Recurrent Respiratory Papillomas

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Recurrent Respiratory Papillomas

• Presented by Jeff Pacheco, M.D.
• Discussant Soham Roy, M.D.

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Recurrent Respiratory Papillomas(RRP)

• Result from epithelial proliferation usually
  induced by human papilloma virus (HPV)
• May involve entire aerodigestive tract, most
  commonly effects the larynx

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Recurrent Respiratory Papillomas(RRP)

• Border of ciliated and squamous epithelium,
  within epithelial cells
• Common sites limen vestibuli, nasopharyngeal
  surface of soft palate, laryngeal epiglottis,
  ventricles, under surface of TVC, carina

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Recurrent Respiratory Papillomas(RRP)

• Extra laryngeal spread
• 31 of children vs. 16 of adults (Derkay, 1995)
• Most frequent sites oral cavity, trachea,
  bronchi

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Recurrent Respiratory Papillomas(RRP)

• Most common benign neoplasm of the larynx in
  children and adults
• 2nd most common cause of hoarseness in children
• In children diagnosis occurs between 2-3 years of
  age, 75 are diagnosed before 5

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Recurrent Respiratory Papillomas(RRP)

• Variable course spontaneous remission versus
  recurrent papillomatous growths requiring
  multiple surgical interventions
• 2 general forms juvenile onset and adult onset
• Age at time of diagnosis is primary determinant
  of disease severity

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RRP Incidence

• malefemale 11(kids)
• 41(adults)
• 4.3/100,000 (under 14),
• 1.8/100,00 (over 14)
• 2,500 new cases/year, 6,000 active cases/year
• Total cost 150 million per year

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RRP Operative Procedures
Derkay, C. Task Force on recurrent respiratory
papillomas Arch Oto HN, December 1995
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Recurrent Respiratory Papillomas(RRP)

• Juvenile
• young, first time mothers
• vaginal delivery
• low socioeconomic status

• Adult onset
• more lifetime sexual partners
• higher frequency of oral sex

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Human Papilloma Virus(HPV)

• Cause WARTS
• ds DNA virus
• non enveloped
• 80 different types identified by PCR

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Human Papilloma Virus(HPV)
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HPV and RRP

• Association between HPV and RRP first made in
  1980s
• Types 6 and 11 have been identified by PCR and in
  situ hybridization in RRP
• Types 6 and 11 have also been identified in
  condyloma accuminata (i.e. anogenital warts)

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HPV and RRP Transmission

• Mode of transmission unknown
• Possibly exposure during vaginal delivery
• 50 of RRP with h/o active or previous condylomas

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HPV and RRP Transmission

• Clinically apparent HPV infection noted in 5 of
  pregnant women in US
• 1/3 of children born to mothers with condyloma
  have nasopharyngeal swabs positive for HPV
• 1400 children born to mothers with active
  condyloma will develop RRP

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Factors contributing to RRP

• Child immune status unable to manage HPV with
  appropriate T Cell response
• Time in birth canal
• Viral load in birth canal
• Local trauma

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Signs and Symptoms

• Begins as an inspiratory stridor or mild
  hoarseness, progressing to worsening airway
  obstruction
• Cough, pneumonias, and dysphagia
• Often misdiagnosed as asthma, croup, allergies,
  vocal nodules, or bronchitis

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Diagnosis

• No labs, no clinical use for typing
• Flexible fiberoptic nasopharyngoscopy, followed
  by rigid bronchoscopy
• CT/MRI are not good initial studies, may be
  helpful in evaluating distal spread into trachea
  and bronchi

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RRP Treatment

• Historically considered a surgical disease only
• High recurrence rate and viral etiology changed
  management strategies

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Approaches for surgical removal of RRP are
controversial...It must be emphasized that RRP is
an epithelial disease and that it is critical to
preserve the underlying superficial lamina
propria (SLP) and other vital structures... These
factors must be omnipresent in the surgeon's mind
because the preservation of normal laryngeal
tissue will facilitate optimal function for the
future, since a medical solution will ultimately
be conceived
Casiano, et al
Oto HNS, April
2002
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Surgical Therapy

• Cold steel excision with phonomicrosurgical
  instruments
• Laser CO2, pulse dye
• Laryngeal microdebrider AKA skimmer, shaver
• Tracheostomy

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Phonomicrosurgery
Infusion
Dissection
Excision
Miller time
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CO2 Laser

• Considered standard method of RRP excision
• 244 patients treated every 2 months (Dedo, 2001)
• 37 remission(2 months)
• 6 clearance (3 years)
• 17 cure (5 years)

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585 nmPulse Dye Laser
Pre op

• Reduce thermal damage by selective eradication of
  microvasculature
• 10 patient pilot study (Shapshay 2001)
• Benefits no mucosal injury, flexible delivery
  system, ?no viral seeding?

Post PDL
1 month
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Adjuvant Medical Therapy

• Interferon alpha
• Photodynamic Therapy
• Indole-3-carbinole
• Ribavirin -Acyclovir
• Methotrexate
• Isotretinoin -Cidofovir
• Mumps Vaccine

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Interferon Alpha

• Protein produced by leukocytes in response to a
  variety of stimuli, including viral infections
• Blocks viral replication of RNA and DNA
• Alters the cell membrane, thus making them less
  susceptible to viral penetration

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Interferon Alpha

• Large multi-center study (n66 juvenile onset
  RRP), Leventhal, et al. 1988
• Randomized crossover trial
• Group 1
• 5 megaunits/m2/IM QD x 28 days, then 3x per week
  for 5 months, followed by observation (surgery
  only) for 6 months

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Interferon Alpha

• Group 2 observed first then treated
• Both groups brought to OR every 2 months to grade
  extent of disease
• 47 of patients had a fall in their score of 1/2
  from their baseline, and 14 had complete
  clearance during treatment arm

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Interferon Alpha

• Conclusions
• IFN could prolong intervals of recurrence
• Response to therapy not durable
• Side effects of IFN therapy significant

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Interferon Alpha Side Effects

• Influenza like syndrome fever, malaise,
  headache, chills, nausea
• Delayed effects include SLE, rash, alopecia,
  fatigue, decreased growth rate, liver
  dysfunction, leukopenia, thrombocytopenia, and
  neurological problems

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Photodynamic Therapy

• Photosensitizing agent
• dihematoporphyrin ether (DHE)
• taken up preferentially in rapidly dividing
  tissues (e.g., papillomas)
• 24-48 hours after IV dose a pump-dye laser system
  emits a red light at 630 nanometers that
  photocoagulates papillomas

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PDT Side Effects

• Photosensitivity for up to 9 months
• SLE like reactions from sun exposure
• Newer photosensitizers (i.e. MTPHC) under
  investigation

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Indole-3-Carbinol

• (I3C) is a compound found in cruciferous
  vegetables (e.g., cabbage, Brussels sprouts,
  broccoli, cauliflower)
• Induces estrogen metabolite that inhibits
  papilloma growth

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Indole-3-Carbinol

• 55-60 of RRP showed some response in pilot
  studies
• Phytosorb-DIM at 8-10mg/kg/day x 3months, then
  5mg/kg/day
• Well tolerated, minimal side effects

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Ribavirin

• Analogue of guanosine , inhibits viral nucleic
  acid synthesis, particularly in RSV
• 4 patient pilot study
• Aggressive JORRP treated for 6 months, after
  an initial IV bolus
• All 4 patients had a response to the drug, 2
  partial and 2 complete
• Results not durable

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Ribavirin

• Teratogen
• Transient headaches, mild fatigue, anemia, and an
  increase in reticulocytes.
• Aerosolized form costs over 1000/QD

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Acyclovir

• Purine nucleoside analogue used to treat HSV
• Binds to HSV thymidine kinase and is
  phosphorylated and incorporated into replicating
  DNA molecules, where it breaks strands preventing
  replication
• Human thymidine kinase does not activate
  acyclovir.

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Acyclovir

• Mechanisms of action in RRP are unknown
• Coinfection of HPV and herpes virus has been
  shown
• Several small studies have shown benefit with PO
  (800 mg per day adults children received 10
  mg/kg or 400 mg per day)

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Methotrexate

• Antimetabolite that inhibits dihydrofolic acid
  reductase, blocks the synthesis in purine
  nucleotides, and interferes with DNA synthesis
  and repair
• Active proliferating cells are most affected by
  methotrexate
• 1 study (n3), refractory to IFN, doubled time
  interval between excisions

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Isotretinoin

• Vitamin A derivative that regulates growth and
  differentiation of epithelial cells by inhibiting
  epithelial proliferation
• No direct antiviral properties
• In randomized trials, no significant clinical
  improvement over placebo has been observed

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Mumps Vaccine

• Used for warty tissue in other body regions
• Utilized to elicit local inflammation to
  encourage immunomodulatory responses to the
  papilloma

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Mumps Vaccine

• Pashley, Archives 2002
• 2 series conducted with CO2 laser debulking
• Pilot study, remission was induced in 9 (82) of
  11 patients by 1 to 10 injections, with follow-up
  of 5 to 19 years
• In subsequent series, remission was induced in 29
  (76) of 38 patients by 4 to 26 injections, and
  follow-up was 2 to 5 years

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Cidofovir

• Cytosine nucleotide analogue
• Broad-spectrum antiviral activity against HSV
  types 1,2,6,8 , varicella, CMV, adeno, and
  papilloma viruses
• FDA approved for treatment of CMV retinitis in
  AIDS

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Cidofovir

• Pransky (1999) Arch OTO HNS
• Prospective trial, n5
• Severe JORRP (gt1 CO2 debulking per month)
• Used staging system
• 2-9 month follow up
• 1 patient disease free, 3 had dramatic
  improvement, 1 improved with IFN

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Cidofovir

• Bielamowicz, 2002
• 14 adults
• Injected monthly with 37.5mg/6cc saline without
  surgical debulking
• Good response in all 14

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RRP and Squamous Cell Carcinoma

• Malignant degeneration rare
• Reported in cases of RRP treated with XRT
• Permanent sections from biopsy still recommended

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RRP and Squamous Cell Carcinoma

• Thomas (2002)
• Investigated whether severity of RRP correlated
  with malignant degeneration, and if high risk HPV
  types found
• 7.8 (4/51)of patients with RRP developed SCCA
• 2/4 had ETOH/tobacco history other 2/4 had
  either HPV types 16/18

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Conclusion

• RRP is a potentially devastating disease with
  significant morbidity
• Hopes for cure rely mainly in better
  understanding of HPV and host factors
• Diverse treatment therapies that are under
  investigation are encouraging