Risk Factors for Aggressive Recurrent Respiratory Papillomatosis in Adults and Juveniles

In this cohort study we examined whether gender, age at onset, observation time or human papillomavirus (HPV) genotype are risk factors for an aggressive clinical course in Recurrent Respiratory Papillomatosis (RRP). Clinical data from patient records comprised gender, age at onset, date of first endolaryngeal procedure with biopsy, date of last follow-up, total number of endolaryngeal procedures, and complications during the observation period. Disease was defined as juvenile (JoRRP) or adult onset (AoRRP) according to whether the disease was acquired before or after the age of 18. Aggressive disease was defined as distal spread, tracheostomy, four surgical operations annually or >10 surgeries in total. DNA was extracted from formalin-fixed paraffin-embedded tissue. HPV genotyping was performed by quantitative PCR assay identifying 15 HPV genotypes. The study included 224 patients. The majority were males (141/174 in AoRRPs and 31/50 in JoRRPs; p = 0.005). The median follow-up from initial diagnosis was 12.0 years (IQR 3.7–32.9) for JoRRPs and 4.0 years (IQR 0.8–11.7) for AoRRPs. The disease was more aggressive in juveniles than adults (p<0.001), a difference that disappeared after 10 years' observation. JoRRPs with aggressive disease were younger at onset (mean difference 4.6 years, 95%CI [2.4, 6.8], p = 0.009). HPV6 or −11 was present in all HPV-positive papillomas. HPV11 was more prevalent in aggressive disease, and HPV6 in non-aggressive disease (p<0.001). Multiple logistic regression revealed that only age at onset (OR = 0.69, 95% CI [0.53, 0.88], p = 0.003) was associated with aggressive disease in juveniles, while HPV11 (OR = 3.74, 95% CI [1.40, 9.97], p = 0.008) and observation time >10 years (OR = 13.41, 95% CI [5.46, 32.99[, p<001) were risk factors in adults. In conclusion, the only significant risk factor for developing aggressive disease in JoRRPs was age at onset, but both HPV11 and observation time >10 years were risk factors for an aggressive disease course in AoRRPs.

Related papers:

title: Identification of HPV DNA in patients with juvenile-onset recurrent respiratory papillomatosis using SYBR Green real-time PCR.
abstract: Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm affecting the larynx and upper respiratory tract in children. Human papillomavirus (HPV) has been implicated as the cause of RRP, most commonly types 6 and 11. The present study was undertaken to evaluate the occurrence of HPV types in a group of patients with juvenile-onset RRP (JORRP).



The study group consists of 23 patients with JORRP. The clinical records of the patients were reviewed, and JORRP was classified as non-aggressive or aggressive. The laryngeal biopsies were taken and investigated for HPV DNA presence using real-time polymerase chain reaction (PCR) with a set of consensus primers (MY09/11). Viral typing was subsequently performed by real-time PCR with type-specific primers for HPV types 6, 11, 16, 18, 31, and 33.



HPV presence was detected in all samples with amplifiable DNA. HPV-11 was revealed in 61.9% of the patients and HPV-6 in 23.8%. Double positivity for HPV types 6 and 11 was identified in 14.3%. Our findings suggest that RRP runs a more aggressive clinical course when HPV-11 infection is present (p=0.0265).



Our results suggest a high frequency of HPV infection in the upper respiratory tract of the studied patients. We believe that the routine application of molecular techniques such as PCR for detection and analysis of HPVs in patients with RRP has diagnostic and prognostic significance.

title: Molecular identification of 7 human papillomavirus types in recurrent respiratory papillomatosis.
abstract: Recurrent respiratory papillomatosis (RRP) is the most frequent benign neoplasm in childhood; it originates as a mild dysphonia and results in asphyxia. The RRP has been associated with an infection caused by human papillomavirus (HPV), mainly types 6 and 11, the latter being associated with more severe RRP.



To analyze the frequency of the association of RRP with the HPV types in our juvenile population and to classify it according to severity.



Observational descriptive trial.



Forty-seven samples of paraffin-embedded papillomas, from 26 female and 21 male children (age range, 2 weeks to 17 years) were analyzed. DNA was isolated and a 188-base pair fragment was amplified from a consensus sequence in the E1 open reading frame of several HPVs by polymerase chain reaction. The corresponding band was recovered and reamplified. The fragment was digested with the restriction enzyme RsaI. The digestion products were compared with patterns of molecular weight markers for viral type identification. The patients' clinical records were reviewed, and RRP was classified as mild or aggressive.



The presence of HPV types 6, 11, 16, 31, 33, 35, or 39 was confirmed in all the cases with different combinations. The chi(2) test showed no significant differences in clinical aggressiveness among the viral types. A logistic regression analysis demonstrated no association between clinical aggressiveness and any viral type or viral combination.



These results show that RRP is caused by infection with HPV types 6 and 11 in addition to many other types, with no relationship between HPV type and clinical severity.

title: Human papillomavirus genotype detection in recurrent respiratory papillomatosis (RRP) in Colombia
abstract: Knowledge on human papillomavirus (HPV) genotype distribution in recurrent respiratory papillomatosis (RRP) is essential to assess the impact of HPV vaccine. It is provided information for Colombia.

title: The role of HPV type in Recurrent Respiratory Papillomatosis.
abstract: Human Papillomavirus (HPV) 6 and 11 are the aetiological agents responsible for Recurrent Respiratory Papillomatosis (RRP). There is general consensus that HPV11 results in more aggressive disease compared to HPV6.



Pubmed was searched using the terms respiratory papillomatosis, HPV 6 and HPV11. Comparisons were made in the outcomes of HPV6 versus HPV11 positive RRP disease.



There are numerous sub-types or variants of both HPV6 and HPV11. These sub-types have different activities at least in-vitro. The numbers of different HPV types within RRP tissue may be more extensive than initially appeared. This depends specifically upon the HPV types tested for.



The clinical differences between HPV6 and HPV11 disease may not be accurately predictable as these viruses exist in numerous sub-types. Also, RRP tissue may contain more than one subtype or even be co-infected with other viruses that may influence outcome. In-vitro studies upon cell lines are a reasonable starting point for evaluation of these differences.

title: Recurrent Respiratory Papillomatosis: HPV Genotypes and Risk of High-Grade Laryngeal Neoplasia
abstract: Patients with recurrent respiratory papillomatosis (RRP) in Norway treated between 1987 and 2009 were recruited to this cohort study. They were followed from disease onset and data recorded until January 2012. Here, we describe the distribution of human papillomavirus (HPV) genotypes, the prevalence of multiple HPV infections, and the risk of high-grade laryngeal neoplasia and respiratory tract invasive carcinoma in a large cohort of patients with RRP. We also examined whether HPV genotype, gender, age or clinical course are risk factors for this development. Clinical records and histological specimens were reviewed. Using formalin-fixed paraffin-embedded biopsies, HPV genotyping were performed by quantitative polymerase chain reaction assays identifying 15 HPV types. HPV-negative specimens were analyzed by metagenomic sequencing. Paraffin blocks were available in 224/238 patients. The DNA quality was approved in 221/224 cases. HPV DNA was detected in 207/221 patients and all were HPV 6 or HPV 11 positive, comprising HPV 6 in 133/207, HPV 11 in 40/207 cases and HPV 6/11 in 15/207 cases. Co-infection with one or two high-risk HPV types together with HPV 6 or HPV 11 was present in 19/207 patients. Metagenomic sequencing of 14 HPV-negative specimens revealed HPV 8 in one case. In total, 39/221 patients developed high-grade laryngeal neoplasia. 8/221 patients developed carcinoma of the respiratory tract (six patients with laryngeal carcinoma and two patients with lung carcinoma). High-grade laryngeal neoplasias were found more frequently in HPV-negative versus HPV-positive patients, (RR = 2.35, 95% CI 1.1, 4.99), as well as respiratory tract carcinomas (RR = 48, 95% CI 10.72, 214.91). In summary, the majority of RRP were associated with HPV 6 and/or 11. HPV-negative RRP biopsies occurred more frequently in adult-onset patients, and were associated with an increased risk of laryngeal neoplasia and carcinoma in the respiratory tract.

title: Incidence and prevalence of recurrent respiratory papillomatosis among children in Atlanta and Seattle.
abstract: The incidence and prevalence of recurrent respiratory papillomatosis (RRP) for children aged <18 years were estimated in 2 US cities, Atlanta and Seattle, in 1996. All otolaryngologists in a 24-county area in metropolitan Atlanta (101 physicians) and an 8-county area in metropolitan Seattle (139 physicians) agreed to participate in the study. Medical record chart abstraction was performed only for children with documented current residence in the study area (21 patients in Atlanta and 14 patients in Seattle). The incidence rate for juvenile RRP was 1.11/100,000 population in Atlanta and 0.36/100, 000 in Seattle. The prevalence rate was 2.59/100,000 population in Atlanta and 1.69/100,000 in Seattle. In neither city did prevalences differ significantly when stratified by sex or race. Extrapolation of these estimates to the US population suggests that 80-1500 incident cases and 700-3000 prevalent cases of juvenile RRP will occur in the United States during 1999.

title: Epidemiological aspects of recurrent respiratory papillomatosis: A population‐based study
abstract: The incidence of genital infections, cervical cancer, and oropharyngeal cancer induced by human papillomaviruses (HPV) is increasing in Western countries. Primarily, this study was conducted to estimate the incidence rate of recurrent respiratory papillomatosis (RRP) in juveniles and adults in two Norwegian subpopulations for each year between 1987 and 2009. The secondary objective of the study was to investigate whether there are trends in the incidence rates of RRP in the study period similar to what we have seen for HPV‐related cancer.

title: Sites of Predilection in Recurrent Respiratory Papillomatosis
abstract: Florid and widespread respiratory papillomatosis is a devastating disorder occurring in a subset of patients with recurrent respiratory papillomatosis, and it poses a major dilemma for the patient and the surgeon. Contrary to common belief, the distribution of papilloma lesions is not random, but follows a predictable pattern, with lesions occurring at anatomic sites in which ciliated and squamous epithelia are juxtaposed. The predominant sites of disease in recurrent respiratory papillomatosis are the limen vestibuli, the nasopharyngeal surface of the soft palate, the midzone of the laryngeal surface of the epiglottis, the upper and lower margins of the ventricle, the undersurface of the vocal folds, the carina, and bronchial spurs. These sites have the common histologic feature of a squamociliary junction. Papillomata also occur at the tracheostomy tract and at the midthoracic trachea in patients with tracheostomies. At the latter sites, abrasion injury to ciliated epithelium heals with metaplastic squamous epithelium and creates an iatrogenic squamociliary junction. The apparent preferential localization of papilloma at squamociliary junctions has at least 2 implications: first, that detection of occult asymptomatic papillomata is enhanced by careful examination of squamociliary junctions, and, second, that iatrogenic papilloma “implantation” is preventable by avoiding injury to nondiseased squamous and ciliated epithelia.

title: Recurrent Respiratory Papillomatosis: A Longitudinal Study Comparing Severity Associated With Human Papilloma Viral Types 6 and 11 and Other Risk Factors in a Large Pediatric Population
abstract: A database was developed for prospective, longitudinal study of recurrent respiratory papillomatosis (RRP) in a large population of pediatric patients. Data recorded for each patient included epidemiological factors, human papilloma virus (HPV) type, clinical course, staged severity of disease at each surgical intervention, and frequency of surgical intervention. The study hypothesizes that patients with HPV type 11 (HPV‐11) and patients younger than 3 years of age at diagnosis are at risk for more aggressive and extensive disease.

title: Condyloma in Pregnancy Is Strongly Predictive of Juvenile‐Onset Recurrent Respiratory Papillomatosis
abstract: To assess the risk of juvenile-onset recurrent respiratory papillomatosis conferred by a maternal history of genital warts in pregnancy, and to identify additional cofactors such as the method of delivery (cesarean versus vaginal) and procedures or complications during pregnancy.  A retrospective cohort design was used to evaluate maternal and infant characteristics associated with respiratory papillomatosis among Danish births between 1974 and 1993. Using data from Danish registries, we identified 3033 births with a maternal history of genital warts during pregnancy. Fifty-seven respiratory papillomatosis cases were identified by review of medical records from ear, nose, and throat departments.  Seven of every 1000 births with a maternal history of genital warts resulted in disease in the offspring, corresponding to a 231.4 (95% confidence interval 135.3, 395.9) times higher risk of disease relative to births without a maternal history of genital warts. In women with genital warts, delivery times of more than 10 hours were associated with a two-fold greater risk of disease. Cesarean delivery was not found to be protective against respiratory papillomatosis, and no other procedures or complications during pregnancy were observed to increase the risk of respiratory papillomatosis.  A maternal history of genital warts in pregnancy is the strongest risk factor for respiratory papillomatosis in the child. Future studies should examine the efficacy of genital wart treatment for the prevention of disease.

title: A comparison of risk factors in juvenile‐onset and adult‐onset recurrent respiratory papillomatosis
abstract: The clinical triad of a firstborn delivered vaginally to a young (teenage) mother has been previously noted among juvenile onset recurrent respiratory papillomatosis (JO‐RRP) patients. This study was based on a questionnaire survey of JO‐RRP patients, adult onset recurrent respiratory papillomatosis (AO‐RRP) patients, and juvenile and adult controls. The survey results revealed that the complete or partial triad was observed in 72% of JO‐RRP patients, 36% of AO‐RRP patients, 29% of juvenile controls, and 38% of adult controls. As compared with juvenile controls, JO‐RRP patients were more often firstborn (P <.05), delivered vaginally (P <.05), and born to a teenage mother (P <.01). Among adult participants, AO‐RRP patients reported more lifetime sex partners (P <.01) and a higher frequency of oral sex (P <.05) than reported by adult controls.

title: Risk factors for adult‐onset recurrent respiratory papillomatosis
abstract: To evaluate risk factors strongly associated with adult‐onset recurrent respiratory papillomatosis (AO‐RRP).

title: Identical human papillomavirus (HPV) genomic variants persist in recurrent respiratory papillomatosis for up to 22 years.
abstract: Seventy initial and 125 follow-up tissue specimens of laryngeal papillomas, obtained from 70 patients who had had recurrent respiratory papillomatosis for from 1-22 years, were investigated for the presence of human papillomavirus (HPV) DNA and HPV E5a, LCR and/or full-length genomic variants. HPV-6 was found in 130/195, HPV-11 in 63/195, and HPV-6/HPV-11 in 2/195 samples. Within 67/70 (95.7%) patients, all follow-up HPV isolates genetically matched completely initial HPV isolate over the highly variable parts of the genome or over the entire genome. Frequent recurrence of laryngeal papillomas is a consequence of long-term persistence of the identical initial HPV genomic variant.

title: Task force on recurrent respiratory papillomas. A preliminary report.
abstract: To obtain pilot data about the incidence, need for surgical intervention, and demographics of recurrent respiratory papillomas in the United States.



Otolaryngologists were surveyed using a questionnaire with structured and open-ended questions.



One thousand board-certified otolaryngologists practicing in the United States as of January 1, 1993, through a random mailing list provided by the American Academy of Otolaryngology-Head and Neck Surgery and all active US members of the American Society of Pediatric Otolaryngology and the American Bronchoesophagological Association. A total of 1346 questionnaires were distributed.



Physician's responses to questions about their current patient load of children and adults with recurrent respiratory papillomas, their surgical and anesthetic management of the disease, and their clinical experiences with risk factors for developing recurrent respiratory papillomas.



Projected totals for recurrent respiratory papillomas among children were 2354 new cases (95% confidence interval [CI], 1448 to 3260) and 5970 active cases (95% CI, 3465 to 8474), requiring 16,597 surgical procedures (95% CI, 6938 to 26,255) at a cost of $109 million (95% CI, $45 to 172 million) for March 1, 1993 to March 31, 1994. Projected totals for adult recurrent respiratory papillomas were 3623 new cases (95% CI, 2359 to 4887) and 9015 active cases (95% CI, 6435 to 11,591) requiring 9284 surgical procedures (95% CI, 6003 to 12,565) at a cost of $42 million (95% CI, $27 to $59 million) for March 1, 1993 to March 31, 1994. The incidence of recurrent respiratory papillomas among children is estimated at 4.3 per 100,000; among adults, 1.8 per 100,000. The carbon dioxide laser was favored by 92% of respondents. No consensus was reached on the role for cesarean section. Forty-six percent of respondents favored the use of a laser-safe endotracheal tube for anesthetic management.



A registry of patients with recurrent respiratory papillomas would benefit future research protocols and provide long-term follow-up of patients.

title: Female Genital Warts: Global Trends and Treatments
abstract: The increasing incidence of human papillomavirus (HPV) infection and HPV-associated conditions such as genital warts in women is a global concern. Genital warts are a clinical manifestation of HPV types 6 and 11, and are estimated to affect 1% of sexually active adults aged between 15 and 49. HPV infection is also strongly associated with cervical cancer, and is prevalent in as many as 99% of cases. The psychological stress of having genital warts is often greater than the morbidity of the disease, and therefore successful treatment is crucial. Current treatments are patient-applied and provider-administered therapies. Imiquimod 5% cream, a patient-applied therapy, is an efficacious treatment with tolerable side-effects and a low recurrence rate, and has the potential to be an effective strategy for the management of genital warts.

title: Epidemiology of genital warts in England and Wales: 1971 to 1994.
abstract: To describe the epidemiology of genital warts in England and Wales over the period 1971 to 1994.  Retrospective study of available statistics.  The rate of attendance for genital warts increased by 390% and 594% for men and women respectively between 1971 and 1994. Most of this increase occurred between 1980 and 1986. From 1986 to 1991 virtually no change occurred, but since 1992 the rate of attendance has risen by 15%. The ratio of male to female cases has declined steadily from 1.85 in 1971 to 1.34 in 1994. Rates of attendance for first attack in men were highest in the 20 to 24 year age group whereas for women it peaked in those aged 16 to 24 years. Regional data indicate that the rate of attendance has increased consistently over England and Wales during this period.  Rates of genital warts have risen substantially over the past 25 years. If these are a reflection of changes in sexual behaviour then the rise since 1992 is of considerable concern particularly for the incidence of cervical cancer in the coming decades.

title: Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis.
abstract: Human papillomavirus (HPV) infection is causally associated with benign and malignant diseases of the upper airway, including respiratory papillomatosis and oropharyngeal cancer. Low-risk HPV types 6 and 11 are the predominant cause of papillomatosis, whereas only HPV16 definitively satisfies both molecular and epidemiological causal criteria as a carcinogenic or high-risk type in the upper airway. HPV16 E6/E7 mRNA expression and integration are observed predominantly among oropharyngeal cancers, and experimental models have shown E6/E7 expression to be necessary for the initiation and maintenance of the malignant phenotype of these cancers. From an epidemiological perspective, a strong and consistent association between markers of HPV16 exposure and oropharyngeal cancer has been demonstrated in numerous case-control studies. HPV-positive oropharyngeal cancers have also been shown to be distinct from HPV-negative head and neck squamous cell cancers with regard to risk-factor profiles, molecular genetic alterations, population-level incidence trends over time, and prognosis. Tumor HPV status (as determined by certain HPV16 in situ hybridization assays or certain p16 immunohistochemistry assays) is the strongest determinant of survival for patients with local-regionally advanced oropharyngeal cancer: patients with HPV-positive cancer have at least a 50% improvement in overall survival at 5 years, which is equivalent to an approximate 30% difference in absolute survival. Thus, HPV status determination is now part of the routine diagnostic evaluation for prognostication. Preliminary evidence indicates that a small proportion of head and neck cancers may be caused by additional HPV types (e.g., 18, 31, 33, 35) and that HPV-caused cancers may rarely arise from non-oropharyngeal sites (e.g., the oral cavity, nasopharynx, and larynx). Whether or not HPV vaccination has the potential to prevent oral HPV infections that lead to cancer or papillomatosis in the upper airway is currently unknown, as is the potential for secondary prevention with HPV detection. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30,

title: Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels
abstract: collaborate annually to provide updates on cancer incidence and death rates and trends in these outcomes for the United States. This year’s report includes incidence trends for human papillomavirus (HPV)–associated cancers and HPV vaccination (recommended for adolescents aged 11–12 years).  Data on cancer incidence were obtained from the CDC, NCI, and NAACCR, and data on mortality were obtained from the CDC. Long- (1975/1992–2009) and short-term (2000–2009) trends in age-standardized incidence and death rates for all cancers combined and for the leading cancers among men and among women were examined by joinpoint analysis. Prevalence of HPV vaccination coverage during 2008 and 2010 and of Papanicolaou (Pap) testing during 2010 were obtained from national surveys.  Death rates continued to decline for all cancers combined for men and women of all major racial and ethnic groups and for most major cancer sites; rates for both sexes combined decreased by 1.5% per year from 2000 to 2009. Overall incidence rates decreased in men but stabilized in women. Incidence rates increased for two HPV-associated cancers (oropharynx, anus) and some cancers not associated with HPV (eg, liver, kidney, thyroid). Nationally, 32.0% (95% confidence interval [CI] = 30.3% to 33.6%) of girls aged 13 to 17 years in 2010 had received three doses of the HPV vaccine, and coverage was statistically significantly lower among the uninsured (14.1%, 95% CI = 9.4% to 20.6%) and in some Southern states (eg, 20.0% in Alabama [95% CI = 13.9% to 27.9%] and Mississippi [95% CI = 13.8% to 28.2%]), where cervical cancer rates were highest and recent Pap testing prevalence was the lowest.  The overall trends in declining cancer death rates continue. However, increases in incidence rates for some HPV-associated cancers and low vaccination coverage among adolescents underscore the need for additional prevention efforts for HPV-associated cancers, including efforts to increase vaccination coverage.

title: The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries.
abstract: To assess the burden and correlates of genital warts in women.



We conducted a population-based cross-sectional study in 69,147 women (18-45 years of age) randomly chosen from the general population in Denmark, Iceland, Norway, and Sweden. Information on clinically diagnosed genital warts and lifestyle habits was collected using a questionnaire.



Overall, 10.6% reported ever having had clinically diagnosed genital warts. In addition, 1.3% reported having experienced genital warts within the past 12 months. The cumulative incidence for different birth cohorts, estimated on the basis of age at first diagnosis of genital warts, increased with each subsequent younger birth cohort (P<.01). The lifetime number of sex partners was strongly correlated with a history of genital warts (odds ratio for > or =15 partners vs. 1 partner, 9.45 [95% confidence interval, 7.89-11.30]). The likelihood of reporting genital warts also increased with a history of sexually transmitted disease, use of hormonal contraceptives, use of condoms, smoking, and higher education.



The data suggest that 1 in 10 women in the Nordic countries experience genital warts before the age of 45 years, with an increasing occurrence in younger birth cohorts. These data are important for developing and evaluating strategies (e.g., human papillomavirus [HPV] vaccination) to control and prevent HPV infection and disease in the population.

title: Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer
abstract: Smoking and alcohol are well‐known etiological factors in tonsillar cancer. However, as in cervical cancer, human papillomavirus (HPV) is currently found in a sizable proportion of tonsillar cancer. Recent reports from the U.S. and Finland show an increase in the incidence of tonsillar cancer, without a parallel rise in smoking and alcohol consumption. This study investigates whether the incidence of tonsillar cancer has also changed in Sweden and whether a possible explanation of the increase is a higher proportion of HPV‐positive tonsillar cancer. The incidence of tonsillar cancer between 1970 and 2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin‐embedded tonsillar cancer biopsies taken during 1970–2002 from patients in the Stockholm area were tested for presence of HPV DNA by PCR. The incidence of tonsillar cancer increased 2.8‐fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV‐positive tonsillar cancer cases was observed, as it increased 2.9‐fold (p < 0.001). The distribution of HPV‐positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000–2002. We have demonstrated a highly significant and parallel increase both in the incidence of tonsillar cancer and the proportion of HPV‐positive tumors. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. This should definitely influence future preventive strategies as well as treatment for this type of cancer.

title: Time trends in pharyngeal cancer incidence in Norway 1981–2005: a subsite analysis based on a reabstraction and recoding of registered cases
abstract: ObjectiveIncidence rates of oropharyngeal squamous cell carcinoma (SCC) have been reported to be increasing in several countries in recent decades, contrasting with trends of SCCs diagnosed in neighboring anatomical sites. We investigated whether changes in classification systems and/or coding/registration practices might explain the trends in Norway, focusing on changes in oropharyngeal cancer.MethodsTrends in cancers of the oropharynx, base of tongue, nasopharynx, hypopharynx were graphically presented for the period 1981–2005, before and after recoding. Age-period-cohort and future prediction models were fitted to oropharyngeal SCC incidence. total of 85 (3.7%) of the 2315 pharyngeal cancers required recoding. Rates of oropharyngeal cancer in Norway were consistently two to three times higher in men, with rapid increases in both men (5% per annum) and women (4.2% per annum). Assuming generational effects, male cohorts born 1915–1950 were at increasingly higher risk of the disease. The number of oropharyngeal cancer cases is expected to double in Norway by 2020.ConclusionsThe trends were not considered materially biased by potential artefacts. The increasingly higher proportion of oropharyngeal SCC cancers is more likely explained by other factors, including an increasing high-risk HPV prevalence among recent cohorts. These results will likely have consequences on treatment and health care provision in the near future.

title: Age of Child, More than HPV Type, Is Associated with Clinical Course in Recurrent Respiratory Papillomatosis
abstract: RRP is a devastating disease in which papillomas in the airway cause hoarseness and breathing difficulty. The disease is caused by human papillomavirus (HPV) 6 or 11 and is very variable. Patients undergo multiple surgeries to maintain a patent airway and in order to communicate vocally. Several small studies have been published in which most have noted that HPV 11 is associated with a more aggressive course.  Papilloma biopsies were taken from patients undergoing surgical treatment of RRP and were subjected to HPV typing. 118 patients with juvenile-onset RRP with at least 1 year of clinical data and infected with a single HPV type were analyzed. HPV 11 was encountered in 40% of the patients. By our definition, most of the patients in the sample (81%) had run an aggressive course. The odds of a patient with HPV 11 running an aggressive course were 3.9 times higher than that of patients with HPV 6 (Fisher's exact p = 0.017). However, clinical course was more closely associated with age of the patient (at diagnosis and at the time of the current surgery) than with HPV type. Patients with HPV 11 were diagnosed at a younger age (2.4y) than were those with HPV 6 (3.4y) (p = 0.014). Both by multiple linear regression and by multiple logistic regression HPV type was only weakly associated with metrics of disease course when simultaneously accounting for age.  The course of RRP is variable and a quarter of the variability can be accounted for by the age of the patient. HPV 11 is more closely associated with a younger age at diagnosis than it is associated with an aggressive clinical course. These data suggest that there are factors other than HPV type and age of the patient that determine disease course.

title: Recurrent Respiratory Papillomatosis: A Review
abstract: Recurrent respiratory papillomatosis (RRP), which is caused by human papillomavirus types 6 and 11, is the most common benign neoplasm of the larynx among children and the second most frequent cause of childhood hoarseness. After changes in voice, stridor is the second most common symptom, first inspiratory and then biphasic. Less common presenting symptoms include chronic cough, recurrent pneumonia, failure to thrive, dyspnea, dysphagia, or acute respiratory distress, especially in infants with an upper respiratory tract infection. Differential diagnoses include asthma, croup, allergies, vocal nodules, or bronchitis. Reports estimate the incidence of RRP in the United States at 4.3 per 100,000 children and 1.8 per 100,000 adults. Infection in children has been associated with vertical transmission during vaginal delivery from an infected mother. Younger age at diagnosis is associated with more aggressive disease and the need for more frequent surgical procedures to decrease the airway burden. When surgical therapy is needed more frequently than four times in 12 months or there is evidence of RRP outside the larynx, adjuvant medical therapy should be considered. Adjuvant therapies that have been investigated include dietary supplements, control of extra‐esophageal reflux disease, potent antiviral and chemotherapeutic agents, and photodynamic therapies; although several have shown promise, none to date has “cured” RRP, and some may have serious side effects. Because RRP, although histologicallybenign, is so difficult to control and can cause severe morbidity and death, better therapies are needed. The potential for a quadrivalent human papilloma vaccine is being explored to reduce the incidence of this disease.

title: Recurrent respiratory papillomatosis: Juvenile versus adult forms
abstract: Recurrent respiratory papillomatosis (RRP) has been described to have a juvenile or aggressive form and an adult or less aggressive form. However, the aggressive form may occur in an adult and vice versa. Some authors have reported a quiescence in the juvenile form with the onset of puberty. In order to further characterize these two forms of RRP and to analyze the effects of puberty, we reviewed the records of 32 patients treated for RRP at our institution over a 10‐year period. We found that the aggressive form typically occurs in the very youngest of patients (average of 2 years old as compared to an average of 17 years old in the less aggressive form). Although subglottic involvement universally occurred in our group with aggressive disease, approximately 40% developed subglottic disease very early as compared with 20% of patients with less aggressive disease. Additionally, our data do not support the theory of spontaneous regression with the onset of puberty. These and other findings will be discussed in detail. We also propose a new classification for RRP to eliminate confusion.

title: Longitudinal measures of human papillomavirus 6 and 11 viral loads and antibody response in children with recurrent respiratory papillomatosis.
abstract: To measure human papillomavirus (HPV) 6 and 11 viral load and antibody response in longitudinal specimens obtained from children with recurrent respiratory papillomatosis and to examine the association of type-specific viral load with clinical severity of disease.



Longitudinal pilot study with a median follow-up of 5.4 months.



The study included 15 children undergoing therapy for recurrent respiratory papillomatosis at the Egleston Children's Hospital, Atlanta, GA, between January 22, 1999, and June 13, 2000.



The kinetics of HPV-6 and HPV-11 viral load and antibody level were examined over time. Longitudinal HPV-6 and HPV-11 viral loads were analyzed for associations with clinical indicators of disease severity.



Four children were infected with HPV-11, 4 were infected with HPV-6, and 7 had mixed infections. The HPV-6 and HPV-11 viral loads were stable over time in most of the children. Among children with mixed infections, HPV-6 viral loads were inversely correlated with those of HPV-11 (r = -0.80, P<.001). The HPV-11 infection was significantly associated with more annual surgical procedures (P=.02). Neither HPV-6 nor HPV-11 viral loads were associated with demographic factors or markers of clinical severity. None of the children had detectable antibodies against HPV-6, and only 3 had detectable antibodies against HPV-11 virallike particles.



Our data support the association of HPV-11 infection with clinical severity. Measures of HPV-6 and HPV-11 viral loads are relatively stable over time in most children with recurrent respiratory papillomatosis, suggesting that multiple samples may not be necessary. Cytobrush samples may substitute for tissue biopsy specimens in HPV detection and typing, but not for absolute viral load determination.

title: Human Papillomavirus-11-associated Recurrent Respiratory Papillomatosis Is More Aggressive Than Human Papillomavirus-6-associated Disease
abstract: The aim of this study was to determine whether viral type (HPV-6 vs. HPV-11) could predict the clinical course of recurrent respiratory papillomatosis in children. Viral typing, using the polymerase chain reaction, was performed on laryngeal biopsies of 61 patients treated at Children's Hospital of Michigan. HPV-6 was detected in 29 of the patients' biopsies and HPV-11 in 32 biopsies. HPV-11 was more common among the African-American patients than among Caucasians (P = 0.001). Patients with HPV-11 were diagnosed at a younger age (36.2 vs. 48.2 months; P = 0.04) and were more likely to have active disease (P = 0.0311) at the time of this study. They tended to have longer periods of disease activity (8 years vs. 5 years; P = 0.026), required more surgical procedures (42 procedures/patient vs. 13.6; P = 0.02), and more procedures per patient, per year (2.9 vs. 5.3; P = 0.0164). Three of the patients infected with HPV-11 developed invasive papillomatosis and bronchogenic squamous cell carcinoma, and two of these patients died of disease. Our findings suggest that HPV-11 infection confers a more aggressive course to recurrent respiratory papillomatosis.

title: Pediatric Respiratory Papillomatosis: Prognostic Role of Viral Typing and Cofactors
abstract: Children with recurrent respiratory papillomatosis vary greatly in their clinical disease course. Many have mild disease with eventual remission while others present with an early aggressive airway obstructive course. This study consisted of 24 pediatric patients whose specimens underwent polymerase chain reaction analysis for cytomegalovirus (CMV), herpes simplex virus (HSV), and human papillomavirus (HPV) type. Nineteen of 24 specimens contained enough DNA for this study. None of the specimens were found to contain DNA from HPV‐16, ‐18, ‐31, ‐33; CMV; or HSV, which contrasts with our previous findings in adults. Ten patients were infected by HPV‐11 and seven of these underwent tracheotomy because of an aggressive tumorigenic clinical course. Nine patients were infected by HPV‐6 alone of whom only two required a tracheotomy (P = 0.05, Fisher's Exact Test). The early airway obstructive course associated with HPV‐11, however, had no bearing on achieving eventual disease remission, with decannulation achieved in eight of nine children.

title: Adult Respiratory Papillomatosis: Human Papillomavirus Type and Viral Coinfections as Predictors of Prognosis
abstract: Pathologic material and the records of 29 patients with laryngeal papillomatosis were reviewed. The relationship between the type of human papillomavirus (HPV) and the presence of viral coinfections was correlated with clinical outcome. Using polymerase chain reaction, paraffin-embedded specimens were analyzed for the presence of HPV, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV). The HPV type could be identified in 24 patients' specimens. Twenty-one patients were infected with HPV type 6. The other 3 were infected with HPV type 11 or 16. Three patients developed squamous cell carcinoma, of whom 2 had HPV type 11 or 16. We found HSV, EBV, and CMV in 50%, 12.5%, and 0% of specimens, respectively. An aggressive clinical course was observed in 17 patients. Evidence of coinfection with other viruses was identified in 11 (65%) of these patients. In contrast, a benign clinical course was observed in 7 patients, of whom 2 (29%) had viral coinfections. We conclude that the HPV type and the presence of viral coinfections may be predictive of an aggressive clinical course.

title: Human papillomavirus and host variables as predictors of clinical course in patients with juvenile-onset recurrent respiratory papillomatosis
abstract: This study provides the first systematic evaluation of papillomavirus type and viral mutation occurring during the course of juvenile-onset recurrent respiratory papillomatosis. One hundred ninety-nine consecutive papillomas excised from 47 children between 1981 and 1996 at The New Children's Hospital in Sydney, Australia, were tested for human papillomavirus (HPV) DNA by PCR. PCR products from the viral upstream regulatory region (URR) enhancer were sequenced, and variation was related to clinical variables. Forty-four of the 47 children had HPV-induced papillomas, with type 11 accounting for 24 (55%) and type 6 accounting for 19 (43%); one (2%) was positive for either type 6 or 11. Overall, 183 (98%) of the 186 samples with amplifiable DNA were HPV positive. There was no change in HPV type over time and no statistically significant association between HPV type and disease aggressiveness. One novel, large-scale URR duplication was identified in an HPV type 11 isolate in the last of a series of six papillomas examined and the first from the bronchus. However, the duplication was not found in HPV type 11 isolates from the associated pulmonary carcinoma and its metastases in other organs. Three of 14 URR point mutations coincided with transcription factor binding sites, but there were no obvious associations with clinical course. Chi-square and multiple linear regression analyses of clinicopathological variables revealed early age at diagnosis (less than 4 years) as an independent predictor of aggressive disease (P < 0.001). A bimodal distribution of the age at diagnosis was noted, with peaks at 2 and 11 years of age.

title: Relationship between the clinical course and HPV typing of recurrent laryngeal papillomatosis. The Red Cross War Memorial Children's Hospital experience 1982-1988.
abstract: During the period 1982-1988, 20 new cases of laryngeal papillomatosis in children were seen at The Red Cross War Memorial Children's Hospital. HPV typing of biopsy specimens was performed. Their clinical course was reviewed and age at presentation ranged from 1 to 10 years. There was no correlation between age and either aggression or a prolonged clinical course. HPV DNA was identified in all 20 cases (100%). Fifteen (75%) were HPV Type 11 and 5 (25%) were HPV Type 6. There were no mixed infections. HPV Type 6 infection was more clinically aggressive than HPV Type 11 infection. The intensity of the virus signal in the biopsy specimens was not in general indicative of the clinical behavior of the disease, although two children with particularly strong intensity exhibited aggressive disease. It is suggested that identification of HPV type 6 infection has prognostic significance.

title: A Staging System for Assessing Severity of Disease and Response to Therapy in Recurrent Respiratory Papillomatosis
abstract: Recurrent respiratory papillomatosis (RRP) is a perplexing and frustrating disease for both the families it afflicts and the physicians who care for them. Although RRP is a benign disease of viral etiology (most commonly HPV types 6 and ll), it has potentially morbid consequences owing to its involvement of the airway and the risk of malignant conversion. Treatment of RRP has been mainly surgical over the past half century, relying on operative debulking, although adjuvant medical therapies have been utilized for recalcitrant cases. Among the most frustrating aspects of this disease is the observation that whereas some patients demonstrate limited disease with an infrequent need for intervention, others are confronted with recurrent airway compromise and a repeated need for laser surgery. Although it is considered the most common benign neoplasm of the larynx,l RRP is an orphan disease with an incidence in the United States estimated at between 1500 and 2500 new cases per year.2 Owing to the relative paucity of cases and the complicated nature of their treatment, the

title: Real-time Taqman PCR targeting 14 human papilloma virus types.
abstract: Subtyping of human papilloma virus (HPV) may enhance the precision of vaginal cytological assessments and will be important for investigating the effect of the recently introduced vaccine against types 16 and 18.



To evaluate an in-house real-time PCR targeting HPV types 16-18-31-33-35-39-45-51-52-56-58-59-6-11, by analysing 107 liquid-based cytology specimens representing various degrees of dysplasia.



In all, 71 samples were HPV positive, with multiple types present in 37 (52%). Comparison with Roche Linear Array on a subset of 24 of these 71 samples showed a good agreement. One or several types were detected in 17/17 (100%) samples with cervical intraepithelial neoplasia grade 2-3 (CIN 2-3), 16/19 (84%) with CIN 1, 32/43 (74%) with Atypical Squamous Cells of Undetermined Significance (ASCUS), and in 6/28 (21%) with benign cytology. Estimates of mean viral load were lower in CIN 1-3 than in ASCUS ( approximately 4000 vs. approximately 25,000 copies/1000 cells), and clearly lower in samples with benign cytology ( approximately 50 copies/1000 cells).



The HPV rates in groups with different degrees of dysplasia agrees with previous reports and support a strong link between types 16/18 and severe dysplasia. The high rate of multiple type infection might influence the outcome of HPV vaccination. The possible importance of viral load should be further studied.

title: Viral etiology of juvenile- and adult-onset squamous papilloma of the larynx.
abstract: Juvenile- and adult-onset laryngeal papillomas were examined for the presence of a human papillomavirus (HPV) genome and capsid antigens. DNA was isolated from a portion of tissue removed for therapeutic purposes, and the presence of a papillomavirus genome was detected by Southern transfer analysis. The viral DNA found in the 12 juvenile-onset and the 8 adult-onset laryngeal papillomas examined was identified as HPV-6 on the basis of size, restriction endonuclease digestion patterns, and homology detected under stringent conditions. Restriction endonuclease analysis of the viral genomes revealed at least four different subtypes, designated HPV-6c through HPV-6f. The most common subtype, HPV-6c, was detected in over half of the papillomas studied, including both juvenile and adult types. The remaining tissue was fixed and processed for immunocytochemistry. The immunoperoxidase technique was used with an antiserum that reacts with capsid antigen(s) common to all HPV serotypes. HPV antigen was found in two of the juvenile-onset papillomas and two of the adult-onset papillomas. The antigen was localized to the nucleus and was distributed in the superficial layers of the epithelium. HPV capsid antigen had not previously been detected in cases of adult-onset papilloma, and the HPV genome in both juvenile- and adult-onset laryngeal papillomas had not been characterized. Despite the absence of detectable viral antigen in most of the specimens examined, the presence of the HPV genome provides strong evidence for the papillomavirus etiology of these tumors.

title: Association of human papillomavirus subtype and clinical course in respiratory papillomatosis
abstract: The relationship of human papillomavirus type 6 (HPV‐6) subtypes to the clinical manifestations of respiratory papillomatosis was investigated. DNA was isolated from biopsy specimens of 21 patients and the viral genome analyzed by molecular hybridization. Four subtypes, designated HPV‐6c through HPV‐6f, were distinguishable by restriction endonuclease cleavage patterns of the viral genome. Patient records were reviewed to identify associations between viral subtype and sex, race, age at onset of papilloma, duration of disease, frequency of operations, history of tracheotomy and anatomical extension of papilloma. HPV‐6c was present in 13 cases which were characterized by extensive anatomical spread of disease, higher frequency of operations, and a need for tracheotomy. HPV‐6d occurred in 4 black patients with juvenile onset papilloma. HPV‐6e was found in 2 white patients — 1 with juvenile onset and 1 with adult onset papilloma. HPV‐6f was identified in 2 white patients with adult onset disease.

title: HLA-DQ alleles and human papillomavirus DNA in adult-onset laryngeal papillomatosis.
abstract: Sixty-two patients with histologically confirmed adult-onset laryngeal papilloma were clinically examined; their HLA class II DQA1 and DQB1 alleles and the presence and type of human papillomavirus (HPV) in their laryngeal papilloma biopsies were determined by polymerase chain reaction-based methods. No differences in the DQA1 or DQB1 frequencies appeared between the patients as a group and the reference population. When the patients were divided into groups according to number of laryngeal procedures performed, no HLA association was noticed with any group, nor did the presence of HPV-6 or HPV-11 DNA in the laryngeal specimen correlate with HLA type. A suggestive association was found between the DQB1 *0501 allele and the 16 patients whose laryngeal biopsy was HPV-negative, but because of the small series, additional patients need to be studied. Earlier, the DQB1 *0501 allele was reported to be protective against cervical cancer, another HPV-associated disease.

title: Clinical course of recurrent respiratory papillomatosis in Danish children.
abstract: 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.

title: National registry for juvenile-onset recurrent respiratory papillomatosis.
abstract: Juvenile-onset recurrent respiratory papillomatosis (JORRP) is an infrequent but debilitating disease. Because JORRP is uncommon, it has proven difficult for studies at single institutions to accurately evaluate its natural history.



To characterize the clinical spectrum of JORRP.



Standardized retrospective and prospective medical record abstraction.



Twenty-two tertiary-care pediatric otolaryngology centers throughout the United States.  All patients with JORRP younger than 18 years seen between January 1, 1996, and March 31, 2002.



Demographics, age at diagnosis, anatomic sites of disease, longitudinal disease course, frequency of surgery, need for tracheotomy, and medication history.



The registry includes 603 children. The mean age at diagnosis was 4.0 years. The children underwent a mean of 5.1 surgeries annually. Current age, rather than age at diagnosis, was the primary determinant of surgical frequency. The larynx was involved at the time of diagnosis in 96.1% of children, and 87.4% had only 1 anatomic site involved. Children with 1 site involved were significantly older at diagnosis (mean age, 3.9 years) than those with 2 sites (mean age, 2.9 years). Most (74.2%) had stable disease over time, 5.8% showed progression of papillomas to new sites, and 17.9% had no evidence of disease for at least 1 year. Children with disease progression were diagnosed at a significantly younger age than those who remained stable or became disease-free. Children who required tracheotomy were significantly more likely to have progressive disease.



The registry has established the clinical course of JORRP in a large sample representative of the United States. Young age was the most important determinant of disease severity (frequency of surgery, extent of disease at diagnosis, and progression of disease). Addressing questions of pathogenesis and disease course will require a revised data collection instrument and molecular analysis of tissues.

title: Prognostic value of clinical findings in histologically verified adult-onset laryngeal papillomas
abstract: A retrospective study of adult-onset laryngeal papilloma was performed to clarify whether any clinical features at the time of diagnosis could predict its course. All patients had a histologically confirmed diagnosis of laryngeal papillomas and were treated at Helsinki University Hospital between 1975 and 1994. Those with adult-onset disease and follow-up exceeding 1 year (n = 74) entered the study. Based on the case records surveyed, results suggested two risk factors for frequent laryngeal procedures: young age at onset of papilloma and a lesion extending to the anterior third of the vocal folds. It was not possible to predict the course of the disease by such clinical findings as symptoms or size or number of primary papilloma lesions. As regards the recurrence of disease, the classic division of adult-onset laryngeal papilloma into solitary and multiple type was not found to be clinically relevant.