Recurrent respiratory papillomatosis can present with a highly variable clinical course. The disease can cause serious morbidity and can be fatal because of airway obstruction. We examined whether the age of onset, gender, human immunodeficiency virus (HIV) infection and dysplasia on analysis of histological specimens were predictive of an aggressive disease course.
To conduct an audit of all patients presenting with Recurrent Respiratory Papillomatosis at our institution and to determine if an earlier age of onset, gender, HIV and dysplasia are predictive factors for an aggressive disease course.
A total of 202 clinical records and histological reports were reviewed at a quaternary-level hospital in Durban, South Africa. The disease was defined as juvenile onset (< 18 years) or adult onset (≥ 18 years). Aggressive disease was defined as a disease requiring 10 or more surgical debulkings in total and or extralaryngeal papilloma.
A total of 184 patients were of juvenile onset and 18 were of adult onset. In the juvenile onset group, a total of 97 patients (52.8%) had aggressive disease. In the juvenile onset group, a later age of onset was associated with less aggressive disease (odds ratio [OR] = 0.77,
An earlier age of onset, HIV infection and dysplasia were predictors of aggressive disease in the juvenile onset group.
Recurrent respiratory papillomatosis (RRP) remains a poorly understood disease that can be difficult to manage. Both juvenile onset RRP (JORRP) and adult onset RRP (AORRP) forms exist. The clinical course is highly variable with a spectrum from indolent to aggressive disease. It is the most common benign neoplasm affecting the larynx of children. Despite its benign nature, it can have potentially fatal consequences because of airway compromise. It is a chronic condition caused by the human papillomavirus (HPV).
Early diagnosis, early surgical intervention and close follow-up are essential in managing the condition. Recurrent respiratory papillomatosis can have devastating consequences as it can be associated with significant morbidity with the potential for mortality as a result of airway obstruction. The disease imposes a significant burden on the patient, their family and community and adversely affects the patient’s quality of life. In this retrospective chart review, we examine whether an earlier age of onset, gender, human immunodeficiency virus (HIV) infection and dysplasia on analysis of histological specimens were predictive of an aggressive course of RRP. An earlier age of onset, gender and HIV infection are considered to be causative factors, while dysplasia is consistent as a marker of aggressive disease. These predictive factors are readily available to the clinician practicing in the developing world.
Three clinical patterns of RRP have been identified: JORRP, juvenile RRP persistent into adulthood and AORRP.
The overall incidence of RRP has been determined in developed countries, and ranges from 0.6 per 100 000 to 2.13 per 100 000. The incidence in the United States is estimated at 4.3 per 100 000 children and 1.8 per 100 000 adults. The incidence in Denmark is estimated to be between 3.62 per 100 000 children and 3.94 per 100 000 adults.
The papillomaviruses are members of the papillomaviridae family. Over 150 HPV subtypes have been identified.
An association between HPV infection of the mother’s genital tract and RRP is well established. Human papillomavirus has been estimated to be present in 25% of all women of child bearing age worldwide. Human papillomavirus 6 and HPV 11 are the most commonly identified in cervical condyloma.
Maternal condylomatas are seen in more than 50% of mothers who give birth to children with RRP. Caesarean delivery of children seems to be preventative. Patients with childhood onset of RRP are more likely to be first-born and vaginally delivered in comparison to control patients of a similar age. Primigravid mothers are more likely to have a prolonged second stage of labour and the prolonged exposure leads to a higher risk of infection in the first-born child.
While the presence of HPV is necessary for the development of RRP in observed cases, there does also appear to be a component of host susceptibility in whether or not an individual develops RRP, with the epidermodysplasia verruciformis 1(EVER1) as a postulated gene.
The risk factors for AORRP are different from that of JORRP as the mode of transmission in these two disorders is different. Adult onset RRP is associated with an increased number of lifetime sexual partners and an increased frequency of oral sex.
Respiratory papillomas predominantly affect the larynx. Other sites include the oral cavity, oropharynx, nasal cavities, nasopharynx, oesophagus, trachea and pulmonary spread. The average time between onset of symptoms and diagnosis is 1 year as reported in most paediatric series.
The clinical presentation and course of the disease is highly variable and unpredictable. The mean age of diagnosis is between the age of 3.6–6 years in the paediatric population and 20–30 years in the adult population. The mean age of diagnosis is thought to be higher in developing countries because of later presentation as a result of poorer access to health care.
There is no curative treatment. Management is with repeated microlaryngoscopic examinations with surgical removal of the papillomata until the disease goes into remission. The goal of surgical debulking is to excise the papillomatous lesions and create an adequate airway while maintaining the integrity of the underlying laryngeal tissue, especially the vocal cords. Methods for removal include cold steel technique using cupped forceps, laser excision (CO2 laser, KTP laser, 585 nm flash dye or argon laser), microdebrider and coblation.
A tracheostomy is required when there is airway obstruction because of extensive papillomata, glottic and/or supraglottic stenosis because of repeated surgical debulkings with resultant scarring and fibrosis of the underlying laryngeal tissue. The need for tracheostomy is higher in developing countries and in the paediatric population as a result of poorer access to health care.
Adjuvant treatment is indicated in patients who require four or more surgical debulkings per annum, rapid recurrences of papilloma with short disease-free intervals and or distal spread of papilloma beyond the subglottis.
Human papillomavirus vaccines are designed to elicit an immune response against HPV gene products. Human papillomavirus-like particles (HPV virus-like particles [VLP]) can be generated by the synthesis and self-assembly
The vaccination schedule was revised in 2015, and the World Health Organization recommends administering routine vaccination with one of the three versions of the vaccine to women aged 11–12 or up to age 26 if not previously vaccinated and to men aged 13–26 if not previously vaccinated.
Dysplasia occurs in 20% of patients. Laryngeal dysplasia is a premalignant condition, with a wide variability of malignant transformation reported in the literature. Malignant transformation occurs in rare cases and is mostly associated with HPV 11. The overall malignant transformation rate is 14% and the mean time to malignant transformation is 5.8 years. The malignant transformation rate is higher with increased dysplasia grade. Severe dysplasia shows a 30% transformation rate and mild or moderate grade shows 11%. Treatment modality does not show significant effects.
The identification of prognostic factors can assist in identifying patients who are at risk of developing a more aggressive clinical course. Identification of patients who are at risk allows for close surveillance, early intervention and prevention of serious morbidity and mortality. Aggressive disease may be defined as extralaryngeal spread and/or >10 debulkings in total.
An earlier age of onset, juvenile onset versus adult onset and genotype are all postulated as factors associated with an aggressive disease course. Several studies have found HPV 11 to be associated with more aggressive disease, whereas other studies have found no correlation between genotype and disease severity.
The aim of this study is to describe the clinical course of RRP in paediatric and adult patients presenting to a quaternary-level hospital in the KwaZulu-Natal (KZN) province of South Africa and to determine whether the age of onset, HIV infection, gender and dysplasia on histological specimens are prognostic factors for developing an aggressive clinical course and complications. The above prognostic factors are readily accessible to the clinicians practising in the developing world.
The study was carried out at Inkosi Albert Luthuli Central Hospital (IALCH) in the KZN province of South Africa. Inclusion criteria comprised all patients presenting to IALCH with histology confirmed RRP. The study period was from January 2005 to December 2014. Patients were identified through the hospital’s electronic medical records database (Meditec and Sorian Information Systems). The data that were extracted included the age of onset, gender, HIV infection, method of surgical debulking, tracheostomy, status at the end of the study period (active or remission or lost to follow-up or demised) and extralaryngeal papilloma. Aggressive disease was defined as the patients requiring a total of 10 or more surgical debulkings and/or extralaryngeal papilloma.
The data were then analysed to determine whether each of the following variables – age of onset, gender, HIV infection and or dysplasia – was associated with an aggressive disease course.
Research data were primarily analysed within a quantitative framework using univariate and multivariate analyses. Data were analysed using Statistical Packages for the Social Sciences (SPSS) version 25. A
A total of 202 clinical records and histological reports were reviewed, of which 184 patients were of juvenile onset and 18 were of adult onset (
Comparison between juvenile onset and adult onset groups.
Variable | Number of patients | Aggressive disease |
Mean age of onset (years) | Gender |
HIV-positive |
Dysplasia and dysplasia category |
||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
% | Men |
Woman |
% | Total |
Mild |
Moderate |
Severe |
|||||||||||
% | % | % | % | % | % | |||||||||||||
JORRP | 184 | 97 | 52.8 | 7.65 | 113 | 61.4 | 71 | 38.6 | 20 | 10.9 | 39 | 21.2 | 11 | 6 | 23 | 12.5 | 5 | 2.7 |
AORRP | 18 | 2 | 11.1 | 30.6 | 7 | 38.9 | 11 | 61.1 | 8 | 44.4 | 2 | 11.1 | - | - | Dysplasia | - | - | - |
JORRP, juvenile onset recurrent respiratory papillomatosis; AORRP, adult onset recurrent respiratory papillomatosis; HIV, human immunodeficiency virus.
In the juvenile onset group, a total of 97 (52.8%) had aggressive disease. Sixty patients (32.6%) had extralaryngeal papilloma. Eighty-eight (43.6%) had less than 10 surgical debulkings. At the end of the study period, 73 (39.7%) patients were active, 97 (52.7%) had gone into remission, 13 (7.1%) were lost to follow-up and one (0.5%) had demised. In the adult onset group, only two patients (11.1%) had aggressive disease. Sixteen (88.9%) had gone into remission, and two (11.1%) patients were active at the end of the study period. No adult patients had demised during the study period (
The mean number of surgical debulkings was 11.79 (standard deviation [s.d.] 14.20). The mean number of surgical debulkings in the juvenile onset group was 12.6 (s.d. 14.60). The mean number of surgical debulkings in the adult onset group was 3.4 (s.d. 3.4). The mean age of onset was 5.2 (s.d. 3.7) years in the juvenile onset group and 33 (s.d. 12) years in the adult onset group. In the juvenile onset group, a later age of onset was associated with less aggressive disease (odds ratio [OR] = 0.77,
In the juvenile onset group, there were 113 (61.4%) men and 71 (38.6%) women. Gender was not a predictor of aggressive disease (OR = 0.76,
Gender, human immunodeficiency virus, dysplasia and age of onset as predictors of aggressive disease in the juvenile onset group.
Variable | Predictor of aggressive disease | Odds ratio | 95% Confidence interval | |
---|---|---|---|---|
Gender | No | 0.76 | 0.41–1.4 | 0.449 |
HIV | Yes | 3.0 | 1.1–7.8 | 0.029 |
Dysplasia | Yes | 7.0 | 2.817 | < 0.05 |
Age of onset | Yes | 0.77 | 0.69–0.86 | < 0.05 |
HIV, human immunodeficiency virus.
In the juvenile onset group, there were 20 (10.9%) HIV-positive patients and 164 (89.1%) HIV-negative patients, and HIV infection was a significant predictor of aggressive disease (OR = 3.0,
Analysis of histological reports revealed that 39 (21.2%) of patients in the juvenile onset group had dysplasia. Eleven (6%) had mild dysplasia, 23 (12.5%) had moderate dysplasia and five (2.7%) had severe dysplasia (
Dysplasia categorisation in the juvenile onset group.
To our knowledge, this is the first study in the KZN province of South Africa to determine the risk factors associated with an aggressive disease course of RRP. The cohort size of 202 cases over a 10-year period suggests an impressive burden of disease in the province and is one of the largest reported in the literature. By comparison, the entire US National Registry for JORRP contained only 603 patients as of 2003 and the Canadian national database identified 243 cases of JORRP nationally. The disease predominantly affects the larynx, and as a result, patients are at risk of developing serious morbidity because of airway obstruction. Identification of risk factors for aggressive disease is important to determine the frequency of follow-up visits and early surgical intervention to prevent serious complications.
We defined aggressive disease as disease requiring 10 or more surgical debulkings and or extralaryngeal spread of papilloma.
A smaller glottic diameter in younger patients can result in the need for more frequent debulkings, qualifying for a diagnosis of aggressive disease. Other studies have speculated that the developing immune system may permit older children to have slower papilloma growth. Patients who present at an earlier age of onset are at greater risk of developing aggressive disease and need to be closely monitored with regular follow-up visits and early surgical intervention.
Analysis of histological reports found that dysplasia occurred in 21.2% of patients in the paediatric cohort, which is in keeping with international literature. Dysplasia on histological analysis was a predictor of aggressive disease in the paediatric cohort. Furthermore, given the risk of malignant transformation, patients with dysplasia need to be followed up for a period of at least 5 years after going into remission. Even after discharge, patients should be carefully counselled on early warning signs of malignancy.
In the juvenile onset group, there were 20 (10.9%) HIV-positive patients. The cluster of differentiation 4 (CD4) count varied from 224 to 1215. A depressed immune system is a known risk factor for developing RRP. HIV infection proved to be a marginally significant predictor for aggressive disease in our paediatric cohort of patients. Hence, patients who are HIV-positive require close surveillance and early surgical debulking.
In the juvenile onset group, there were 113 (61.4%) men and 71(38.6%) women. Gender was not a predictor of aggressive disease in our cohort of patients, which is in line with international literature. Most studies have found an equal gender distribution.
Our adult onset group was very small, with only 18 patients. Only two (11.1%) had aggressive disease. The age of onset, gender, HIV infection or dysplasia were not predictors of aggressive disease in the adult onset group, but this was probably limited because of the small sample size.
A limitation of this study is that we did not have access to HPV genotyping because of cost factors. However, some studies have shown no relationship between HPV types and disease aggressiveness.
None of the patients in our cohort were vaccinated at the time of the study. Although HPV vaccination programmes have been rolled out in certain public schools, large sectors of the population remain unvaccinated worldwide. In a resource-limited, developing world setting, it is useful to identify clinical and histological parameters that predict aggressive disease and prevent fatal consequences.
Recurrent respiratory papillomatosis presents with a highly variable clinical course in both juvenile and adult patients, with a spectrum from indolent to aggressive disease. All patients need to be monitored with regular follow-up visits and early surgical debulking when indicated. Patients with aggressive disease require close surveillance in order to prevent the devastating consequences of airway obstruction. Laryngeal dysplasia is a premalignant condition, with a wide variability of malignant transformation reported in the literature; however, to our knowledge, the association between dysplasia and severe respiratory papilomatosis is poorly documented. In our paediatric cohort of patients, an earlier age of onset, dysplasia on histological analysis and HIV infection were all predictive factors of aggressive disease.
The authors would like to thank Prof. J. Van Wyk for the support provided.
The authors have declared that no competing interest exist.
M.K. was the project leader, made a substantial contribution to conception and design of the study, acquisition and analysis of data and drafting of the manuscript.
T.K. made a substantial contribution to conception and design of the study, analysis of the data, drafting of the manuscript and final approval.
The study proposal was reviewed and full ethics approval was granted by the Biomedical Research Ethics Committee (BREC) at the University of KwaZulu-Natal (UKZN) (Reference number BE672/17). Approval was also granted by the Provincial Health Research Committee (PHRC) and the medical manager at Inkosi Albert Luthuli Central Hospital (IALCH).
No sources of funding were received to conduct the study.
Data sharing is not applicable to this article.
The views expressed in this article are the authors’ own views and not that of the authors’ affiliated institutions.