Recurrent respiratory papillomatosis is a rare and potentially life-threatening benign neoplasm caused by human papillomavirus (HPV). RRP is characterized by recurrent proliferation of the papillomata anywhere in the respiratory tract from the nasal vestibules to the terminal bronchi. Predominant sites are where there is a change of epithelium (e.g., from squamous to ciliated) and especially the tonsillar pillars, uvula, vocal folds, and laryngeal commissure. It can occur in both children and adults. The juvenile form is more frequent and more aggressive requiring repeated surgeries [1, 2].
Etiology
Human papillomavirus (HPV) was confirmed as the causative agent in RRP [1]. A study has revealed more than 180 HPV genotypes, with specific affinity for squamous epithelial cells but different tissue preferences, resulting in various clinical presentations [3]. HPV has etiological associations with many benign and malignant tumors of the epidermal tissues. It is associated avidly with malignancies of the cervix and other anogenital tumors, such as carcinoma of the anus, penis, vulva, and vagina, as well as tumors of the head and neck region [4]. The subtypes of HPV are classified as being of high and low risk according to their potential for malignant transformation of epithelial cells [4, 5]. Subtypes 6 and 11 are responsible for more than 90% of RRP cases [3, 6]. Patients infected with type 11 HPV develop more aggressive disease [6] which may lead to significant airway obstruction requiring frequent surgical procedures and adjuvant medical treatment, and sometimes even tracheostomy, to maintain airway patency [6]. Other subtypes, such as 16, 18, 31, and 33, are also associated with RRP, although with a lower prevalence [5, 6]. Subtypes 16 and 18 are considered to be high risk, with the higher potential for malignant transformation, particularly to squamous cell carcinoma, which occurs in less than 1% of juvenile RRP cases [3, 7, 8].
Recurrent respiratory papillomatosis (RRP) appears grossly as sessile or pedunculated pinkish masses with fingerlike projections giving it the feature of irregular exophytic clusters. It is important for the surgeon to be meticulous when approaching the patients endoscopically as any injury to the healthy ciliated epithelium may catalyze its metaplasia to non-ciliated squamous epithelium which will lead to an iatrogenic squamo-ciliary junction which is considered as the favorite site for the offending virus to be implanted which may explain why RRP flourishes in patients with uncontrolled gastroesophageal reflux. Histologically, these fingerlike projections are of nonkeratinized stratified squamous epithelium laid over a vascularized connective tissue stoma. It is likely that the host immune system plays an integral role in the pathogenesis of HPV-induced lesions [9].
Epidemiology
RRP shows a characteristic bimodal distribution, affecting children and young adults. The juvenile form occurs in patients younger than 20 years of age. This form of the disease is generally more aggressive, with multiple papillomatous lesions, and has a high recurrence rate. The adult form develops after 20 years of age, in the third and fourth decades of life, more commonly in males. In this form, the papillomas are often solitary, with a high degree of inflammatory reactivity; they do not usually spread and recur less frequently than those seen in the juvenile form [7]. Malignant transformation has been reported in patients with RRP (less than 1 %), and the mechanism of such transformation is still under debate [10, 11].
Transmission
The exact mode of transmission of the virus remains unclear. There are many researches debating the likelihood of acquiring the infection through transmission of the virus from mothers with genital HPV infection to their babies [12, 13]. Different studies observed a relation between adult-onset RRP and the oral–genital contact. It is also found that patients with AORRP were more likely to have had more sexual partners and oral sex than their controls. But, it is also confirmed that HPV has the capability to cause latent infections in the basal layer of otherwise healthy-appearing mucosa. These dormant foci may be reactivated later after vertical transmission of the virus to vaginally delivered children [14, 15].
The clinical presentation depends on the anatomical location of the papilloma. Common clinical symptoms include hoarseness of voice (voice changes in general), cough, wheezing, shortness of breath, choking, syncope, etc. The hallmark of RRP in juvenile cases is the triad of relentlessly progressive hoarseness of voice, stridor, and respiratory distress. Due to its non-specific clinical manifestations, RRP is easily misdiagnosed as asthma, acute laryngitis, upper respiratory infection, or bronchitis. It is strongly advised to warrant laryngoscopy in cases of children with symptoms of dysphonia and obstructive airway symptoms [10, 11].
Management
Nowadays, there is no available cure for this disease, and treatment is basically focused on maintaining airway patency and voice quality. Patients often require frequent surgeries and occasionally adjuvant therapy (interferon, Cidofovir, bevacizumab, Celecoxib, PD-1 inhibitor) when surgery is unable to control the disease.
Prevention via HPV vaccine is probably the most exciting advancement in RRP management. Three types of vaccines are already in use in many countries.