Anatomic representation of laryngeal (a) and respiratory tract (b) epithelium indicating squamociliary junctions at which recurrent respiratory papilloma predilection occurs (Republished with permission from Kashima et al. 1993)
The clinical setting in which dysphonia presents will dictate the acuity of the evaluation. Certainly, in a child presenting in severe respiratory distress, airway management will take precedence over voice concerns. In contrast, a patient presenting in the ambulatory setting, with a chronic or recurrent voice disturbance, may undergo a more systematic evaluation (Faust 2003). When possible, a complete history, including birth, medical, and surgical, is necessary, in addition to a detailed voice history.
Factors pertinent to birth history include maternal age, number and method of previous deliveries, and history of HPV infection. It is assumed that the majority of children with RRP acquire the disease by vertical transmission, occurring during delivery through an infected birth canal. Overt maternal condylomata are seen in more than 50% of mothers who give birth to children with RRP (Hallden and Majmudar 1986). It has also been noted that patients with JORRP are not only delivered vaginally, but also the firstborn child to a young woman (<20 years old). It is hypothesized that primigravid mothers have a longer second stage of labor, resulting in prolonged exposure to genital HPV. In addition, recently acquired lesions are more likely to shed virus than long-standing lesions, exacerbating the risk in younger women (Shah et al. 1998).
There are multiple medical conditions, which can both cause and exacerbate dysphonia, including allergies, asthma, bronchitis, and gastroesophageal reflux disease (GERD) . Of these, GERD has been implicated as a potential risk factor for RRP, as well as complications following surgical management. In fact, patients with severe RRP, requiring multiple surgeries and poor response to systemic therapy, showed a significant decrease in recurrence after therapy for GERD (Borkowski et al. 1999). In addition, antireflux therapy in patients considered “high risk” based on frequency of procedures and disease at the anterior commissure has been shown to reduce the presence of soft tissue complications, specifically scarring and laryngeal web formation (Holland et al. 2002).
A thorough surgical history is necessary to identify surgical procedures that may place the recurrent laryngeal nerve at risk (e.g. ligation of persistent ductus arteriosus). In addition, details of previous intubation should be documented, including circumstances necessitating intubation, difficulty of intubation, tube size, length of time of intubation, and need for re-intubation following extubation (Faust 2003). This same approach should be utilized when considering any intubations that occurred in the perinatal period.
Vocal history, including time of onset, precipitating causes, chronology, exacerbating or alleviating factors, and severity, should be obtained. Additionally, it is pertinent to assess for symptoms that may represent disturbances with swallowing (e.g. dysphagia, aspiration) or breathing (e.g. stridor).
8.3.2 Physical Examination
Children who present with dysphonia must undergo an organized and thorough physical examination. Regardless of the setting, every evaluation must begin with a rapid assessment for respiratory distress. The respiratory rate should be assessed, as well as changes in the rate that may indicate fatigue. The patient should be observed for the presence of nasal flaring or the use of accessory neck or chest muscles. Finally, evidence of cyanosis may indicate impending respiratory collapse. If there is evidence of significant distress, further examination is best undertaken where equipment for endoscopic evaluation, airway intubation, and possible tracheostomy is readily available. Depending on resource capabilities, this may be the emergency room, pediatric intensive care unit, or operating room.
Assessment of vital signs, particularly pulse oximetry, can provide objective information on respiratory status (Derkay and Faust 2015). However, oxygen saturation may not be the most reliable indicator of disease severity in proximal (i.e., laryngeal or tracheal) airway obstruction, since the mechanism of hypoxemia in such cases is frequently hypoventilation. Due to the principles of the alveolar gas equation, partial carbon dioxide tension of the arterial blood (PaCO2) increases disproportionately to decreases in arterial hemoglobin oxygen saturation by pulse oximetry (SPO2) (Fouzas et al. 2011). As a result, clinical appearance is generally more reliable, as infants can appear to maintain adequate perfusion up until the point of sudden decompensation.
Auscultation is often considered the most important part of the evaluation (Derkay and Faust 2015). With the aid of a stethoscope, listening over the nose, open mouth, neck, and chest may help localize the site of respiratory obstruction. Changes in the normal respiratory cycle, which consists of a shorter inspiratory phase and longer expiratory phase, may be assessed. While stridor may begin as inspiratory, it often progresses to biphasic as airway obstruction worsens. Fluctuation in the quality of the stridor with changes in position may assist with diagnosis. For example, children with RRP do not generally experience changes due to the static nature of the lesions, whereas infants with laryngomalacia improve in the prone position (Derkay and Faust 2015).
In a stable patient with dysphonia , a complete head and neck examination is essential. The ears should be examined for evidence of previous or current otologic disease. A thorough, age-appropriate hearing assessment should be performed. Nasal examination should identify any septal deviation or turbinate abnormalities, as well as the presence of rhinorrhea or polyps. Oropharyngeal examination includes inspection of the structural integrity and mobility of the palate. In some cases, papillomas may be noted in the oral cavity or oropharynx, as it has been noted as the most frequent site of extralaryngeal spread, which occurs in approximately 30% of children with RRP. Palpation should be performed to evaluate for the presence of any neck masses. Finally, the cranial nerves should be assessed.
8.3.3 Airway Endoscopy
Flexible fiber laryngoscopy provides the cornerstone for evaluation in the dysphonic patient. When the scope is passed into each nasal cavity, choanal patency can be assessed. At the level of the nasopharynx, adenoid size and velopharyngeal function can be determined. With continued passage, the position and function of supraglottic and glottic structures, including the true vocal cords, can be observed. Finally, inspection of mucosal and squamous surfaces for the presence of masses or lesions within the oropharynx, hypopharynx, and larynx is possible. Video recording of the fiber-optic examination allows for frame-by-frame review, which can be helpful in an uncooperative patient in whom the examination must be performed quickly. In addition, it provides opportunities for education of the patient and family (Faust 2003).
Histologically, recurrent respiratory papillomatosis is associated with mucosal proliferation resulting in multiple fingerlike projections with a central fibrovascular core covered by stratified squamous epithelium (Abramson et al. 1987). Two growth patterns are possible. When microscopic, the mucosal surface can exhibit a velvety appearance due to a superficial spreading configuration (Derkay and Faust 2015). The macroscopic or exophytic growth pattern is more noticeable. These lesions are pink to white in color, are sessile or pedunculated, and exhibit “cauliflower” or “grapelike” projections (Fig. 8.2).
Gross appearance of bulky, exophytic papillomatosis during laryngoscopy
At the completion of a thorough history, physical, and fiber-optic examination, it should be possible to diagnose nearly all cases of recurrent respiratory papillomatosis. However, there are occasional cases that require operative endoscopy for diagnosis (Faust 2003). Any patient in which there is a suspicion for RRP but who is unable to tolerate flexible laryngoscopy should be evaluated in the operating room under anesthesia. In addition, due to the variety of sites in which RRP may present, including the undersurface of the vocal folds, operative endoscopy may be necessary to provide enhanced visualization in order to obtain an accurate diagnosis (Kashima et al. 1993).
8.4 Anesthesia Considerations
Anesthesia management in patients with recurrent respiratory papillomatosis can be challenging. As with any laryngeal surgery, the anesthesiologist and surgeon must share the same space in order to maintain control of the airway and treat the disease process. As a result, effective communication between the anesthesiologist and surgeon during preoperative planning and intraoperative management is paramount. Anesthetic technique may be modified depending on the child’s age, suspected diagnosis, underlying impairment of oxygenation and ventilation, and potential treatment modalities (Swanson et al. 2015).
In spontaneous ventilation, the patient maintains their own respiratory effort, resulting in an unobstructed operative field, aiding in diagnosis and management. Anesthesia can be induced with either IV (sodium thiopental, ketamine, or propofol) or inhalation (sevoflurane) agents with oxygen (Swanson et al. 2015). With inhalation techniques, the delivered concentration requires a delicate balance that is high enough to prevent coughing and laryngospasm but also low enough to avoid cardiovascular depression and apnea. This can be difficult to achieve with short-acting agents. Thorough topical anesthesia with 4% lidocaine, delivered either by atomizer or syringe, can provide additional anesthesia and reduce systemic requirements. When using topical lidocaine, it is important to remain cognizant of the maximum dosage limits based on the child’s weight. In addition, adjunctive agents, such as propofol infusion, may be used to reduce or replace the need for inhalational anesthesia (Swanson et al. 2015).
The apnea-(re)intubation technique provides unobstructed access to the larynx but only on an intermittent basis (Swanson et al. 2015). Induction is performed along with topical anesthesia of the airway prior to intubation. The laryngoscope is inserted until adequate exposure is achieved, at which point it is placed into suspension. The tube is then withdrawn, and the surgeon may proceed with diagnosis or treatment while the patient is apneic. The tube can then be replaced under direct visualization if carbon dioxide rises or oxygenation falls. These efforts can be repeated until the procedure is complete (Swanson et al. 2015). While it can provide visualization and access similar to spontaneous ventilation, concerns have been raised about potential viral spread due to repeated placement of the endotracheal tube (Derkay and Faust 2015).
In cases in which continuous intubation is planned, the use of a wrapped or “laser-safe” endotracheal tube is advised in order to protect the tube from accidental ignition during laser use (Derkay and Faust 2015). While the tube is protected, the cuff remains susceptible to rupture and should be covered with moist surgical cottonoids. As an added measure of protection, the cuff is filled with saline. Methylene blue or other visible dyes are generally mixed with the saline to help detect cuff perforation. Regardless, the tube remains in the operative field throughout the procedure, potentially reducing visualization, particularly in the posterior glottis and subglottis (Derkay and Faust 2015).
Jet ventilation provides another anesthetic alternative with complete visualization of the glottis. Induction requires the use of an IV anesthetic, such as propofol, with a muscle relaxant. After topical anesthesia is provided, the suspension laryngoscope is introduced with attached jet-ventilating device (Swanson et al. 2015). Due to the high pressures involved, it is preferable to place the jet cannula proximal to the end of the laryngoscope. In this location, however, there is the potential risk of disseminating papilloma further into the tracheobronchial tree (Derkay and Faust 2015). The use of jet ventilation is also limited in patients with higher disease burden, as it predisposes them to serious complications. In particular, with large laryngeal lesions, narrowed airways, or ball-valve lesions, high degrees of outflow obstruction may occur, resulting in increased intrathoracic pressure with subsequent pneumothorax or pneumomediastinum (Derkay and Faust 2015). Inadequate muscle relaxation can also produce outflow obstruction. Therefore, jet ventilation requires a certain level of experience on behalf of the anesthesiologist, prior to considering its use.
In some cases, patients present with severe, acute respiratory distress that may require tracheostomy. In general, tracheostomy has been approached with hesitation in the management of RRP surrounding concerns that the mucosal injury may initiate the progression of disease to the distal airway (Cole et al. 1989; Kashima et al. 1993). For example, in a series of 40 patients with lower airway RRP in Russia, placement of a tracheostomy tube was noted to be the basic cause of papilloma extension in 92.5% of patients (Soldatski et al. 2005). In contrast, Shapiro and colleagues noted that their tracheostomy patients presented at a younger age with more widespread disease, often involving the distal airway prior to tracheotomy (Shapiro et al. 1996). Thus, whether the tracheostomy itself predisposes the mucosa to papillomatous spread or whether the necessity of tracheostomy indicates a more severe state remains unclear. Regardless, in cases in which tracheostomy is unavoidable, decannulation is advised as soon as the disease burden is cleared and airway patency restored.
Several different anesthetic techniques may be utilized in the diagnosis and management of RRP. The best option will depend on the child’s age, disease burden, respiratory status, and potential treatment modalities. In addition, the familiarity and comfort of the anesthesiologist and surgeon must be taken into consideration. Regardless of the technique, constant communication among all members present in the operating room is essential to successful airway management.
8.5 Staging Assessment
Initial staging systems were often developed during the performance of clinical trials. While several were proposed, most researchers and clinicians had not adopted a uniform system, leading to confusion in the recurrent respiratory papillomatosis literature, as well as in communications between physicians regarding patient management. The original concept of a uniform scoring system was introduced by Kashima et al. as part of a multi-institutional study evaluating interferon therapy (Kashima et al. 1985). Unfortunately, this system had limited laryngeal subsite information such that there was no indication of the side of involvement. In addition, there was substantial subjectivity in determining the percentage of airway lumen obstruction and a lack of clinical measures of disease severity (Derkay et al. 1998). While Lusk and colleagues divided the right and left halves of the airway, this was done within the glottis only, failing to take into consideration disease outside the larynx (Lusk et al. 1987). Similar to Kashima and colleagues, there was still considerable subjectivity, as well as absent functional assessment (Kashima et al. 1985; Derkay et al. 1998).
The authors of the most frequently used assessments, along with the Task Force on RRP and the Collaborative Anti-Viral Study Group HPV Subcommittee, developed a comprehensive staging system, which incorporated functional evaluation, numerical grading of subsite involvement, and final disease severity score, as well as diagrammatic interpretation of disease burden (Figs. 8.3 and 8.4, Derkay et al. 1998). Initially, six questions are posed about the patient’s clinical course, including interpretation of the patient’s voice, stridor, respiratory status, and urgency of current intervention. Adding the scores for four of the six subjective assessments generates a clinical score. Then, a score of 0 to 3 (0 = absent, 1 = surface lesion, 2 = raised lesion, 3 = bulky lesion) is assigned to nine laryngeal subsites, five tracheal subsites, and six additional subsites. A total score is calculated by summing the scores from the various subsites. In addition, lesions are marked on a standardized diagram, along with biopsy and treatment sites. Finally, a total score, incorporating both the clinical and anatomic score, is generated (Derkay et al. 1998).
Staging assessment with component clinical and anatomic score
Standardized diagram of laryngeal sites that compose anatomic score
Some authors have demonstrated variability between intra-rater and inter-rater agreement among pediatric otolaryngologists when scoring endoscopic videotapes (Behar and Todd 1999; Todd 1997). In contrast, Hester et al. found high reliability in using the previously mentioned staging system by Derkay et al. (Hester et al. 2003; Derkay et al. 1998). Ten videotaped recordings of endoscopic assessment of patients with RRP were reviewed by 15 fellowship-trained pediatric otolaryngologists. In 90% of patients, the standard errors of the mean total score were less than 1, indicating low variance and subsequent high reliability of the total score (Hester et al. 2003). Furthermore, elements of this staging system have shown promise for their predictive value on surgical interval (Derkay et al. 2004). Seventeen patients with RRP at a large academic medical center were assessed using the staging system, and various regression models were built. As one of the significant findings, children with a total subsite score of 20, considered a high-risk category, could expect to have their next surgery 120 days sooner than children with a total score less than 20 (Derkay et al. 2004). While pilot in nature, this study provides support for continued development work on a larger scale. To help with such efforts, the staging system is now computerized and made available through the American Society of Pediatric Otolaryngology (ASPO) for use by its members and colleagues (Derkay et al. 1998).
8.6 Surgical Management
The current standard of care for pediatric RRP is focused on debulking of papillomatous lesions while preserving normal anatomical structure. The goal is to provide an adequate airway, improve voice quality, and limit complications, such as web formation or airway stenosis. The mainstay of surgical therapy has been performed using the CO2 laser, coupled with the operating microscope (Wiatrak et al. 2004). In fact, 92% of survey respondents used the CO2 laser as their preferred method of treatment for initially diagnosed RRP, with 70% continuing to use this modality exclusively for treatment (Derkay 1995).
The CO2 laser has an emission wavelength of 10,600 nm and converts light to thermal energy, which is absorbed by intracellular water, effectively vaporizing the cells. The newest generation of laser microspot micromanipulators enables surgeons to use a spot size of 250 mm at 400 mm focal length and 160 mm at 250 mm focal length (Derkay and Faust 2015). Therefore, thermal energy can be delivered with precision, reducing collateral tissue damage. The surgeon, however, must remain cognizant of deeper tissue layers and surrounding structures, particularly in difficult treatment areas, such as the true vocal cords and anterior and/or posterior commissure, as excessive laser usage may cause unacceptable scarring and abnormal vocal fold function. The smoke plume that is created contains water vapor, as well as vaporized tissue material, including active viral DNA (Abramson et al. 1990; Hallmo and Naess 1991; Kashima et al. 1991). As a result, a mechanical smoke evacuation system along with appropriate personal protective equipment, including N95 or N100 respirators, is necessary for the safety of operating room personnel (Kuhar 2013). Finally, as with all laser usage, the potential for airway fire exists, and appropriate safety precautions should be taken throughout the procedure.
Due to inherent limitations with access when using the micromanipulator partnered with the microscope, investigators began to explore alternative technologies. In 1997, Bergler et al. used argon plasma coagulation (APC) with flexible fiber endoscopy to manage a 7-year-old girl with progressive RRP, refractory to CO2 laser and interferon-alpha treatment. APC is a monopolar electrosurgical procedure in which electrical energy is transferred to the target tissue using ionized (i.e., conductive) argon gas, without the electrode coming into direct contact with the tissue. Since the plasma follows the path of least electrical resistance, it allows treatment to occur both en face and tangentially, allowing less accessible regions to be treated. They noted very good disease control, including management of distal tracheal disease, without side effects or complications (Bergler et al. 1997).
Beginning in the late 1990s, additional laser treatment options were evaluated. Bower and colleagues evaluated the feasibility and safety of the flash pump dye (FPD) laser in a prospective nonrandomized trial comparing FPD to CO2 laser management (Bower et al. 1998). Nine patients from 2 to 20 years of age with severe RRP were enrolled. Patients underwent CO2 debulking of the left hemilarynx and FPD treatment of the right hemilarynx. Five patients had a 90% or more decrease in size of papillomas on the FPD-treated side 2 weeks postoperatively. The authors noted that the FPD laser coagulates, rather than vaporizes the tissue, which may limit scar formation, as well as enhance safety due to the lack of a smoke plume (Bower et al. 1998).