Recurrent respiratory papillomatosis: an overview of current thinking and treatment

Human papillomaviruses (HPV) infection in benign laryngeal papillomas is well established. The vast majority of recurrent respiratory papillomatosis lesions are due to HPV types 6 and 11. Human papillomaviruses are small non-enveloped viruses (>8 kb), that replicate within the nuclei of infected host cells. Infected host basal cell keratinocytes and papillomas arise from the disordered proliferation of these differentiating keratinocytes. Surgical debulking of papillomas is currently the treatment of choice; newer surgical approaches utilizing microdebriders are replacing laser ablation. Surgery aims to secure an adequate airway and improve and maintain an acceptable quality of voice. Adjuvant treatments currently used include cidofovir, indole-3-carbinol, ribavirin, mumps vaccine, and photodynamic therapy. The recent licensing of prophylactic HPV vaccines is a most interesting development. The low incidence of RRP does pose significant problems in recruitment of sufficient numbers to show statistical significance. Large multi-centre collaborative clinical trials are therefore required. Even so, sufficient clinical follow-up data would take several years.     

Recurrent respiratory papillomatosis associated with gastroesophageal reflux disease in children

The hallmark of gastroesophageal reflux disease (GERD) is an increased exposure of esophageal and laryngeal mucosa to gastric juice. This exposure can cause complications such as chronic laryngitis or chronic respiratory diseases. We report our experience in managing three pediatric patients with severe recurrent juvenile laryngeal papillomatosis (JLP) associated with GERD. All patients showed a high rate of recurrence requiring multiple laser surgeries. Systemic αinterferon therapy over a period of more than 1 year and photodynamic therapy with dihematoporphyrin produced no improvement. However, after therapy for GERD, the rate of recurrence of JLP decreased significantly. Although the course of respiratory papillomatosis is known to fluctuate, our findings suggest that gastroesophageal reflux may have a role in aggravating papillomatosis. Received: 22 September 1998 / Accepted: 12 November 1998     

Aggressive recurrent respiratory papillomatosis in a neonate

Recurrent respiratory papillomatosis is the most common benign laryngeal neoplasm in children. We report an infant with widespread papillomatosis at the time of diagnosis and rapidly progressive disease as a neonate. This child did not have the usual risk factors for recurrent respiratory papillomatosis, being the second child born by cesarean section to a mother without history of condyloma. Repeated surgical debulking has been used to control the disease, along with adjuvant therapies that included systemic therapy with an epidermal growth factor receptor inhibitor and intralesional cidofovir. We report our experience with these therapies.     

Current advances in the basic research and clinical management of juvenile-onset recurrent respiratory papillomatosis

Juvenile-onset recurrent respiratory papillomatosis is a relatively uncommon disease that presents clinically with symptoms ranging from hoarseness to severe dyspnea. Human papilloma viruses type 6 and 11 are important in the etiology of the papillomata and are most probably transmitted from mother to child during childbirth. Although spontaneous remission is frequent, a rare fatal course because of pulmonary spread or malignant transformation has occurred. CO₂ laser evaporation of papillomas and adjuvant drug therapy using lymphoblastoid α-interferon are the most common treatment modalities at present. However, several other treatment modalities have been tried with varying success. Recent advances in basic research and different therapeutic approaches are reviewed. Received: 13 October 1999 / Accepted: 3 December 1999     

Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis

Abstract

Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).

Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.

Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).

Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.

Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.     

Efficacy of microsurgery in combined with topical-PDT in treating recurrent respiratory papillomatosis: compare JORRP with AORRP

Abstract

Background: Recurrent respiratory papillomatosis (RRP) remains a challenging and frustrating disease to treat.

Objective: To explore the efficacy of microsurgery in combined with Topical-PDT in treating recurrent respiratory papillomatosis.

Materials and methods: Fifty patients with RRP were treated with microsurgery in combined with Topical-PDT. Medical document of each patient was retrospectively reviewed. Detailed clinical information, metrics of clinical course, and current results were evaluated.

Results: Juvenile onset RRP (JORRP) might experience a more aggressive course than AORRP (adult onset RRP) with higher Derkay score (p?<?.01) and higher operation frequency per year (p?<?.01). Microsurgical excision combined with Topical-PDT every 25?days achieved “remission” of disease in 78% of patients, “clearance” of disease in 52%, and “Cured” in two patients. Each patient who achieved “remission” of disease, performed 6.82?±?3.39 operations, and continued 8.93?±?7.03?months of treatment duration. No statistically differences were found in these two aspects between JORRP and AORRP. A negative correlation between tracheotomy and the efficacy of microsurgery in combined with Topical-PDT was found (p?=?.025, Pearson’s r = –0.3).

Conclusions and significance: Microsurgery in combined with Topical-PDT might be a powerful method to treat RRP. Tracheotomy is a negative factor for this therapy.     

Intersurgical interval increased with use of quadrivalent human papillomavirus vaccine (Gardasil) in a pediatric patient with recurrent respiratory papillomatosis: A case report

This is a case of a 4 year old female with recalcitrant recurrent respiratory papillomatosis with decreasing intersurgical interval that had improvement in clinical course after administration of the quadrivalent HPV vaccine.     

The predictive value of serum interleukins in recurrent respiratory papillomatosis: a preliminary study

OBJECTIVE: IL-2 is the primary interleukin responsible for activation of the cell-mediated (Th1) arm of the immune response. Our objective was to determine whether a correlation existed between circulating levels of interleukin-2 as well as its soluble receptor (sIL-2R) and the clinical course of recurrent respiratory papillomatosis. METHODS AND MATERIALS: Fifteen children with a histological diagnosis of RRP were recruited. Age at the time of study, time since first diagnosis, and number of surgical interventions were recorded. The number of surgically treated recurrences per year was then calculated. We obtained serum samples from each of these 15 children and from 10 normal control subjects. We then performed in vitro determination of serum IL-2 and soluble IL-2 receptor levels using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: IL-2 was significantly lower (136.6 vs. 199.9 pg/mL, P =.035) in papilloma patients than in control subjects. IL-2R was also lower in papilloma patients (531.7 vs. 785.8 U/mL, P =.025). There was no statistical age difference between the papilloma and control groups. Among patients with papillomatosis, IL-2 and sIL-2R levels were significantly higher in those with aggressive disease (>4 surgically treated recurrences per year) versus non-aggressive disease (179.2 vs. 99.2 pg/mL, P =.024; and 697 vs. 387 U/mL, P =.022). Age was also significantly lower in the aggressive papilloma group (P =.002). CONCLUSIONS: Levels of interleukin-2 and IL-2 receptor were significantly lower in patients with recurrent respiratory papillomatosis compared with normal children. These data support the presence of an aberrant cell-mediated immune response in children with recurrent respiratory papillomatosis.     

Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: A systematic review

Objectives

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few develop JoRRP and the clinical course of the disease varies from one child to another. This systematic review seeks to provide an up-to-date understanding of the risk factors for acquisition and severity.

Methods

We conducted a comprehensive literature search in EMBASE, MEDLINE and EBMR databases using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also searched Google Scholar and the reference lists of eligible studies. Our search was limited to original studies published in French or English between 1995 and July 2012 and to patients under 20 years of age.

Results

Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32 studies meeting inclusion criteria. All were observational and together included 2296 JoRRP cases. Risk factors could be classified mainly as maternal and birth history, viral genotype, and host factors. A history of genital warts during pregnancy and delivery was strongly linked to the development of JoRRP. Depending on ethnicity, specific human leukocyte antigen class II alleles and immune response factors were important determinants of JoRRP acquisition and severity. HPV-11 genotype and younger age at onset of JoRRP were important predictors of severity.

Conclusions

Genetic and immunological profiles underlying the acquisition and clinical course are not readily modifiable. Thus, preventing condylomas in women of childbearing age could reduce the burden of this life-threatening disease.     

Protein expression of the tumor suppressors p16INK4A and p53 and disease progression in recurrent respiratory papillomatosis

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a benign condition that rarely metastasizes as invasive squamous cell carcinoma. Although this disease is associated with human papillomavirus, the role of this virus in tumorigenesis is unclear. OBJECTIVES: The aim of this study is to assess the involvement of the tumor suppressors P16INK4A and p53 in RRP tumor progression. DESIGN: Immunohistochemistry of p16INK4A and p53 was performed on biopsies of recurrent squamous papillomas and invasive lesions in nine patients. RESULTS: Twenty biopsies were graded as papillomas (RP), three as papillomas with high-grade dysplasia/carcinoma in situ (HGD/CIS), and two as invasive squamous cell carcinoma (SCCA). Forty-five percent of RP and 60% of HGD/CIS/SCCA expressed p16INK4A. Fifty percent of RP and 100% of HGD/CIS/SCCA expressed p53. The difference in the frequency of p53-positive staining between HGD/CIS and SCCA (100% of tissues examined) and RP (50% of tissues examined) approached statistical significance. Neither p16INK4A nor p53 was predictive of invasive transformation. CONCLUSIONS: Expression of p16INK4A, which is a surrogate for the tumor suppressor retinoblastoma (Rb), did not immediately lead to invasive disease. There is no correlation between disease severity of RRP and level of p16INK4A.     

新疆部分地区儿童复发性喉乳头状瘤HPV6和HPV11病毒感染在维吾尔族及汉族患者之间的差异

目的：研究新疆部分地区喉乳头状瘤病毒HPV6,HPV11在汉族及维吾尔族儿童复发性喉乳头状瘤（JRRP）患儿中的表达差异。方法：采用聚合酶链反应（PCR）技术对喉乳头状瘤组织中HPV11和HPV6 DNA进行定型分析,结合回顾性分析1996—01—2008—03期间在新疆医科大学第一附属医院耳鼻咽喉科连续收治的42例JRRP患者。结果：HPV6／11阳性检出率97．61％（41／42）,HPV6阳性36．58％（41／15）,HPV11阳性63．41％（41／26）,HPV6阳性组中维族HPV6阳性53．33％（8／15）,汉族HPV6阳性46．67％（7／15）,HPV11阳性组中维族HPVll阳性65．38％（17／26）,汉族HPV11阳性34．61％（9／26）。结论：新疆部分地区JRRP以HPV11,6感染为主,HPV11感染者占多数,HPV病毒类型与维汉间的发病率之间差异无统计学意义。     

Prevalence and clinical implications of low-risk human papillomavirus among patients with recurrent respiratory papillomatosis in Rio de Janeiro,Brazil

ObjectiveThe aim of this study was to investigate the presence of human papillomavirus (HPV) in biopsy specimens from juvenile and adult patients with histopathological diagnosis of recurrent respiratory papillomatosis (RRP) treated in two public hospitals in Rio de Janeiro, Brazil.MethodsWe performed the detection and genotyping of HPV by PCR technique for the types 6, 11, 16, and 18 in biopsy specimens from 41 RRP patients.ResultsThe juvenile onset RRP (JoRRP) corresponded to 61% and the adult onset RRP (AoRRP) corresponded to 39% of the study group. Prevalence of males was observed in both the adult (81.3%) and the juvenile (56%) groups. Lesions in the larynx were more frequent in the glottis (46%). Genotyping analysis only revealed patients with HPV-6 (34.1%), HPV-11(17.1%), and co-infection HPV-6 and -11 (48.8%). RRP severity was significantly associated with the JoRRP (p < 0.001), with extralaryngeal disease and more surgeries. However, no significant association between RRP severity and HPV types was found. One co-infected patient in the JoRRP died due to the evolution of the disease with lung involvement.ConclusionThese results show the strong association of HPV-6 and/or HPV-11 types with RRP and could complement the diagnosis, prognosis, and therapies for these patients. In addition, the HPV vaccination should be encouraged to prevent the disease.