Recurrent Respiratory
Papillomatosis
Ryan W. Ridley, MD
Jing Shen, MD
University of Texas Medical Branch
Department of Otolaryngology
Grand Rounds Presentation
June 25, 2008
History
• Sir Morrell Mackenzie
(1837-1892) was the first
to identify papillomas as
a lesion of the laryngo-
pharyngeal system in
children in the late 1800s
• In the 1940s, Chevalier
Jackson (1865-1958)
coined the term “juvenile
laryngeal papillomatosis”
• HPV demonstrated in
laryngeal papillomas of
pts with juvenile RRP in
1982.
Chevalier Jackson
Sir Morrell Mackenzie
Introduction
• Most common benign neoplasm of the larynx among children
– 2nd most common cause of pediatric hoarseness
• Causes exophytic airway lesions
• May involve entire aerodigestive tract
• Morbidity due to airway involvement and risk of malignant conversion
• Viral etiology
• 2 forms: Juvenile & Adult
Etiology
• HPV
– DNA virus
• 7,900 bp long dsDNA
– Nonenveloped,
icosahedral
– HPV type 6 and 11
• Also cause genital warts
• Type 11= more severe
– Other types identified
• Type 16 and 18 (most
malignant potential)
• Type 31 and 33
(intermediate malignant
potential)
Transforming abilities
Viral capsid
proteins
Viral replication
& transcription
Viral release
Etiology cont’d
• HPV infection process initiates in basal layer
– Viral DNA enters the cell
– DNA then transcribed into RNA
– RNA translated into viral proteins
• 3 regions in genome:
– URR
– Early genes (E)
» Involvement in oncogenes
» Replication of viral genome
» Transforming activity
– Late genes (L)
» Blueprints for viral structural proteins
Etiology cont’d
• Host immune response thought to play a
role
– Humoral/cellular immune responses may
be compromised in pts with RRP
• Malfunction of cell mediated response
associated with cytokines and MHC
antigens
–Certain papillomas have a stealth-
like effect on immune surveillance
due to reduced antigen expression
Etiology
• HPV infection can be actively expressed or latent
– Can remain clinically and histologically normal
• HPV DNA detected in the normal mucosa of
RRP patients in remission
– Reactivation can occur at any time!
• AORRP could be:
– Activation of latent virus acquired since birth
– Activation of infection contracted during adult
life/adolescence
RRP Lesion Characteristics
• Histological description
– Appears as finger-like projections of nonkeratinized stratified squamous epithelium with highly vascularized connective tissue stroma at the core.
• Gross description
– Sessile or pedunculated
– Irregular exophytic clusters
– Pinkish to white color
Finger-like projections
Core of vascularized
Connective tissue stroma
Lesion Characteristics (cont’d)
• Most often occur at sites where ciliated and squamous epithelium are juxtaposed
• Most common RRP sites:
– Limen vestibuli
– Nasopharyngeal surface of soft palate
– Laryngeal surface of epiglottis
– Upper/lower margins of ventricle
– Undersurface of vocal folds
– Carina
– Bronchial spurs
Pruess et al. Acta Oto-Laryngologica, 2007; 127: 11961201
Lesion Characteristics
• Ciliated epithelium in response to repetitive
trauma will undergo squamous metaplasia
– Iatrogenic
• Tracheotomy pts
–RRP often located at
mucocutaneous junction and mid-
thoracic trachea
– Uncontrolled GERD/LPR
• RRP exacerbated these processes
Epidemiology
• Childhood onset
– Often dx 2-4 yrs old
– boys = girls
– No gender/ethnic
difference regarding
surgical frequency
– More aggressive
– 19.7 surgeries per child
• 4.4 per year
• Adult onset
– Peaks btwn 20-40 yrs
– Slight male
predominance
– Less aggressive
– 50% pts need < 5
procedures over their
lifetime as opposed to
<25% of children who
can say the same
Transmission
• Exact mode of transmission unclear
• Childhood disease linked to mothers with
genital HPV infection
– Pts most likely to be first born, vaginally
delivered to primigravid mothers
• Adult-onset RRP possibly associated with
oral-genital contact.
Transmission
• Although there is close relationship btwn CORRP and maternal condylomata, few pts exposed to genital warts at birth manifest clinical symptoms.
– Not well understood why this is the case
• Direct contact via the birth canal is the most likely method of maternal-fetal transmission of HPV
– The majority of children with RRP development are born to mother with a history of genital condylomatas
• Exposure to genital lesions alone is not enough to explain transmission, other factors must play a role
– Pt immunity
– Time/volume of virus exposure
– Local tissue trauma
Cesarean Section?
• Seems to be an obvious risk reducer for
RRP transmission, but…
– Higher morbidity and mortality for the mother
– Higher cost compared to vaginal delivery
– Approx. 1 in 400 children delivered vaginally to mothers with active condylomatous lesions will contract RRP.
– Few cases have reported in utero development
of the disease
Take home point: Presently, not enough evidence to warrant C-
section in all pregnant mothers with condylomata.
Clinical Features
• Hallmark triad:
– Progressive hoarseness
– Stridor
– Respiratory distress
• Most often present with dysphonia
– Stridor is usually 2nd symptom to manifest
• Inspiratory biphasic
• 1 year = duration of sx prior to diagnosis
RRP “The Great Masquerader”
• RRP often
misdiagnosed as:
– Asthma
– Croup
– Tracheomalacia
– Allergies
– Vocal nodules
– bronchitis
Clinical Features
• Extralaryngeal spread of papillomas
– 13-30% children and 16% adults
– Most frequent sites
• Oral cavity
• Trachea
• bronchi
Patient Assessment
• History (aka “The Interrogation”)
– Onset of symptoms?
– History of airway trauma/previous intubation?
– Rate of progression?
– Associated infection?
– How is the cry?
– Presence of respiratory distress?
Patient Assessment
• Voice characteristics
– Low-pitched, coarse, fluttering voice =
subglottic lesion
– High-pitched, cracking, aphonic, or breathy =
glottic lesion
***Hoarseness ALWAYS indicates some
abnormality in structure/function
***Neonates CAN present with papillomatosis
Patient Assessment
• Ask about perinatal period/STD history
– You may uncover history of parental
condylomata/HPV
• Alternative Dx to think about:
– Vocal cord nodules
– Tracheomalacia (stridor since birth)
– Vocal cord paralysis
– Subglottic cysts
– Subglottic hemangioma
– Subglottic stenosis
Patient Assessment
• Physical Exam – Respiratory rate/degree of distress
• Nasal ala flaring
• Use of accessory neck & chest muscles
– Cyanosis/air hunger
• Child may be sitting with hyperextended neck
***If child is very sick, examination should be performed in setting where resuscitation/endoscopic equipment is READILY available (i.e. OR, ER, ICU)
Patient Assessment
• Physical exam
– Auscultation of airway with stethoscope
– Airway endoscopy needed for definitive
diagnosis
• Flexible fiberoptic at bedside (consider
pt cooperation/age!)
• Exam under anesthesia (esp. if pt
won’t cooperate)
Malignant Transformation
• Estimated to occur in
1-7% of patients with
RRP
• Occurs in those
patients with advanced
disease, usually
pulmonary extension
• Third or fourth decade
of life
• Lesions contain HPV
type 11 as opposed to
type 6
• Gerien et al
– average duration of RRP until malignant transformation lies within a range of approximately 19-35 yrs
– Time period from pulmonary extension dx until malignant transformation approximately 9-21 yrs
Treatment Modalities
• Surgical
– Microlaryngoscopy
with cups forceps
removal
– Microdebrider
– CO2 laser
– Phono-Microsurgical
– KTP/Nd:YAG laser
– Flash scan lasers
• Adjuvant
– α-Interferon
– Indole-3-carbinol
– Photodynamic therapy
– Cidofovir
– Acyclovir
– Ribavirin
– Retinoic acid
– Mumps vaccine
– Methotrexate
– Hsp E7
Microdebrider vs. CO2 Laser
• CO2 laser has been instrument of choice since 1970s
– Excellent hemostatic ability
– Precision
– Cons:
• Risk of laser fire
• Increased cost
• Potentially increased procedure time
• Microdebrider is now replacing laser
– Avoidance of thermal injury and fire
– Precision
– Same qualities of laser except faster with possibly less cost
Microdebrider vs. CO2 Laser
• Randomized
prospective study
– 19 patients randomized
into microdebrider or
laser group
• Compared:
– Pt discomfort (5 pt
scale)
– Voice quality (10 pt
scale)
– Procedure time
– Cost
Pasquale, et al. Microdebrider Versus CO2 Laser
Removal of Recurrent Respiratory Papillomas:
A Prospective Analysis. Laryngoscope 2003;113: 139-43
vs
Microdebrider vs. CO2 Laser
• Results:
– For disease of equal severity:
• Microdebrider assoc. with equal pain score 24hrs
post-op
• Microdebrider group rated better voice quality
• Microdebrider had shorter procedure times
• Microdebrider use resulted in lower procedure cost
• Conclusion
– Microdebrider may be as safe and at some institutions,
more cost-effective than CO2 laser removal.
24 Hour Post-op Pain Scores
Voice Quality
Procedure Time
Cost
Important to Note…
• The choice to use microdebrider vs. CO2 laser not only depends upon the aforementioned factors (cost, procedure time, pain, etc.) but also, the characteristics of the lesions
– i.e. Some lesions may be more sesssile in appearance and be safest to remove using CO2 laser.
– Ultimately, the surgeon must decide which surgical modality will yeild the best result in each circumstance and not merely subscribe to trends found in the literature.
Adjuvant Treatments: Antivirals
Note: Cochrane database review of antivirals as adjuvant treatment of RRP
was unable to identify randomized controlled trials with subsequent
conclusion that insufficient evidence exists about the efficacy of their use.
Soma and Albert. Current Opinion in Head and Neck Surgery 2008, 16:86-90
Cidofovir
• First intralesional use for RRP was by Snoeck et
al in 1998.
• Most commonly used adjuvant therapy in the
treatment of pediatric RRP according to the
American and British Societies of Pediatric
Otolaryngology (ASPO and BAPO)
• Approx 10% of patients undergoing treatment for
RRP are receiving intralesional cidofovir (in
addition to surgery)
Cidofovir Mechanism of Action
• Cytosine nucleoside
analogue
– Incorporated in
growing viral and
mammalian DNA
chains
– Inhibits viral DNA
polymerization
– Antiviral effect lasts
for days-weeks
– Not known if cidofovir
is more active against
specific HPV subtypes
Risks of Cidofovir
• FDA approved only for CMV retinitis in AIDS pts
– Current use for RRP is “off label”
• Nephrotoxicity associated mostly with intravenous use
• Shown to be carcinogenic in rodent studies but no tumors detected in primate studies
• Recently, there have been case reports, although scant, of malignant transformation associated with cidofovir use for RRP in humans, but no randomized, double blind, placebo controlled trials to substantiate this.
“Antiviral agents for the
treatment of recurrent respiratory
papillomatosis: A systematic
review of the English-language
literature”
Chadha and James. Otolaryngology-
Head and Neck Surgery (2007) 136,
863-869
Chadha & James
• Objective: determine
efficacy of antiviral
agents in RRP
• Design: systematic
review
• Results:
– No RCTs
– Meta-analysis not
possible
– Strongest evidence was
for intralesional
cidofovir
• Cidofovir
– 57% pts with complete
resolution, 35% with
partial response, 8%
with no response
• Conclusions
– Insufficient evidence
from controlled trials
to make reliable
conclusions.
– Placebo-controlled,
double-blinded,
randomized controlled
trial is needed.
RRP Taskforce Recommendations
on Cidofovir
• Should be routinely offered as a treatment option
in moderate-severe cases of RRP patients.
– Frequent surgery, airway compromise, poor
communication/voice, pts who would otherwise be
considered for tracheostomy
• Should be discouraged in patients with mild
disease until results of long term use established.
• Informed consent obtained prior to use
• Adverse responses (i.e. dysplasia/malignancy)
should be reported
Acyclovir
• Actual benefit derived
from action against
co-infectors (i.e. HSV,
EBV, CMV)
• 3 small case-series
– disease-free periods
range from 14-42mos
– True efficacy can’t be
determined due to lack
of controlled studies
Chadha and James. Otolaryngology-Head
and Neck Surgery (2007)
Ribavirin • 1 case series, 1 case
report in literature
– 5 patients
demonstrating
complete remission
at 2-4 mos f/u.
• Ability to assess
efficacy due to lack of
controlled studies
• Toxicity: anemia,
reticulocytosis,
headache, fatigue
Chadha and James. Otolaryngology-Head and
Neck Surgery (2007)
Interferon • Binds to specific membrane
receptors altering cell
metabolism
– Antiproliferative
– Antiviral
– Immunomodulatory
• Exact action against RRP
unknown
• Healy, et al 1988
– Multicenter controlled
study with 123 pts.
– Demonstrated decrease
in disease progression in
the 1st 6 mos but effect
was unsustained
Tasca and Clarke. Recurrent Respiratory
Papillomatosis. Arch. Dis. Child. 2006; 91;689-691
Indole-3-carbinol
• Abundant in
cruciferous
vegetables
• Affects papilloma
growth in vitro via
modulation on
estrogen
metabolism
Indole-3-Carbinol for Recurrent
Respiratory Papillomatosis: Long
Term Results • Prospective study, 49 pts enrolled, 33 available
for long-term follow-up
• Pts had complete surgical removal, then treated
with I3C
– Further surgery done as “as needed basis”
• Pts categorized as having complete, partial or no
response.
• 33% complete responders, 30% partial responders,
36% nonresponders
Rosen and Bryson. Journal of Voice, Vol 18, no.2
Mumps Vaccine
• Uncontrolled study
by Pashley, 2002
– Mumps vaccine as
adjuvant to laser
excision
– 23/29 children and
15/20 adults
achieved remission
• Mechanism unclear
Pashley NR. “Can Mumps Vaccine Induce
Remission in Recurrent Respiratory
Papilloma?” Arch Otolaryngol Head Neck Surg
2002; 128:783-6
Control of EERD in RRP
• EERD thought to be an exacerbator of RRP
– Factor that can activate latent virus
• Case series by McKenna & Brodsky
• 4 pts with RRP who had increase in severity of
disease with the recognition of concurrent EERD
• Results: In all 4 cases, control of RRP improved,
with identification and treatment of EERD
– Rebound of RRP symptoms/signs occurred due
to lapses in med compliance/dietary/behavioral
reflux modifications in 3 out of 4 pts
Control of EERD in RRP
• Conclusion
– Link btwn EERD and
RRP
– inflammation via
chronic acid
exposure may cause
expression of HPV in
susceptible tissues
– Prompt dx and ctrl of
EERD should be
considered
McKenna M, Brodsky L. Extraesophageal acid
reflux and recurrent respiratory papilloma in children.
Int J Pediatr Otorhinolaryngol
2005; 69: 597-605
New Frontier: Hsp E7
• Recombinant fusion protein derived from m. bovis BCG heat shock protein 65 (Hsp65) and E7 protein of HPV 16.
• Activity has been demonstrated in genital wart treatment
• Clinical responses observed in HPV 16-negative lesions
– Suggesting cross-reactivity for other HPV types
HspE7
• Derkay, et al 2005.
– Obj: Eval effectiveness of HspE7 in improving clinical
course of pediatric RRP
– Methods: Open-label, single-arm intervention study
conducted in 8 university-affiliated medical centers
• 27patients (13 F, 14 M) aged 2-18yo
• After baseline debulking surgery, pts received
HspE7 500µg subQ monthly for 3 doses over 60
days
• Primary endpoint was comparing the pretreatment
intersurgical interval with the posttreatment
intersurgical interval. Derkay, et al. HspE7 Treatment of Pediatric Recurrent
Respiratory Papillomatosis: Final Results of an Open-Label Trial. Annals of
Otology, Rhinology & Laryngology 114(9): 730-37
HspE7
• Results
– Mean of the first ISI increased 93% (from 55
days to 106 days; p<.02)
– Median ISI for all surgeries after treatment was
prolonged (mean, 107 days; p < .02)
– Decrease in number of required surgeries
(p<.003)
– Unexpected better result in females
• First posttreatment ISI improved by 142%
(p<.03)
• Median ISI was increased 147% (p<.03)
HspE7
• Conclusion
– In pediatric patients with RRP, treatment with
HspE7 seems to improve clinical course by
decreasing the number of required surgeries
– Confirmatory studies needed.
HPV Vaccine
• Currently 2 vaccines in development:
– Gardasil® (Merck)
• Quadrivalent
– Cervarix ® (GlaxoSmithKline)
• Bivalent
• Phase II trials have demonstrated excellent safety without major side-effects
• Phase III trials have shown effective prevention of genital wart expression and progression to CIN II/III.
HPV Vaccine: Questions to
Consider
• Questions
– Sex preference
for vaccine?
– When?
(adolescence v.
early adult)
– How often?
HPV
Controversy
• Controversy
– Many groups feel that the HPV vaccine will encourage promiscuity among young people.
– Many parents are angered over the thought of immunizing their pre-teen daughters against a sexual transmitted disease.
– There is a common misconception that the HPV vaccine protects against all types of HPV. Parents are concerned that their children will be misinformed and think they are being protected.
– Many parents believe that their children are not at risk for developing HPV.
http://cancer.about.com/od/hpvcervicalcancervaccine/a/controversyHPV.htm
Summary/Conclusions
• Relatively rare
– Negative impact on
evaluation of treatment
modalities
• Multiple recurrences =
poor quality of life for
patients
-numerous treatments
which can be costly
• Advances in surgical
techniques allow safe
airway and acceptable
voice.
• Adjuvant meds can
reduce frequency of
surgical excisions, but
none can totally
eradicate disease
Summary/Conclusions
• There is much to uncover regarding the
HPV virus and pathogenesis of RRP.
• The stage has been set for future studies
which may one day yield effective
prevention, early diagnosis and
management.
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