Seminar Series Recurrent Respiratory Papillomatosis

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Seminar Series
Recurrent Respiratory Papillomatosis
Craig S. Derkay, MD; David H. Darrow. MD. DDS
Recurrent respiratory papillomatosis is a frustrating and challenging disease for surgeons, patients, and patients' families. Although the voice and airway manifestations are managed surgically, a "cure" for this disease remains elusive. In
this edition of the "Seminar Series." we endeavor to review the currenl literature regarding the epidemiology, etiology,
clinical manifestations, and surgical and medical treatments of this disorder. The key to future management of recurrent
respiratory papillomatosis may lie in its prevention, if current efforts to develop an effective vaccine come to fruition.
Key Words: cidofovir. human papillomavirus, inierferon. microdebrider. recurrent respiratory papillonia, vaccine.
INTRODUCTION
Recurrent respiratory papillomatosis (RRP) is a
disease of viral origin that is associated with exophytic lesions of the airway. Although it is a benign
disease. RRP has potentially morbid consequences
due to airway complications and to the risk of malignant conversion. The disease is often difficult to
treat because of its tendency to recur and spread
throughout the respiratory tract. The course of RRP
is variable: some patients experience spontaneous remission and others suffer from aggressive papillomatous growth that requires multiple surgical procedures
over many years. An estimated 15.000 procedures
are performed in the United States each year for
adults and children with RRP at a total annual cost
of more than $150 million.'
ETIOLOGY
Until the 1990s, human papiliomavirus (HPV) had
been suspected but not confirmed as the causative
agent in RRP. This uncertainty developed from an
inability to culture the virus in vitro, and from the
failure to demonstrate viral particles consistently in
papilloma lesions with electron microscopy or HPV
antibodies. Today, with the use of viral probes. HPV
DNA has been identified in virtually every papilloma
lesion studied.
The HPV is a small. DNA-containing. nonenveloped icosahedral (20-sided) capsid virus with a double-stranded circular deoxyribonucleic acid 7.900
base pairs long. The HPVs are grouped on the basis
of genetic homology: viruses that exhibit less than
909^ identity in specific regions of the viral genome
are defined numerically as separate types. On this
basis, nearly 100 different HPV types have been identified. These groupings correlate with tissue preference, disease severity, and clinical course. Among
those that affect the aerodigestive and genital tracts,
HPV types 6 and 11 are associated with the lowest
malignant potential, whereas HPV 16 and 18 have
the greatest malignant potentiai; HPV 31 and 33 have
a malignant potential that lies somewhere in between.
Children infected with HPV 11 appear to have a more
obstructive airway course early in the disease and a
greater need for tracheotomy.--^
The induction of cellular proliferation is a fundamental property of HPV. although its mechanism of
action remains unclear. The present understanding
is that HPV establishes itself in the basal layer of the
mucosa."^"^ in which viral DNA enters the cell and is
transcribed into RNA; the RNA is. in tum. translated
into viral proteins. After infection of the stem cells.
the viral DNA either can be actively expressed or
can exist as a latent infection in mucosa that remains
clinically and histologically normal. During latency,
very little viral RNA is present. In fact. HPV DNA
can be detected in normal-appearing mucosa in patients with RRP who have been in retnission for years,
and its presence explains why reactivation and clinical recurrence can occur after many years of remission.^'^ Thus, reactivation of viral expression can occur at any time after establishment of a latent infection. Adult-onset respiratory papillomas could reflect
either activation of virus present since birth or an
From the Departments of Otolaryngology and Pediatrics. Eastern Virginia Medical School, and the Department of Pedialric Otolaryngokigy. Children's Hospital of The King's Daughters. Norfolk, Virginia.
Correspondence: Craig S. Derkay. MD. Depi of Ololaryngology. Eastern Virginia Medical School, 825 Fairfax Ave, Suite 510,
Norfolk. VA 23507.
Derkay A Darnnv, Rfcurrfrtl Respiratory Papillomatosis
infection acquired in adolescence or adult life.
The viral genome consists of three regions: an upstream regulatory region and the two regions named
according to the phase of infection in which they are
expressed: the early (E) and late (L) regions. The E
genes are involved in potent oncogcncs that arc responsible lor the replication of the viral genome, interaction with host cell intermediate filaments, and
transforming activities. The L region genes encode
the viral structural proteins.'"
Several factors are involved in the regulation of
cell proliferation. The virus must have a means to
reactivate the necessary host replication genes to facilitate its own DNA replication and must rely on
the host DNA replication mechanism. One growth
factor that is known to be associated with the proliferation of epithelial cells is the epidermal growth factor receptor. Human papillomavirus might induce epithelial proliferation by increasing the level of expression of epidermal growth factor receptor or its ligands. It may also induce cell proliferation by interacting with p53 or other tumor suppressor proteins.
inhibiting their normal functioning.
It is likely that the host immune system plays an
important role in the pathogenesis of HPV-induced
lesions. Both humoral and cellular immune responses
may be compromised in children with RRP. and a
patient's immunocompetence also may inOuence the
clinical course of disease. Both children and adults
with the acquired immunodeficiency syndrome or
congenital immunodeficiencies and patients on immune suppression after organ transplantation have
been identified with RRP." The role of cytokines
such as interleukin-2, interleukin-4, and interleukin10 and expression of the major histocompatibility
complex antigens in the malfunction of the celt-mediated immune response has been demonstrated in
children with RRP.'- Papillomas with a reduced expression of the.se antigens may evade immune surveillance and allow the disease to progress more rapidly.
EPIDEMIOLOGY
Recurrent respiratory papillomatosis may have its
clinical onset during either childhood or adulthood.
Although juvenile-onset RRP is generally more aggressive, adult-onset disease may occasionally be severe as well. Among children. RRP is the most common benign neoplasm of the larynx, and the second
most frequent cause of hoarseness.'-^
Incick'iicc. The true incidence and prevalence of
RRP arc uncertain. In a Danish subpopulation incorporating 50% of the population of that country, the
incidence of laryngeal papillomatosis was 3.84 cases
per 100.000.'•'The rate among children was 3.62 per
100.000; adult-onset cases occurred at a rate of 3.94
per 100.f)00. These figures are comparable with those
found in a US survey, which estimated an incidence
in the pediatric population of 4.3 per 100.000 children and 1.8 per 100.000 adults.' Armstrong et al'"^
estimated the incidence of new cases of juvenile-onset RRP at between 80 and 1.500 per year and a prevalence of between 700 and 3.000 active cases based
upon a 1999 epidemiological analysis of two US cities.
Recurrent respiratory papillomatosis may affect individuals of any age. The disease has been observed
in patients as young as 1 day of age and as old as 84
years.' Adult-onset RRP peaks between the ages of
20 and 40 years and has a slight male predilection.
Juvenile-onset RRP (arbitrarily defined as patients
with a diagnosis at less than 12 years of age) is most
often diagnosed between 2 and 4 years of age; 75%
of the children receive the diagnosis before their fifth
birthday."^Children with disease progression receive
the diagnosis at younger ages than those who remain
stable or become disease-free.'^The distribution
among boys and girls is approximately equal.'^
In most pediatric series, the diagnosis of RRP is
established an average of I year after the initial onset of symptoms.''*-^ Anecdotal observations suggest
that most patients arc firstborn, have young, primigravid inothers, and come from families of low socioeconomic status.'•"•^'
The universality of HPV in the lower genital tract
rivals that of any other sexually transmitted disease
in humans. It is estimated that at least 1 million cases
of genital papillomas occur per year in the United
States, affecting about 1% of the population.—These
most often manifest as condylomata acuminata involving the cervix, vulva, or other anogenital sites
in women or the penis of male sexual partners of
affected women. In addition, it is estimated that colposcopic (subclinical) changes affect nearly 5 million US women. An additional 14 million women,
or about 10% of the female population of child-bearing age. are DNA-positive but have no visible lesions; more than 80 million women, or 609? of the
at-risk population, are HPV antibody-positive but
DNA-negative. The incidence of HPV infection in
young, sexually active college women is high, with
a cumulative incidence of 43% over a 36-month period in a recent study.-^ Clinically apparent HPV infection has been noted in 1.5% to 5% of pregnant
women in the United States.^4 As in RRP, HPV 6
and 11 are the most common subtypes identified in
cervical condylomata.
Transmission. The precise mode of HPV transmis-
Dcrkdv & Darrow. Recurrenl Respirartiiy PupiUomatosis
sion remains unclear. Several studies have convincingly linked childhood-onset RRP to mothers with
genital HPV infections; among adults, circumstantial evidence suggests that the disease may be associated with oral-genital contact.
Retrospective and recent prospective studies have
confirmed that HPV may be passed by vertical transmission from mother to child.-•''"^^ In addition. Kashima et aP' found that patients with childhood-onset RRP were more likely to be firstborn and vaginally delivered than were control patients of similar
age. The researchers hypothesized that primigravid
mothers are more likely to have a long second stage
of labor and that the prolonged exposure to the virus
leads to a higher risk of infection in the firstborn child.
They also suggested that newly acquired genital HPV
lesions are more likely to shed virus than long-standing lesions, thus explaining the higher incidence of
papilloma disease observed among the offspring of
young mothers of low socioeconomic status, the same
group that is more likely to acquire sexually transmitted diseases such as HPV. Despite the apparent
close association between maternal condylomata and
the development of RRP. few children exposed to
genital wails at birth actually develop clinical symptoms.^**-^^ It is not well understood why RRP develops in so few children whose mothers have condylomata. The most likely method of maternal-fetal HPV
transmission is through direct contact in the birth canal. This would explain the clinical observation that
most children in whom RRP develops are delivered
vaginally to mothers with a history of genital condylomata.-^ Although HPV could be recovered from
the nasopharyngeal secretions of 30% of infants exposed to HPV in the birth canal,-^ the number of infants expected to manifest evidence of RRP is only a
small fraction of this. Clearly, other factors (patient
immunity; timing, length, and volume of virus exposure: and local trauma) must be important determinants of the development of RRP. Even though cesarean section would seem to reduce the risk of transmission of the disease, this procedure is associated
with a higher incidence of morbidity and mortality
for the mother and a much higher economic cost than
elective vaginal delivery. Shah et aP^ estimated that
the risk of a child contracting the disease from a
mother who has an active condylomatous lesion and
delivers vaginally is only about 1 in 400. The characteristics that differentiate this 1 child from the other
399 are elusive. In light of the uncertainty surrounding intrapartum exposure, there is presently insufficient evidence to support delivery by cesarean section for all pregnant women with condylomata.''-^"
However, there may be some benefit in managing
condyloma during pregnancy if it can be accom-
plished without increasing the miscarriage rate. Reports of neonatal papillomatosis suggest that in at
least some cases, development of the disease may
occur in utero. Because cesarean .section still does
not prevent the development of papillomatosis in all
cases, a better understanding of the risk factors associated with RRP is needed before the efficacy of
cesarean delivery in preventing papillomatosis can
be fully assessed. Discussion between the at-risk
mother and her obstetrician regarding the issue of
HPV transmission would seem appropriate.^'
Currently, a quadrivalent (HPV type 6. 11. 16. 18)
vaccine is undergoing phase III clinical studies. The
preliminary results regarding the HPV 16/18 vaccine
for prevention of cervical dysplasia in women of
child-bearing age were very encouraging.•'- If similar results were obtained with the quadrivalent vaccine, one might expect to see a reduction in the susceptibility of neonates to the virus among vaccinated
mothers.
HISTOLOGY
Histologically. RRP appears as sessile or pedunculated masses, pink to white in color, that often occur in irregular exophytic clusters (Fig l).The masses
consist of fingerlike projections of nonkeratinized
.stratified squamous epithelium supported by a core
of highly vascularized connective tissue stroma (Fig
2). The basal layer may be either normal or hyperplastic, and mitotic figures are generally limited to
this layer. Cellular differentiation appears to be abnormal, with altered expression and production of
keratins. The degree of atypia may be a sign of premalignant tendency. Malignant transformation of
RRP into squamous cell carcinoma has been documented in several case reports.
The RRP lesions occur most often at anatomic sites
in which ciliated and squamous epithelium are juxtaposed.^^ The most common sites for RRP are the
limen vestibuli of the nose, the nasopharyngeal surface of the soft palate, the midline of the laryngeal
surface of the epiglottis, the upper and lower margins of the ventricle, the undcrsurface of the vocal
folds, the Carina, and bronchial spurs.-' Areas of transition from ciliated respiratory epithelium to native
or metaplastic squamous epithelium are commonly
involved, as in patients with tracheotomies, in whom
RRP is often encountered at the stoma and in the
midthoracic trachea. Similarly, children with bronchopulmonary dysplasia, in whom prolonged cndotracheal intubation may result in interruption of the
continuous respiratory mucosal surface, also may be
at increased risk for the development of RRP. Injury
to the respiratory mucosa may also explain the observation that RRP flourishes in the presence of un-
Derkay & Darrow. Recurrent Respiratorx PapUiomalo.iis
hoarseness may present somewhat later. Stridor is
often the second clinical symptom to develop, beginning as an inspiratory noise and becoming biphasic
with progression of the disease. Less commonly,
chronic cough, recurrent pneumonia, failure to thrive,
dyspnea, dysphagia, and acute life-threatening events
may be the presenting symptoms.
Fig 1. Sessile papilloma lesions involving true vocal
folds.
controlled gastroesophageal reflux, with an increased
incidence of laryngeal scarring.•*-^ Iatrogenic implantation of papilloma may be preventable by avoiding
injury to nondiseased squamous or ciliated epithelium adjacent to areas of frank papilloma.
CLINICAL PRESENTATION
Although histologically the same lesion, a papilloma that produces hoarseness in one patient may
produce stridor and obstruction in another, depending on the size and location of the lesion. Children
with RRP most often present with some degree of
dysphonia. Because of the preci.sion of laryngeal mechanics, hoarseness may result from a remarkably
small lesion and thus may be an early sign in the
course of the disease process. On the other hand, if
the origin of the lesion is remote from the vocal folds.
Because hoarseness in children is common and
RRP is rare and slowly progressive, many cases are
not recognized until respiratory distress results from
papillomas obstructing the airway. Symptoms are
typically present for a year before a diagnosis of RRP
is made. Not uncommonly, children are treated for
asthma, croup, allergies, vocal nodules, or bronchitis before a definitive diagnosis is arrived at.
A comprehensive medical history is critical in order to determine risk factors for papiilomatosis and
any comorbidities. Information regarding the time of
onset of symptoms, prior airway trauma, including a
history of previous intubation, and characteristics of
the voice or cry is obviously important. A history of
progressive in.spiratory or biphasic stridor also suggests an expanding lesion of the glottis or subglottis.
Although stridor that has been present since birth is
more often associated with congenital airway anomalies, it should be realized that neonates also can present with papiilomatosis. Associated symptoms such
as feeding difficulties, allergic symptoms, vocal abuse,
and the presence of hereditary congenital anomalies
may help distinguish RRP from other diagnoses, including vocal fold nodules, vocal fold paralysis, subglottic cysts, subglottic hemangioma, and subglottic
stenosis. In addition, parents should be que.stioned
about any history of maternal or paternal condylomata. If the onset of stridor and dysphonia is gradual
and progressive over weeks or months, then neoplastic growth compromising the airway must be consid-
Fig 2. Histologic section of papilloma
demonsiraies fingerlikc projcclion of
nonkeralinized stratified squamous epithelium and vascularizcd connective tissue stroma. This was sessile papilloma
lesion that involved true vocal fold.
Derkay & Darrow. Recurrenl Respiratory PapiUomatosis
ered and investigated.
PHYSICAL EXAMINATION
Children who have symptoms consistent with RRP
should undergo a thorough and organized physical
examination. The physician should assess the child
for tachypnea or signs of distress or fatigue that may
indicate impending respiratory collapse, such as flaring of the nasal ala and the use of accessory neck or
chest muscles. In the most acute cases, increasing
cyanosis and air hunger may cause the child to sit
with the neck hyperextended in an attempt to improve airflow. In such cases, additional examination
should not be undertaken outside the operating room,
the emergency room, or the intensive care unit, in
which resuscitation equipment for intubation of the
airway, endoscopic evaluation, and possible tracheotomy are readily available. In a stable, well-oxygenated child, additional examination ean proceed. Auscultation with the aid of a stethoscope over the nose.
open mouth, neck, and chest may help localize the
site of the respiratory obstruction. In small children,
the airway is best examined by pulling the bell off
the stethoscope and listening with the open tube.
Pulse oximetry can add an accurate quantitative analysis of the child's respiratory status.
In most cases, the diagnosis of RRP can be made
definitively by flexible fiberoptic nasopharyngoscopy and laryngoscopy. The procedure is useful in
establishing the extent of involvement, the urgency
of operative intervention, and the potential for airway compromise in the operating room, and should
include careful, sequential inspection of the na.sopharynx, oropharynx. hypopharynx, and supraglottic and
glottic larynx. Although examination under spontaneous ventilation affords the best assessment of airway dynamics, endoscopy under anesthesia in the operating room is warranted in any child in whom RRP
is suspected who cannot be fully examined in the
outpatient setting because of poor cooperation or
equipment limitations.
STAGING
Several scoring and staging systems for RRP have
been proposed to aid in tracking the progression of a
patient's disease, communicating with other surgeons, and treating patients in a protocol format. Although no staging system has been uniformly adopted
by clinicians and researchers, one such system numerically grades the extent of papillomatosis at defined aerodigestive subsites, assesses functional parameters, diagrammatically catalogs subsite involvement, and assigns a final numeric score to the patient's current extent of disease (see Table^^''). Using
software designed at the University of Washington
(Seattle) and licensed to the American Society of Pediatric Otolaryngology f ASPO), this staging system
is now computerized and available to pediatric otolaryngologists and bronchoesophagologists. Use of encryption technology with this software will eventually allow clinicians from around the world to anonymously share their patients" data, thereby enhancing
our knowledge of this disease and its treatment
through multi-institutional investigations while protecting patient confidentiality.
MANAGEMENT
Approaches to Surgery. Once the diagnosis of RRP
has been made, the clinician must determine the urgency for surgical debridement of the papillomas.
Because there is currently no therapeutic regimen that
completely eradicates HPV from the airway, the aims
of therapy in extensive disease should be to reduce
tbe tumor burden, decrease the spread of disease,
create a safe and patent airway, improve voice quality, and increase the time interval between surgical
procedures. Even with the removal of all clinically
evident papilloma. latent virus may remain in adjacent tissue, which may explain the recurrent nature
of RRP. Therefore, it is prudent to accept some residual papilloma rather than risking spread of disease or damage to normal tissue and excessive scarring. Ideally, the procedure should be performed before the lesions become so large or numerous that
the patient is in respiratory distress; conversely, shortening the interval between surgeries may place the
patient at more risk for complications from anesthesia, web formation, stenosis, and fibrosis in the larynx.
It is incumbent upon the surgeon to discuss with
the anesthesiologist before the operation the means
by which anesthesia will be delivered and by which
the patient will be ventilated during the procedure.
Most otolaryngologists prefer to remove gross disease with an endotracheal tube in place, followed by
extubation and apneic excision. When the laser is
used, initial placement of a laser-safe endotracheal
tube is required. Apneic excision with the patient extubated is useful in removing smaller and more posterior lesions that are poorly visualized with an endotracheal tube in place. This technique, however, may
require intermittent interruption of the surgery for
reinsertion of the tube and ventilation of the patient.
Alternatively, the procedure may be performed under spontaneous ventilation or Venturi jet ventilation.
Until recently, the laser had been favored over cold
instruments in the treatment of RRP involving the
airway.' Light from the carbon dioxide (CO2) laser
is absorbed by water in tissues, resulting in controlled
destruction and cauterization of tissue surfaces. When
Derkay & Darrow. Recitrrenl Respiratory Papillomatosis
COLTRERA-DERKAY STAGING AND SEVERITY SCHEME'^
Clinical Score
Describe the patient's voice today:
normal
(0). abnormal
(I). aphonic
(2)
2. Describe the patient's stridor today:
abseni
{.{)). present with activity ,(1), present at rest
(2)
.1.
Describe the urgency of today's intervention:
scheduled, _|O). elective
(1), urgent
(2). emergent
(3)
4. Describe loday's level of respiratory distress:
none
(0), mild .(1), moderate. (2), severe
(3), extreme
(4)
Total Clinical Score (Questions 1 through 4) =
B. Anatomical Score
For each site, score as: 0 = none, 1 = surface lesion. 2 = raised lesion, ?• = bulky lesion
LARYNX:
Epiglottis:
Lingual surface
Laryngeal surface
Aryepiglottic folds:
Righl
Left
False vocal cords:
Right
Left
True vocal cords:
Right
Left
Arytenoids:
Right
Left
Anterior commissure.
Posterior commissure
Subglottis
TRACHEA:
Upper one-third
Middle one-third
Lower one-third
Bronchi:
Right
Left
Tracheotomy stoma
OTHER:
Nose
Palate
Pharynx
Esophagus
Lungs
Oiher
Total Anatomical Score
C. Total Score = Total Anatomical Score plus Total Clinical Score
coupled to an operating microscope, the laser vaporizes the lesions with precision, reducitig collateral
tissue damage, bleeding, and scarring. The newest
generation of laser microspot micromanipulator enables the surgeon to debulk papilloma initially in a
defocused mode and then focus to a 250-nm spot
size to excise papillomas from potentially problematic areas, such as the anterior and/or posterior commissure and true vocal folds. Although their absorption characteristics are less favorable, the potassium
litanyl phosphate (KTP) laser and the argon laser are
also used occasionally, especially in cases in which
fiber-delivered laser light is preferable.
A recent survey of members of the ASPO found
that the microdebrider is now favored over the use
of laser and cold steel microlaryngoscopy techniques.-^''The technique uses a small, protected oscillating blade coupled to suction, which allows pap-
illomas to be brought into the blade for shearing and
removal. Several recent prospective and retrospective reviews have demonstrated that patients whose
papillomas were treated with tbe microdebrider experienced a shorter operating time, less pain, and less
expense than did patients treated with the laser.-^^-*^ This technique may also be less likely to
cause laryngeal scarring than the CO2 laser.
Cold steel excision involves the lowest risk of scar
formation in the true vocal folds, and can be used
successfully by adherence to the principles of phonomicrosurgery, submucosal infusion, and microinstrumentation. This approach may have treatment advantages over CO2 laser surgery, especially in adult patients with RRP.^'*-^'*Zeitels and Sataloff"^" reported
no papilloma recurrence at 2 years of follow-up
among 6 adults who underwent resection for primary
disease. Of those who underwent surgery for recur-
Derkay & Dctrrow. Recurrent Respiratory Ptipillomtilosi.s
rent papillomatosis, 6 of 16 (38%) continued to have
recurrence after their microtlap procedure."**' The
Voice Committee of the American Academy of Otolaryngology-Head and Neck Surgery pronounced in
2002 that cold steel excision is the preferred technique for adults with RRP.-*'
Several puhlications have highlighted the potential benetUs of alternative surgical technologies in
managing RRP. Bower et al"*^ evaluated the feasibility and safety of the flash pump dye laser in 9 children and found good early results. McMillan et aH^
publi.shed preliminary results regarding their positive experience with the 585-nm pulsed dye laser in
3 patients. Bergler et aH"* reported on the successful
use of arg(m plasmacoagulation to treat a 3-year-old
with recalcitrant RRP.
Revision Surgery. No surgical technique has consistently accomplished long-term eradication of RRP.
As a result, most patients with RRP make numerous
trips to the operating room for surgery to maintain
the patency of the airway and improve vocal quality.
A national RRP registry, composed of children from
the clinical practices at 22 pediatric otolaryngology
sites (arguably a skewed population of more severely
affected children), contains a mean lifetime numher
of procedures of 19.7 per child, with an average of
4.4 procedures per year.'^ Children in whom RRP
was diagnosed hefore 3 years of age were found to
be 3.6 times more likely to require more than 4 surgical procedures per year, and 2.1 times more likely
t(i have 2 or more anatomic sites involved than those
in whom RRP was diagnosed after their fourth birthday.-'^ There were no apparent differences in surgical frequencies by gender or ethnicity.'^ Other investigators have also found that younger children are
more likely to have persistent disease and more often experience an increased number of surgeries in
the first year after diagnosis."^"^
The reoperation rate among adults has also been
studied in a survey of practicing otolaryngologists
in the United States.' Whereas more than 75% of
children required 5 or more procedures over their
lifetime, only 50%; of adults required the same frequency of surgery. Approximately equal percentages
of children and adults (17% of children versus 19%
of adults) had aggressive RRP requiring more than
40 lifetime operations, although adults had more
years to accumulate these operations.'
Tracheotomy. In patients with aggressive RRP and
in those who do not have easy access to medical care
in an airway emergency, tracheotomy may be desirable. However, it has been suggested that prolonged
tracheotomy, and the presence of subglottic papilloma at the time of tracheotomy, may be associated
with an increased risk of distal tracheal spread. Cole
et aH^ reported that tracheal papillomas developed
in half of their tracheotomy patients, and that despite attempts to avoid this procedure, 21% of their
patients still required long-term tracheotomy. Conversely, Shapiro et aH^ noted that RRP tracheotomy
patients presented at a younger age and with more
widespread disease, often involving the distal airway before tracheotomy. In their experience with 13
patients, they did not feel that tracheotomy itself led
to spread of disease outside the larynx. In the Centers for Disease Control and Prevention (CDC) registry, children with tracheotomy received the initial
diagnosis of RRP at a younger age (2.7 years) than
did those without tracheotomy (3.9 years).'' Although
the risk of tracheotomy remains controversial, most
researchers agree that it is a procedure to be avoided
unless absolutely necessary. When tracheotomy is unavoidable, decannulation should be considered as soon
as the disease is managed effectively with endoscopic
techniques.
PROGRESSION
Extralaryngeal spread of respiratory papillomas
has been identified in 13% to 30';^ of children and in
16% of adults with RRP.'-^*'The most frequent sites
of extralaryngeal spread are. in order of frequency,
the oral cavity, the trachea, and the bronchi.' In a
recent review of the experience at 3 academic medical centers, 12% of children with RRP had distal
tracheal spread of their disease and 7% had pulmonary dissemination. One common thread in the children with distal spread was the use of jet ventilation
anesthesia techniques in the surgical management of
their disease.''^
Half of the respondents in a recent ASPO survey
of practices in the United States related at least 1
death from RRP within their practice. ^^ When death
occurs, it usually is associated with a complication
of frequent surgical procedures or is caused by respiratory failure due to distal disease progression. Recurrent respiratory papillomatosis presenting in the
neonatal period is thought to be a negative prognostic factor, with a greater likelihood of death and need
for tracheotomy.
ADJUVANT TREATMENT METHODS
Although surgical management remains the mainstay of therapy for RRP. ultimately as many as 20%
of patients with the disea.se will require some form
of adjuvant therapy.-^'' The most widely adopted criteria for initiating adjuvant therapy are a requirement
of more than 4 surgical procedures per year, distal
multisite spread of disease, and/or rapid regrowth of
papilloma disease with airway compromise.
Derkiiy & Darrow. Recurrent Respiratory Papillomotosis
Cidofovir (Vistide) is a nucleoside analog that has
antiviral activity against the herpesvirus family and
is approved by the US Food and Drug Administration
for the treatment of c y to meg alo virus retinitis in patients with human immunodeficiency virus disease.
It has also been shown to induce apoptosis in HPVpositive cells.'*'' Snoeck et al'^" demonstrated a complete initial clinical response in 14 of 17 adult patients with laryngeal RRP who had local injection of
cidofovir, and 10 of the 14 remained disease-free.
Although Pransky et ai'''"''-^ were unable to reproduce
these results in terms of complete responses, they
were able to markedly improve the airway and increase the interval time between surgical procedures
in 10 children severely affected by RRP without the
development of significant adverse events. Off-label
use of cidofovir to treat RRP has become the most
commonly used adjuvant therapy, '^ despite an alarming lack of well-controlled studies to demonstrate its
safety and efficacy. Animal studies have rai.sed the
possibility of nephrotoxicity and carcinogenesis at
doses currently used in humans. Additionally, in pediatric patients, the drug requires repeated infiltration into the larynx under general anesthesia, which
raises the risk of airway compromise and increases
the cost and potential morbidity of this therapy. In
adults, office use of cidofovir in less severely affected
patients is gaining favor. Reports of its use in small
cohorts of patients by Chhetri et al.''"* Bielamowicz
et al,-^'' and Co and Woo''*' have all been favorable,
citing minimal side effects in select groups of adult
patients.
Interferons are a class of proteins that are manufactured by cells in response to a variety of stimuli,
including viral infection. The enzymes that are produced block the viral replication of RNA and DNA
and alter cell membranes to make them less susceptible to viral penetration. When used to treat RRP,
a-interferon therapy is initiated at 5 million units per
square meter of body surface area administered by
subcutaneous injection on a daily basis for 28 days
and then 3 days per week for at least a 6-month trial.
After 6 months in children with excellent responses,
or if side effects are severe, the dosage can be decreased to 3 million units per .square meter administered 3 days per week, with further slow weaning as
tolerated. Common interferon side effects fall into
two categories: acute reactions (fever and generalized flulike symptoms, chills, headache, myalgias,
and nausea, which seem to decrease with prolonged
therapy) and chronic reactions (decrease in the growth
rate of the child, elevation of liver transaminase levels, leukopenia, spastic diplegia. and febrile seizures).
Thrombocytopenia has been reported, as have rashes,
dry skin, alopecia, generalized pruritus, and fatigue.
Acetaminophen has been found to effectively relieve
the fevers, and interferon injections are best tolerated at bedtime. Interferon produced by recomhinant
DNA techniques appears to have fewer side effects
and better efficacy than blood bank-harvested interferon.
Photodynamic therapy in the treatment of RRP has
been studied extensively at Long Island Jewish Hospital by Shikowitz et aL""^ Photodynamic therapy is
based on the transfer of energy to a photosensitive
drug. The original drug used was dihematoporphyrin
ether (DHE). which has a tendency to concentrate
within papillomas more than in surrounding normal
tissue. Patients are typically treated intravenously
with 4.25 mg/kg of DHE before photoactivation with
an argon pump dye laser. A small but statistically significant decrease in RRP growth, especially in those
patients with the worst disease, was seen with the
use of photodynamic therapy and DHE. The drawhack of this therapy is that patients become markedly photosensitive for 2 to 8 weeks. A new drug, mtctra (hydroxyphenyl) chlorine (Foscan, Scotia Holdings, London, England), has shown efficacy in HPVinduced tumors in rabbits with minimal tissue damage and less photosensitivity. A parallel arm, randomized trial with a single photodynamic therapy has recently been completed in 23 adults and children who
had required surgery at least 3 times a year. Only 5
of 15 patients who completed the study achieved remission, and several of these experienced recurrences
after 3 to 5 years.
Recent interest has focused on chemically pure indole-3-carbinol (13C), a dietary supplement not approved by the US Food and Drug Administration,
which has been shown to inhibit papilloma formation in mice."^^ This compound is found in high concentration in cruciferous vegetables such as cabhage,
broccoli, and cauliflower. A small dietary study at
Long Island Jewish Hospital (unpublished observations) showed promise, although there were concerns
regarding how much active drug the patients were
actually receiving. Indole-3-carbinol is now available in pure chemical form, and a clinical trial centered at the University of Pittsburgh demonstrated
cessation of papilloma grow th in 6 of 18 patients who
were given the medication and a reduced papilloma
growth rate in another 6 individuals.'''^ Six patients
showed no clinical response to 13C. There are some
concerns regarding whether the pure 13C will maintain its effectiveness when taken with antacids or histamine (H2) blockers; a new product. Phytosorb-DIM
(BioResponse, Boulder, Colorado), is purported to
overcome this limitation.
Rihavirin, an antiviral drug used to treat respira-
Derkay >& Darrow. Recurrent Respiratory Papillomatosis
tory syncytial virus pneumonia in infants, has also
shown some promise in the treatment of aggressive
laryngeal papillomatosis. McGlennen et aK'" at the
University of Minnesota completed a small trial in 8
patients using ribavirin in an oral form at 23 mg/kg
per day divided 4 times daily after an initial intravenous loading dose. An increase in surgical interval
was seen in those treated.
Another antiviral treatment that has been advocated in the treatment of RRP is acyclovir. Although
the activity of acyclovir is dependent on the presence of virally encoded thymidine kinase. an enzyme
that is not known to be encoded by papillomavirus.
conflicting clinical results have been obtained in several small .series. It has been postulated that in those
cases in which acyclovir has been effective, co-disease factors su.sceplible to the drug may be present.
Viral coinfections with herpes simplex virus type I,
cytomegalovirus, and Epstein-Barr virus have been
demonstrated in patients with RRP. and adult patients
with viral coinfections appear to have a more aggressive clinical course.*''
Optimal control of extraesophageal reflux disease
has been advocated as a means of improving patient
outcomes along with surgical therapy. In a prospective evaluation of 31 children with RRP. antireflux
treatments in patients who were undergoing surgery
for laryngeal RRP reduced the soft tissue complications, especially scarring and web formation. Prophylactic antireflux therapy may be warranted in any patient who undergoes surgery during which laryngeal
mucosal disruption is anticipated.^^"*
Heat shock protein {Hsp) E7, a recombinant fusion protein of Hsp65 from Mycohacterium hovis
BCG and E7 protein from HPV 16, is under development for treatment of HPV-related diseases.^- In a
study conducted in 8 university-affiliated medical
centers, 27 children were enrolled and followed up
to 60 weeks. Before enrollment, these patients required surgery at an average interval of 55 days. After a baseline debulking surgery, patients received 3
doses of HspE7 500 jig subcutaneously 30 days apart.
Treated patients demonstrated a longer mean first
posttreatment intersurgica! interval (ISI; 106 days; p
< .02), a longer median ISI forall surgeries (107 days;
p < .02). and a significant decrease in the number of
required surgeries (p < .003). Unexpectedly, the treatment effect was most striking in the 13 female patients, with statistically significant increases in both
first posttreatment ISI (142%; p < .03) and median
ISI(l47%;p<.03).
OTHER CONSIDERATIONS
Children in whom RRP is newly diagnosed 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 (www.rrpf.org; PO Box
6643, Lawrenceville, NJ 08648-0643) and the International RRP ISA (www.rrpwebsite.org; PO Box
30821, Seattle, WA 98113-0821) can be a vital resource for information and support.
Patients with RRP require frequent office visits
and endoscopic procedures at the out.set to e.stablish
the aggressiveness of their di.sease. 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. Repeat flexible fiberoptic laryngoscopy
may be useful in the office setting, although it is reasonable to return to the operating room with children whose symptoms have recurred once the diagnosis has been established. Speech and language therapy consultation should be obtained early in the course
of tbe disease. Control of comorbidities such as reflux and asthma should be aggressively pursued.
U should be stressed that participation in national
and regional protocols of adjuvant treatment methods is essential for the scientific community to learn
more about RRP. A national registry of patients with
RRP has been formed through the cooperation of the
ASPO and the CDC. '^ The registry has tracked more
than 600 children at 22 sites, and has data on more
than 11,000 surgical procedures. It is hoped that the
national registry will aid in the identification of patients suitable for enrollment in multi-institutional
studies of adjuvant therapies and will help better define the risk factors for transmission of HPV and the
cofactors that may determine the aggressiveness of
RRP
A multicenter initiative organized through the RRP
Task Force is currently ongoing in an attempt to identify the host genes that govern susceptibility to
RRP*"^ It is hoped that by determining tbe bost genes
that govern susceptibility, we will enhance our understanding not only of RRP but also of host-viral
interaction in general. Ultimately, this may lead to
additional innovative treatment methods.
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