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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