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Recurrent Respiratory Papillomatosis

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Recurrent Respiratory Papillomatosis Ryan W. Ridley, MD Jing Shen, MD University of Texas Medical Branch Department of Otolaryngology Grand Rounds Presentation – PowerPoint PPT presentation

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Title: Recurrent Respiratory Papillomatosis


1
Recurrent Respiratory Papillomatosis
  • Ryan W. Ridley, MD
  • Jing Shen, MD
  • University of Texas Medical Branch
  • Department of Otolaryngology
  • Grand Rounds Presentation
  • June 25, 2008

2
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
3
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

4
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)

5
Transforming abilities
Viral replication transcription
Viral release
Viral capsid proteins
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Etiology contd
  • 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

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Etiology contd
  • 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

10
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

11
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

12
Core of vascularized Connective tissue stroma
Finger-like projections
13
Lesion Characteristics (contd)
  • 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

14
Pruess et al. Acta Oto-Laryngologica, 2007 127
11961201
15
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

16
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 lt 5 procedures over their lifetime
    as opposed to lt25 of children who can say the
    same

17
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.

18
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

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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.
21
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

22
RRP The Great Masquerader
  • RRP often misdiagnosed as
  • Asthma
  • Croup
  • Tracheomalacia
  • Allergies
  • Vocal nodules
  • bronchitis

23
Clinical Features
  • Extralaryngeal spread of papillomas
  • 13-30 children and 16 adults
  • Most frequent sites
  • Oral cavity
  • Trachea
  • bronchi

24
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?

25
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

26
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

27
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/endoscopi
    c equipment is READILY available (i.e. OR, ER,
    ICU)

28
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 wont cooperate)

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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

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33
Treatment Modalities
  • Surgical
  • Microlaryngoscopy with cups forceps removal
  • Microdebrider
  • CO2 laser
  • Phono-Microsurgical
  • KTP/NdYAG laser
  • Flash scan lasers
  • Adjuvant
  • a-Interferon
  • Indole-3-carbinol
  • Photodynamic therapy
  • Cidofovir
  • Acyclovir
  • Ribavirin
  • Retinoic acid
  • Mumps vaccine
  • Methotrexate
  • Hsp E7

34
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

35
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

vs
vs
Pasquale, et al. Microdebrider Versus CO2 Laser
Removal of Recurrent Respiratory Papillomas A
Prospective Analysis. Laryngoscope 2003113
139-43
36
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.

37
24 Hour Post-op Pain Scores
38
Voice Quality
39
Procedure Time
40
Cost
41
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.

42
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, 1686-90
43
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)

44
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

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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.

47
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

48
Chadha James
  • 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.
  • Objective determine efficacy of antiviral agents
    in RRP
  • Design systematic review
  • Results
  • No RCTs
  • Meta-analysis not possible
  • Strongest evidence was for intralesional cidofovir

49
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

50
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 cant be determined due to lack of
    controlled studies

Chadha and James. Otolaryngology-Head and Neck
Surgery (2007)
51
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)
52
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
91689-691
53
Indole-3-carbinol
  • Abundant in cruciferous vegetables
  • Affects papilloma growth in vitro via modulation
    on estrogen metabolism

54
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
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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 128783-6
59
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

60
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
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64
New Frontiers in RRP Management
65
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

66
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
67
HspE7
  • Results
  • Mean of the first ISI increased 93 (from 55 days
    to 106 days plt.02)
  • Median ISI for all surgeries after treatment was
    prolonged (mean, 107 days p lt .02)
  • Decrease in number of required surgeries (plt.003)
  • Unexpected better result in females
  • First posttreatment ISI improved by 142 (plt.03)
  • Median ISI was increased 147 (plt.03)

68
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.

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72
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.

73
HPV Vaccine Questions to Consider
  • Questions
  • Sex preference for vaccine?
  • When? (adolescence v. early adult)
  • How often?

74
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/hpvcervicalcancervaccin
e/a/controversyHPV.htm
75
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

76
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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