CHICAGO-Recurrent respiratory papillomatosis (RRP) begins with a pretty small virus, relatively speaking, but it can lead to some pretty big problems for both the patient and the treating physician. Recent surgical and pharmaceutical advances, however, are already making a difference and researchers may be on the verge of answering some big questions that may lead to improved treatments and, ultimately perhaps, prevention.
The American Laryngological Association (ALA) and the American Society of Pediatric Otolaryngology (ASPO) joined forces to present a special panel discussion here at the 2006 Combined Otolaryngology Spring Meetings (COSM). Robert T. Sataloff, MD, Professor of Otolaryngology-Head and Neck Surgery at Thomas Jefferson University Hospital in Philadelphia, Pa., served as moderator of the discussion, which covered some of the current issues surrounding the treatment of RRP.
Etiology and Natural History
The viral etiology of RRP is the human papilloma virus (HPV), which is also associated with genital warts and cervical cancer.
It is a fiendishly simple virus, said Andrew Inglis, MD, Associate Professor of Otolaryngology-Head and Neck Surgery at the University of Washington Medical Center in Seattle. It only has about 8000 base pairs-there’s not a lot of kilobytes of information in that virus.
I find [the microdebrider] a much more elegant way to remove papilloma and I find it is as effective as the CO2 laser. – -Marvin Fried, MD
HPV encompasses a large family of types that are based on the homology of the genome; more than 100 types and subtypes have been characterized, with types 6 and 11 being the most common in RRP. Many others have also been reported, including types 16 and 18, which are considered the most carcinogenic.
It only has eight proteins that it codes for, so it’s very efficient, Dr. Inglis said. There are two capsid proteins, four kind of housekeeping proteins, and then the two oncogenes-E6 and E7 oncoproteins.
Initially, the virus particle enters the stem cells at the basal layers, where it may remain latent or it may express the viral proteins. Expression of the E6 and E7 oncogenes then leads to continued proliferation in the upper mucosal layer.
The cells don’t divide faster, they just continue to divide when they should be differentiating, Dr. Inglis said. It also stimulates angiogenesis and that’s what leads to a papilloma forming.
Investigating Juvenile RRP
There are two types of RRP-juvenile onset, which is generally observed to be most severe, and adult onset. The conventional wisdom is that the juvenile RRP viral infection is acquired in the birth canal, according to Dr. Inglis, who noted a recently published Danish study suggesting that the biggest risk factor is maternal history of genital warts.
In looking at patients over an almost 20-year period, they found that if there was a maternal history of genital warts, RRP was seen in 1 of 144 births, but with no warts it was only seen in about 1 of 30,000, Dr. Inglis reported. Only a very small percent of maternal patients were producing about 37 percent of juvenile RRP cases.
The researchers also reported that longer delivery times resulted in a slightly increased risk of developing the disease; they saw no association with birth order and only a weak association with younger maternal age.
This study certainly raises the question as to whether elective C-section might be effective to protect against juvenile RRP, Dr. Inglis said. In the US, we have a rate of C-section among juvenile RRP patients of about three percent, compared to a national rate of at least ten percent. The Danish study, though, showed no difference in the rates of elective C-section when comparing the two groups. So, I’d have to say that the jury is still out as to whether elective C-section is actually protective.
The clinical course of juvenile RRP is something like a tale of two databases, said Dr. Inglis, referring to data from a US study and a Danish study.
The US study is based on the National Registry for Juvenile-Onset Recurrent Respiratory Papilloma, which was done by the CDC and included more than 600 children from 22 tertiary care centers across the country. The clinical course, as defined by the number of surgeries that the patients had over time, was reported with a median follow-up of 3.6 years.
In some respects, the results of the American study paint a pretty bleak picture, in that the children underwent a mean of 5.1 surgeries annually, Dr. Inglis said. Fortunately, there was not a lot of disease-site progression. In about 75 percent of the patients, the disease remained in the presenting site.
The Danish study included 57 children diagnosed with RRP born between 1974 and 1993. Follow-up averaged approximately 14 years after diagnosis.
Their results painted a much brighter picture. The total median number of surgeries-not the annual, but the total-was five surgeries and 14 percent only required one surgery, he said. With both studies, however, we need to remember that the clinical course does not equal the natural history. I think we need to be skeptical of uncontrolled therapeutic studies.
Traditional Therapies
Obviously, the surgical removal of papilloma requires access and the traditional methods are direct laryngoscopy or bronchoscopy with the possible use of flexible endoscopes.
The traditional methods of therapy are standard-dissection with cold instrumentation, said Marvin Fried, MD, Professor of Otorhinolaryngology-Head and Neck Surgery at Albert Einstein College of Medicine in the Bronx, NY. It used to be just cup forceps. Then came the use of lasers, the first technology that brought kind of something new to laryngeal surgery and predated almost everything else we’ve done subsequently. Now we have the adjunct of cryosurgery, and the growing popularity of endoscopic resection.
Many physicians are currently using the latest laser devices to achieve resection, Dr. Fried noted, which allows improved precision, accuracy of visualization and quality of micromanipulation. With advances in technology, however, he cautions not to forget safety issues.
Many years ago I did a study to look at the risk of laser hazards in the operating room, particularly in patients with airway lesions, he said. It was surprising to find out that experience with the CO2 laser did not make you safer; it actually lulled people into complacency. Airway catastrophes still can occur and a laser fire in the airway is probably one of the more frightening things that a surgeon can experience.
Putting the laser aside, Dr. Fried believes that, in many physicians’ hands, the microdebrider has superseded the use of the laser in the operating room.
I find it a much more elegant way to remove papilloma and I find it is as effective as the CO2 laser, he said. One thing that I have noticed is that sometimes the angulation of the microdebrider makes it very difficult to get anterior commissure submucosal disease. The trick is to bend the distal end of the microdebrider and that seems to work fine to remove the disease there.
Antiviral Issues
The bottom line when it comes to the treatment of RRP is that surgical removal is rarely curative, so physicians really need to look at something else to manage this devastating disease, according to Seth Pransky, MD, Assistant Clinical Professor of Otolaryngology-Head and Neck Surgery at the University of California, San Diego.
Some promising new therapies are coming down the pike but what we currently have, from an antiviral perspective, are interferon and intralesional cidofovir, Dr. Pransky said. Interferon is really one of our mainstays that goes back a ways. With interferon, what we get is a tremendously variable response rate, but there are adverse reactions; it’s a prolonged treatment protocol and there are significant concerns about rebound.
When it comes to cidofovir, although scientists are not entirely sure exactly how it works, they know that it inhibits the viral DNA polymerase and it definitely targets rapidly dividing cells.
One important thing to remember is the RRP is different in juvenile disease than it is in adult disease and, consequently, when you look at the literature, you tend to see much different response rate in adults than in children, he said. The tendency we see is that adults seem to respond better to cidofovir, perhaps because their presentation of disease is generally far less severe.
The main issue, and the 800-pound gorilla when it comes to cidofovir, is the question of toxicity-the carcinogenesis of cidofovir.
The concern is that you’re injecting this medicine into the cells, it’s being taken up by the cells, and it may disrupt the genomic integrity of the cell and that’s what ultimately may generate a problem with progressive dysplasia, Dr. Pransky said. It’s difficult to know whether what we’re seeing is the natural history of the disease that might be particularly severe, or if the cidofovir is actually acting as an agent bringing about the changes.
Prevention on the Horizon?
The most promising glimpse into the future of RRP, however, does not involve treatment-it’s about prevention and the development of two extremely promising vaccines: the quadrivalent Gardasil, which recently received FDA approval, and the bivalent vaccine Cervarix, which is expected to be submitted for approval later this year.
Early trials have been so successful that things are moving ahead fairly quickly with both of these vaccines, Dr. Pransky said. We hope they will pave the way to make RRP a disease of the past. This is where the future is and where we will need to focus a lot of our efforts.
©2006 The Triological Society