth factor receptor (EGFR) signaling regulates a variety of cellular functions, including proliferation, gene expression, and differentiation. Infection of laryngeal epithelial cells by human papillomaviruses causes recurrent respiratory papillomas, benign tumors characterized by an altered pattern of differentiation. Papilloma cells overexpress the EGFR and have constitutively active extracellular signal-regulated kinase (ERK) and enhanced phosphatidylinositol 3-kinase (PI3K) activity, but overexpression of the lipid phosphatase PTEN (Phosphatase and Tensin Homolog) reduces activation of Akt by PI3K. We hypothesized that the altered differentiation of papillomas reflects these changes in signaling from the EGFR-ERK and PI3K-Akt pathways and that one or both of these pathways is required for the normal differentiation process in mucosal epithelium. Inhibiting either the enzymatic activity or the synthesis of PI3K in uninfected laryngeal cells blocked expression of keratin-13 (K13), a protein induced during normal differentiation. In contrast, inhibiting activation of ERK had minimal effect. Using ribonucleic acid interference to reduce protein levels of integrin-linked kinase 1 or phosphoinositide-dependent protein kinase 1, intermediates in the activation of Akt by PI3K, or reducing levels of Akt-1 itself did not inhibit K13 expression by normal laryngeal keratinocytes. We conclude that PI3K activation is an important regulator of expression of K13, a marker for the normal differentiation process in human mucosal keratinocytes, that this function does not require activation of Akt-1, and that the failure to express K13 in papilloma cells is not because of reduction in activated Akt.

Metachronous squamous cell carcinomas evolving from independent oropharyngeal and pulmonary squamous papillomas: Association with human papillomavirus 11 and lack of aberrant p53, Rb, and p16 protein expression

Squamous cell carcinoma evolving from squamous papilloma in both the upper and lower respiratory tract in the same patient is uncommon. The molecular mechanisms underlying the progression have not been well investigated. We herein describe a case of squamous cell carcinoma arising from respiratory papilloma in two independent occasions. The patient initially had oropharyngeal squamous cell carcinoma arising in a squamous papilloma at the age of 25 years. He subsequently developed squamous cell carcinoma in the left lower lobe of the lung, which was also associated with squamous papilloma, 8 years after the complete excision of the oropharyngeal lesion. Polymerase chain reaction-based broad-spectrum human papillomavirus DNA amplification and typing showed the presence of human papillomavirus type 11 DNA in both oropharyngeal and pulmonary tumors. Immunohistochemical studies showed that the expression status of p53, Rb, and p16 proteins was unaltered during tumor progression. These observations indicate that human papillomavirus 11-assocated neoplastic transformation and tumor progression in the respiratory tract may not involve aberrant regulation of the p53 and Rb signaling pathways.

Metachronous squamous cell carcinomas evolving from independent oropharyngeal and pulmonary squamous papillomas: Association with human papillomavirus 11 and lack of aberrant p53, Rb, and p16 protein expression

Squamous cell carcinoma evolving from squamous papilloma in both the upper and lower respiratory tract in the same patient is uncommon. The molecular mechanisms underlying the progression have not been well investigated. We herein describe a case of squamous cell carcinoma arising from respiratory papilloma in two independent occasions. The patient initially had oropharyngeal squamous cell carcinoma arising in a squamous papilloma at the age of 25 years. He subsequently developed squamous cell carcinoma in the left lower lobe of the lung, which was also associated with squamous papilloma, 8 years after the complete excision of the oropharyngeal lesion. Polymerase chain reaction-based broad-spectrum human papillomavirus DNA amplification and typing showed the presence of human papillomavirus type 11 DNA in both oropharyngeal and pulmonary tumors. Immunohistochemical studies showed that the expression status of p53, Rb, and p16 proteins was unaltered during tumor progression. These observations indicate that human papillomavirus 11-assocated neoplastic transformation and tumor progression in the respiratory tract may not involve aberrant regulation of the p53 and Rb signaling pathways.

American Society of Pediatric Otolaryngology members' experience with recurrent respiratory papillomatosis and the use of adjuvant therapy.

To evaluate how evolving treatment technologies have affected our management of recurrent respiratory papilloma (RRP) since the last comprehensive survey of pediatric otolaryngologists in 1998. Web-based survey of all American Society of Pediatric Otolaryngology members residing in the United States, Canada, Europe, and Australia. Evaluable survey results were tabulated from 74 practitioners in 62 separate practices managing 700 current children with RRP. A total of 150 (21%) of these patients presently receive adjuvant medical therapies with cidofovir and interferon, accounting for more than two thirds of the total. Sixty-one percent of patients treated with cidofovir have experienced a beneficial response. Distal spread of RRP has occurred in 94 (13%) of the 700 patients. Half of the practices surveyed have experienced a death from RRP, with 89% of deaths directly related to RRP. The laryngeal microdebrider (53%) has supplanted the carbon dioxide laser (42%) as the preferred means of surgically removing papilloma from the larynx in children. Spontaneous, apneic, and jet ventilation (88%) anesthesia techniques have replaced the use of laser-safe endotracheal tubes (10%) as the preferred anesthetic management. Routine human papillomavirus subtyping is practiced by 45% of respondents while 15% treat all their patients with antireflux medications. Half of respondents send lesions for histologic examination only if there is a change in growth pattern while one third send lesions with every surgery. Recurrent respiratory papilloma continues to be a frustrating disease to treat and is associated with significant morbidity and mortality. There has been an evolution in the past decade toward the increased use of antiviral adjuvant therapy and the use of microdebrider techniques for surgical management.

Clinical course of recurrent respiratory papillomatosis in Danish children.

To evaluate the clinical course of juvenile-onset recurrent respiratory papillomatosis (RP) with respect to age, disease duration, and maternal condylomas. Inception cohort study. All ear, nose, and throat departments in public Danish hospitals. Fifty-seven Danish children diagnosed with RP and born between 1974 and 1993 were observed for an average of 14 years after diagnosis. Removal of respiratory papillomas by knife biopsy, laser surgery, or cryotherapy. Children younger than 5 years diagnosed with RP underwent an average of 4.1 surgeries in the first year of disease, the highest rate among all our patients. The overall surgery rate decreased over time after initial diagnosis but remained significantly higher for children with a younger age of onset for the first 4 years of disease (P <.001) and for children with a maternal history of condylomas in pregnancy for years 4 to 10 of the disease (P <.001). We also observed an independent and statistically significant (P <.001) decreasing surgery rate with increasing age and time from initial diagnosis. The trend for children with recurrent disease was a decreasing rate of surgical procedures (28 of 42 patients with recurrent disease); however, a third of patients (14/42) demonstrated a constant or increasing rate of surgical procedures over time. The clinical course of RP is characterized by a high frequency of surgeries soon after diagnosis that diminishes over time and with increasing age. Additional studies are warranted to identify factors associated with cases that do not conform to the usual disease course.

Is cidofovir a useful adjunctive therapy for recurrent respiratory papillomatosis in children?

Objective: To assess the usefulness of cidofovir in treating recurrent respiratory papillomatosis in children. Cidofovir is an acyclic nucleoside phosphonate that has been reported to be effective in the treatment of respiratory papillomatosis in several small series of patients. Methods: A prospective study was conducted in 11 children (mean, 2.1 years; range, 0.5–3 years at diagnosis) with recurrent respiratory papillomatosis who at the start of the study were requiring debridement of papillomas at least every 6 weeks. After microlaryngoscopy with powered microdebridement of papillomas patients received intralesional injection of cidofovir (5 mg/ml). The severity of papillomatosis was rated at each visit using a standardized papilloma severity scoring system. The success of therapy was measured by the trend in the patient’s papilloma severity scores before and after cidofovir therapy and by whether the frequency of operative interventions decreased in the period after treatment began. Results: Three patients had impressive improvements in severity scores and a decrease in the frequency of required operative interventions after cidofovir, two patients had a partial response, and for six patients cidofovir was considered ineffective. Conclusions: Intralesional cidofovir did not decrease the severity or frequency of operative intervention for recurrent respiratory papillomas in the majority of children in this study. The drug did improve papillomatosis in the minority of patients without causing notable morbidity. A large multi-institutional controlled study is needed to better assess the efficacy of this treatment.

Latent Human Papillomavirus infection is comparable in the larynx and trachea.

Recurrent respiratory papillomas are benign airway tumors caused by Human Papillomaviruses (HPVs) types 6 and 11. The disease is characterized by multiple recurrences of papillomas following surgical removal, caused by activation of latent HPV DNA. Most patients have laryngeal disease, while only a small subset has tracheal involvement. We have asked whether the lower frequency of tracheal papillomas was due to reduced prevalence of latent/subclinical tracheal HPV infection or reduced likelihood of activation to clinically apparent disease. A total of 121 biopsies of clinically normal laryngeal and tracheal tissues from 61 patients with laryngeal papillomas were analyzed for HPV DNA by polymerase chain reaction, confirmed by Southern blot hybridization. Patients were followed for 3-18 years (mean = 5.5 +/- 4.4), with only one developing subsequent tracheal disease. There was no significant difference in prevalence of latent HPV DNA between larynx and trachea, analyzing either those patients with a single biopsy or those with more than one biopsy of larynx, trachea, or both. There was also no significant difference between tracheal latency with HPV 6 and HPV 11. We conclude that HPV infects tracheal mucosa and is maintained as a latent infection in the trachea as efficiently as in the larynx. Therefore, we propose that the low frequency of tracheal disease reflects a lower frequency of HPV activation, and postulate that cellular factors that differ between the stratified squamous epithelium of the larynx and the ciliated pseudo-stratified columnar epithelium of the trachea contribute to this difference.

Laryngopharyngeal reflux and laryngeal web formation in patients with pediatric recurrent respiratory papillomas.

To determine whether treatment of laryngopharyngeal reflux reduces the laryngeal soft tissue complications encountered in surgery for recurrent respiratory papillomas. Retrospective chart review. Retrospective chart review of all pediatric patients treated for laryngeal recurrent respiratory papillomas between 1984 and 1999 was performed. Thirty-one such patients were identified. Twenty-four were at "high risk" for developing complications based on the number of operating suite visits and the presence of disease at the anterior commissure. Twelve patients underwent 24-hour double pH probe testing. Overall, 13 of 31 patients (42%) developed laryngeal webs. No other soft tissue complications were encountered. Of the patients who had pH probe testing, 12 of 12 (100%) had at least one pharyngeal episode of acid exposure. Of the "high-risk" patients, 10 were treated for reflux and only 2 of 10 (20%) developed webs. Eleven of 14 (79%) of the "high-risk" patients who were not treated for reflux developed webs. The difference in rate of web formation between patients treated for reflux and those not treated for reflux was statistically significant (P =.011). Antireflux treatments for patients undergoing surgery for laryngeal recurrent respiratory papillomas may reduce the soft tissue complications, especially scarring and web formation. Prophylactic antireflux therapy may be warranted in any patient undergoing surgery during which laryngeal mucosal disruption is anticipated.

Can mumps vaccine induce remission in recurrent respiratory papilloma?

To describe our experience using laser excision and locally injected mumps vaccine to induce remission in patients with recurrent respiratory papilloma (RRP). Tertiary care regional medical center. Initially, 11 children with RRP treated in a pilot study with laser excision at regular intervals for at least a year without adjuvant therapy; later, a series of 18 children and 20 adults with RRP, some of whom had used various adjuvant therapy with interval laser excision. Both patient groups continued their same interval laser excision with the same or similar laser, same clinical setting, and same surgeon. Locally injected mumps vaccine was then administered into the excision site after each laser removal of papilloma. Larynx and trachea were microphotographed with each treatment. Two consecutive disease-free intervals and a follow-up of at least 1 year were required criteria for remission. In the pilot study, remission was induced in 9 (82%) of 11 patients by 1 to 10 injections, with follow-up of 5 to 19 years. In the subsequent series, remission was induced in 29 (76%) of 38 patients by 4 to 26 injections, and follow-up was 2 to 5 years. Combined with serial laser excision, mumps vaccine positively influences induction of remission in children with RRP. The mechanisms of this effect are unclear, but the treatment is readily available, inexpensive, and has a low risk of adverse effects.

Powered instrumentation in laryngeal surgery

The recent use of powered microdebriders in laryngeal surgery has significantly altered the surgical management of supraglottic lesions. We have successfully used these microresectors to treat more than 40 pediatric patients with respiratory papillomas, vocal cord lesions, or vallecular disease. Before positioning the patient with the Lewy suspension system (Pilling, Fort Washington, PA), direct laryngoscopy and bronchoscopy are often performed. This enables determination of the extent of disease and identification of important landmarks before operative intervention. Once the patient is properly suspended and the larynx is adequately visualized, the operating microscope may be positioned, allowing the lesion to be thoroughly resected under direct visualization. Some advantages this technique offers over the use of CO₂ laser include (1) greater flexibility in selection of anesthesia/ventilation; (2) lower risk of thermal injury to the larynx; and (3) lower intraoperative personnel and equipment expenses.

Carcinoma in children with recurrent respiratory papillomas: an update

Carcinoma in children with recurrent respiratory papillomas: an update

Interaction of human papillomavirus type 11 E7 protein with TAP-1 results in the reduction of ATP-dependent peptide transport.

Human papillomaviruses (HPVs) cause benign and malignant epithelial tumors of the respiratory and genital mucosa. We previously reported that recurrent respiratory papillomas caused by HPV 6/11 express low levels of antibody-detectable TAP-1, the protein that transports peptides into the endoplasmic reticulum for assembly and presentation by MHC Class I, and that the extent of TAP-1 immunostaining is inversely related to the frequency of disease recurrence. We have now determined a mechanism for the reduction in TAP-1 detection. Anti-TAP-1 antibody immunoprecipitated very low amounts of protein from papilloma cells. However, immunoprecipitation of calreticulin, another member of the MHC I assembly complex, coprecipitated TAP-1 at levels comparable to those of uninfected cells. Immunoprecipitation of an HPV-positive cell line with either anti-TAP-1 or anti-calreticulin coprecipitated HPV E7 protein. Finally, purified HPV 11 E7 protein inhibited ATP-dependent peptide transport in vitro. We propose that the interaction of E7 with TAP-1 prevents TAP-1 antibody detection and efficient peptide transport, resulting in poor presentation of viral antigen on HPV-infected cells and thus failure to mount an effective immune-mediated prevention of disease recurrence.

CO(2) laser treatment in 244 patients with respiratory papillomas.

Respiratory papillomas (RP) tend to recur and the difficulty in eradicating the disease makes their treatment frustrating. Meticulous CO(2) laser excisions every 2 months has been the most effective treatment to date. This article analyzes the results of this plan in 244 patients with RP in the nose, nasopharynx, pharynx, hypopharynx, larynx, trachea, lung parenchyma, and skin. Two hundred forty-four patients with recurrent RP were treated by the senior author with CO(2) laser excisions and, in some cases, podophyllum and alpha interferon. Demographics, initial distribution of papillomas, number of operations performed on each patient, and current results were evaluated. Careful laser excisions of RPs every 2 months achieved "remission" of disease (no visible RP on indirect or often direct laryngoscopy 2 mo after last removal) in 37% of patients, "clearance" of the disease process (no RP clinically apparent for 3 y after last removal) in 6%, and "cure" (no clinical recurrence for 5 y after last removal) in 17%. Juvenile-onset RP tends to follow a more aggressive course than adult-onset RP. Four patients (1.6%) developed malignant transformation of their papillomas. Except for ones in lung parenchyma, RP in areas other than the true vocal cords tend to be cleared faster because aggressive removal does not cause hoarseness. Lung parenchyma RPs are eventually fatal because of pulmonary failure from abscesses and cysts resulting from a lack of effective treatment. Frequent and meticulously performed CO(2) laser excisions can achieve significant voice and airway improvement, and some clinical "cures." However, effective antiviral medicines and/or immunologic agents are needed to achieve true cures with elimination of all human papilloma virus 6 and 11 viruses.

Powered instrument papilloma excision: an alternative to laser therapy for recurrent respiratory papilloma.

Powered instrument papilloma excision: an alternative to laser therapy for recurrent respiratory papilloma.