DIAGNOSIS and WORK-UP:
History: Persistent or progressive stridor and dysphonia, with the possible development of respiratory distress characterize the child with newly diagnosed RRP. A maternal or paternal history of genital papilloma or abnormal pap should be sought. Associated symptoms such as feeding difficulties, allergic symptoms, vocal abuse and a history of choking or aspiration of foreign bodies may help to distinguish RRP from other diagnoses.
Physical exam: Findings are dependent upon site and size of papilloma. Clinicians should note the quality of voice, presence of stridor, level of respiratory distress, use of accessory muscles of respiration, and the resting oxygen saturation. The presence of congenital anomalies such as cutaneous hemangiomas may help to distinguish RRP from other diagnoses.
Imaging: Airway fluoroscopy with barium may be helpful to rule out other diagnoses such as FB, GERD, laryngomalacia, and vascular ring. No role for CT or MRI in initial diagnosis but may be helpful to follow for pulmonary extension of disease.
Endoscopy: Flexible fiberoptic laryngoscopy (FFL), (or indirect laryngoscopy in older child), is essential to make the diagnosis outside of the OR. If not technically feasible or child is in such distress that you fear that instrumenting the airway outside of the OR would be hazardous, then operative endoscopy with a rigid telescope/ventilating bronchoscope or FFL in the OR would be the alternative. Making the diagnosis (or strongly suspecting the diagnosis) before the operative procedure is desirable for facilitating the education/expectations of the family and the preparation of the anesthesiologist, surgeon and OR nursing personnel.
Other Considerations: Children newly diagnosed with RRP warrant a substantial time commitment on the part of the otolaryngologist to engage the family in a frank and open discussion of the disease and its management. Support groups such as the Recurrent Respiratory Papilloma Foundation (609-530-1443) can be a vital resource for information and support. RRP patients require frequent office visits and endoscopic procedures at the outset to establish the aggressiveness of their disease. They are encouraged to return to the office or call as often as necessary while family members and the health care team become familiar with the child's symptoms and level of distress. While infant home intercom-type monitors are often recommended, apnea/bradycardia monitors and pulse oximetry are generally not necessary. Speech and language therapy is offered early in the course of the disease. Control of other medical factors such as reflux and asthma is also aggressively pursued.
Preparation: Room should be set up in advance and the equipment checked by the surgical team to ensure that appropriate sized bronchoscopes and telescopes are available, suctions are of proper length to fit through bronchoscopes, video equipment functioning (desirable for education of families and to allow anesthesia and OR team to follow the progress of the surgery), microlaryngoscopes, light cables and light sources all available. Procedure should not be performed in a facility that does not have the necessary complement of equipment to safely instrument a child's airway. CO2 laser ( when utilized) should be tested before the child enters the room to make sure it is functioning properly. Informed consent from the family should include discussion of possible scarring, airway edema and airway fire with the use of the laser (at least on first visit to the OR).
Anesthesia technique: A number of acceptable techniques ranging from ventilation via a laser safe tube with an FiO2 of <30%, to insufflation techniques using Propafol with intermittent intubation if needed, to jet-ventilation (either supraglottic or subglottic). Key is good communication between surgeon and anesthesiologist before and during the procedure so that approach is coordinated. Additional key is to utilize experienced anesthesiologist comfortable with managing obstructed pediatric airways. If no such individual is available, then should consider delaying the procedure or transferring the child to a facility where one is available.
Surgical technique: A number of acceptable techniques are available to the surgeon including use of the CO2 laser, KTP/ND;Yag laser, microlaryngoscopy forceps and powerized laryngeal shavers. New technologies that are just coming available with limited long-term follow-ups that may ultimately prove superior to standard techniques include use of the micro-debriders, flash pump dye and 585-mm pulse dye lasers, argon plasma coagulation, and phonomicrosurgical resection techniques.
Since there is currently no therapeutic regimen that reliably eradicates the HPV, when there is a question about whether papilloma is an area needs to be removed, it is prudent to accept some residual papilloma rather than risk damage to normal tissue and producing excessive scarring. Even with the removal of all clinically evident papilloma, latent virus may remain in adjacent tissue, which may explain the recurrent nature RRP. Therefore, the aim of therapy in extensive disease should be to reduce the tumor burden, decrease the spread of disease, create a safe and patent airway, improve voice quality, and increase the time interval between surgical procedures. Staged papilloma removal for disease in the anterior commissure is appropriate to prevent the apposition of two raw mucosal surfaces. The surgeon who is not aware of injury to deeper tissue layers with injudicious laser usage may encounter unacceptable scarring and subsequent abnormal vocal fold function. Inappropriate and aggressive use of the laser may also cause injury to nonaffected tissues and create an environment suitable for implantation of viral particles.
Biopsy: There is controversy among clinicians regarding the need to send a tissue biopsy with each papilloma surgery. It is our recommendation that a biopsy specimen be sent at the time of the initial diagnosis of RRP. HPV-typing may be performed at that time though its value in terms of predicting prognosis is currently limited. Subsequent surgeries should have specimens sent for monitoring of progression to atypia and malignant transformation to SCCA. Additional HPV-typing would only seem to be needed if there is a significant clinical change (surgical interval shortens substantially, new onset of spread to an extra-laryngeal site). In children who require frequent surgeries, it would certainly seem reasonable to send specimens with every other or every third surgery. An additional benefit that may be derived from serial biopsies is the opportunity to study the archival tissue in the future for clues to prognosis using techniques or markers not currently available.
Documentation: It is highly desirable to have a consistent staging and severity scale to follow progression of RRP disease. A computerized tracking system developed by Coltrera and soon to be available in CD-ROM format via an ASPO grant should simplify this problem by standardizing the nomenclature for describing RRP. This system is ideally suited for tracking results of clinical trials of adjuvant therapies and for physician-to-physician communications.
Follow-up: Individualized follow-up needs to be arranged between the families and their doctors. Circumstances that would influence the timing and location of this follow-up would include the travel distance to the medical center, the reliability of the family and the reliability of their transportation, the rapidity at which the papillomas recur and the degree of airway compromise caused by the papillomas. An acceptable regimen might include monthly follow-up in the office in the first year of disease diagnosis with FFL performed every-other-month and whenever the clinical situation warrants with follow-up extended to every 2-4 months in subsequent years in a local child with stable disease with reliable transportation and guardians. Surgical intervention would then be planned according to clinical needs. In contrast, a family that lives quite a distance from the hospital might be scheduled for interval operating room exams once a pattern of recurrence has been established with use of email or phone contact between the surgeon and the family to monitor the clinical situation between surgeries.
The decision to embark upon adjuvant therapy should also be individualized and based upon the frequency of surgical interventions, the morbidity of frequent surgeries and the recurrence pattern of t he papillomas. A basic rule of thumb to follow would suggest the need for adjuvant therapies if surgery is being required more frequently than 4 times a year for 2 years or if the papillomas begin spreading outside of the endolarynx. Additionally, children who present with disease in their trachea should have early consideration for adjuvant therapy.
Choice of therapy depends upon informed consent and evidence-based research. Ideally, patients should be enrolled in clinical studies whenever possible.
Adjuvant therapies currently recommended would include:
Recombinant Interferon alpha- N2 administered initially at 5 million units per meter squared body surface area by subcutaneous injection daily for 30 days and then 3 times weekly for at least a 6 months trial. The dose can be reduced to 3 million units/m2 3 times a week if side effects are severe. Weaning should be slow to prevent a rebound effect. Reinstitution of therapy after discontinuation has been shown to be effective. Children under the age of a year should be monitored for the possibility of spastic diplegia and should have a baseline neurologic exam. Children on chronic interferon therapy need to have their liver enzymes and leukocytes monitored on at least a quarterly basis.
Indole-3-carbinol, a derivative of cruciferous vegetables, has been shown to alter the growth of papilloma in mice by altering estrogen metabolism. The National Toxicology Program at the National Institute of Environmental Health Sciences has recently embarked upon a toxicology testing program to certify its safety. A large scale, multi-institutional trial based at University of Pittsburgh is still enrolling new patients utilizing chemically-pure I3C.
Photodynamic therapy is currently being investigated at LIJ in a study headed by Abramson and Shikowitz. Preliminary studies using DHE showed promise in reducing surgical intervals but photosensitivity limited its usefulness. The present study utilizing Foscan has shown early promise with minimal tissue damage and less photosensitivity.
Cidofovir (Vistide) has demonstrated promise in clinical series from San Diego and Belgium in adults and children with aggressive RRP disease. This drug, which is approved for use in HIV patients with CMV retinitis, is designed to be injected into the papilloma bed after debulking surgery. This has prompted interest in pursuing a multi-institutional open trial. The protocol for the open trial is being formulated currently and will likely include an arm for children with severe disease as well as a randomized, placebo-controlled arm for children with newly diagnosed papilloma. An ASPO grant and support from the Gilead Pharmaceutical company are being sought to administer the study. A multi-institutional safety study is also in the process of development.
Reflux: Preliminary data from Bowman Gray (Cummins and Koufman) and Great Britain (Harcourt et al) suggests that achieving optimal control of gastro-esophageal reflux disease may have significant benefits in children with laryngeal papillomas. It would seem prudent to investigate and control reflux in RRP patients while this relationship is studied further.
Tissue bank: Through the National Registry established at CDC it may be possible to create a potential tissue bank of RRP specimens that could be utilized by RRP researchers to correlate histopathology with clinical histories of papilloma progression. Confidentiality and logistic issues would need to be worked out to make this a reality.