Recurrent respiratory papillomatosis (ORPHA:60032)
A rare respiratory disease characterized by the development of exophytic papillomas, affecting the mucosa of the upper aero-digestive tract (with a strong predilection for the larynx), caused by an infection with human papilloma virus. Symptoms at presentation vary with the age of patients and the extent of lesions and include dysphonia, chronic cough and recurrent respiratory infections.
Epidemiology
The prevalence of recurrent respiratory papillomatosis (RRP) is estimated at about 1/70,400 in the United Kingdom. Annual incidence of the disease is about 1/23,300 in children and 1/55,500 in adults in the United States. The adult forms affect males more often than females.
Clinical description
A trimodal age distribution is characteristic, with peaks around the ages 7, 35 and 64 years. In sub-Saharan Africa the third peak does not exist. Manifestations depend on the extent and progression of the lesions and in the pediatric population include dysphonia (hoarseness and/ or breathiness), cough, wheezing, chronic dyspnea, rarely choking and syncope. The symptoms tend to be more severe in children because of the rapid growth of the lesions and can lead to potentially life-threatening airway compromise. In the adult population symptoms include dysphonia (hoarseness and/ or breathiness), chronic cough and globus. The clinical course is variable ranging from mild disease with spontaneous remission to an aggressive disease or a chronic clinical course, necessitating dozens of surgical interventions.
Etiology
RRP is caused by infection by human papillomavirus (HPV) types 6 and 11 which are considered to be ''low-risk'', or generally not associated with malignancy. RRP caused by HPV types 16, 18, 31, and 33 are considered to be premalignant lesions, not true RRP. The virus can be transmitted in utero, as a transplacental or ascending infection or during the passage through an infected birth canal. Following infection in humans, HPV is able to promote a specific immune system dysfunction, hence favoring the development of papillomatosis. It is theorized that such behavior is related to specific virus capabilities and a possible genetic predisposition.
Diagnostic methods
Laryngoscopy, followed by histologic examination and HPV genotyping is the most reliable method used to reach a definite diagnosis. Multiple non-necrotic cauliflower-like lesions can be observed on endoscopy. HPV genotyping can be performed by the detection of HPV DNA by polymerase chain reaction with consensus primers and subsequent restriction mapping or hybridization methods.
Differential diagnosis
Differential diagnosis includes asthma and bronchitis in children, and acute laryngitis, upper respiratory tract infection and other benign or malignant laryngeal tumors in all age groups.
Management and treatment
The treatment's goal is to secure airway patency (in children) or preserve the underlying laryngeal tissues (in adults), and thus, maintain an acceptable quality of voice. This is accomplished by surgical intervention with the help of either a microscope or an endoscope in order to debulk or remove the papilloma lesions. Postoperative complications include hampered voice due to scarred vocal folds. A minority of patients requires adjuvant therapy. HPV vaccination appears to be effective in reducing the intersurgical interval. Other adjuvant therapies include intralesional cidofovir and systemic bevacizumab.
Prognosis
The prognosis is often good, although it is a potentially lethal disease. Its morbidity is low in most cases, but dozens of surgical interventions are not uncommon. Malignant degeneration can rarely occur. Patients with pulmonary RRP have an increased risk of malignant transformation.

                            Last update: 
                            January 2023


                            - Expert reviewer(s): 
                            Pr F.G. [Frederik] DIKKERS | ERN CRANIO*


                                * European Reference Network