Recurrent Respiratory Papillomatosis

1. Recurrent Respiratory Papillomatosis Frederick S. Rosen, MD Anna M. Pou, MD June 25, 2003

2. Introduction Exophytic lesions of aerodigestive tract; tend to recur and spread Juvenile Onset (JORRP) vs. Adult Onset (AORRP)

3. Epidemiology Bimodal age distribution: 2-4 years and 20-40 years Children: Most common benign lesion of larynx, second most common cause of hoarseness 4.3/100,000 children Younger age at diagnosis implies more severe disease

4. Epidemiology

5. Epidemiology  1.8/100,000 adults Adult men more than women (3:2) Less aggressive than JORRP Most require <5 procedures over lifetime (vs. 19.7 procedures for children)

6. Etiology and Transmission HPV types 6 and 11 Nearly 100% of RRP 80-90% of condyloma acuminata HPV type 16 rare cause of RRP; associated with increased risk of malignant transformation HPV: Nonenveloped icosahedral (20-sided) capsid virus, double-stranded DNA

7. Etiology and Transmission HPV targets epithelial cells; may be active or latent Type 11 worse prognosis than type 6 Transmission of JORRP: link to maternal condyloma established Direct contact with condyloma in birth canal Transplacental spread (1 of 109 children delivered via C-section still develop RRP) Post-natal exposure

8. Etiology and Transmission Triad of primiparous mother, teenage mother, vaginal delivery known risk factor for JORRP Transmission of AORRP: not well established, but different from JORRP Large number of sex partners and frequent oral sex known risk factors Possible activation of latent infection Possible anogenital-to-oral contact

9. Etiology and Transmission HPV transmission by casual contact NOT a concern

10. Histology Finger-like projections of nonkeratinized stratified squamous epithelium with vascularized core Parakeratosis (retention of nuclei in stratum corneum), koilocytosis (cytoplasmic vacuolization), and acanthosis (epidermal hyperplasia) Variable atypia

11. Histology

12. Histology

13. Histology Commonly at junction between respiratory and squamous epithelium Common occurrence at tracheotomy site (iatrogenic squamo-ciliary junction) Common sites Limen vestibuli Nasopharyngeal surface of soft palate Midline laryngeal epiglottis Upper and lower margins of ventricle Undersurface of TVC�s Carina and Bronchial spurs

14. Clinical Features

15. Clinical Features Extralaryngeal spread in 30% of children, 16% of adults Triad: Progressive hoarseness, stridor, respiratory distress Other presentations: chronic cough, choking, recurrent pneumonia, FTT, dyspnea, dysphagia, ALTE Adults may present w/ globus sensation Frequent misdiagnoses: asthma, croup, allergy, laryngitis, bronchitis

16. Clinical Features Possible outcomes: spontaneous regression, no regression, recurrence after years of remission, malignant transformation NO tendency for regression during puberty Most common: recurrent exophytic lesions requiring frequent debulking Death usually from frequent surgical procedures or respiratory failure from distal progression Bronchopulmonary involvement in 4-11% of children

17. Malignant Transformation Rare; 20 pediatric cases reported in world literature Universally fatal Most common in adults with RFs Tobacco Previous XRT History of Bleomycin Infection with HPV type 16 Usually larynx in adults, bronchopulmonary in children E6 and E7 oncogenic (inactivate p53, pRb)

18. Patient Assessment Stridor present since birth less likely Hoarseness most common presentation Must first determine respiratory distress OR Establish safe airway Auscultate over nose, open mouth, neck, chest Stridor should not change with position Flexible laryngoscopy: If not possible, go to OR

19. Staging

20. Surgical Treatment Standard of care Eradicate disease, assure adequate airway, and improve voice without morbidity Most common options: CO2 laser, cold instrumentation, microdebrider KTP laser may also be useful with ventilating bronchoscope for tracheobronchial lesions

21. Surgical Treatment Complications of CO2 laser: Scarring Webbing Alteration of mucosal wave Stenosis Airway Perforation Airway fire

22. Surgical Treatment Cold instrumentation: useful in adults; stripping usually not indicated; more bleeding, but fewer complications Use of microdebrider major development in last few years 3.5 or 4 mm skimmer blade (angled) Safer and more accurate than laser Can remove tracheal lesions when used with rigid endoscope

23. Surgical Treatment

24. Surgical Treatment Retrospective study (El-Bitar): All complications occurred with laser, none with microdebrider; more procedures required with microdebrider Prospective study (Pasquale): No difference in voice or pain; lower operative time and cost with microdebrider

25. Surgical Treatment Laser-safe tube, Jet ventilation, Apneic technique Jet ventilation: increased risk of distal airway spread, pneumothorax, mucosal drying, gastric distention Up to 14% of JORRP require tracheotomy Prolonged trach associated with distal tracheal spread Decannulate as soon as adequate disease control

26. Adjuvant Treatment Up to 10% of RRP patients require adjuvant medical treatment Criteria: >4 surgical procedures per year, distal multisite spread, rapid regrowth of disease with airway compromise (Average for children=4.4 procedures/year)

27. Adjuvant Treatment Alpha-interferon: used for RRP since 1980s Side effects common and multiple Acute reactions (fever, myalgia, anorexia, etc.) controlled by nighttime administration X 2 weeks Chronic reactions: neutropenia, spastic diplegia, thrombocytopenia, renal insufficiency Given IV, IM, or SC for 6 months Complete response in 30-50%, partial in 20-42%; 50% recurrence rate

28. Adjuvant Treatment Photodynamic therapy: Dihematoporphyrin followed by argon pump dye laser; results in increased light sensitivity X2-8 weeks; may be improved by Foscan Indole-3-Carbinol: dietary supplement from cruciferous vegetables; few side effects; acts on estrogen metabolism: 1/3 complete response, 1/3 partial response, 1/3 no response

29. Adjuvant Treatment Retinoic acid: may have synergistic effect with alpha-interferon; should not use in females of child-bearing age Ribavirin: used to treat RSV pneumonia; initial IV loading dose followed by PO Acyclovir: thought to act on coinfecting organism

30. Adjuvant Treatment Cidofovir: most significant new development Broad spectrum activity against Herpes viruses Inhibits viral DNA polymerase Intracellular half-life=65 hours No adverse effects with intralesional use Dose=2.5-6.25 mg/ml Complete remission common in adults, rare in children

31. Adjuvant Treatment Cidofovir: safety and efficacy Optimal dose, interval, treatment duration, drug combinations yet to be determined Possible tumorigenicity: Adenocarcinoma noted with subcutaneous injection in rats; none noted in humans to date Long-term remission unknown First reported for adult larynx in 1998 (Snoeck)

32. Adjuvant Treatment

33. Adjuvant Treatment Home intercom monitor adequate Optimize treatment of GERD and asthma The future: HPV vaccine, possibly using E6, E7 antigens

34. Adjuvant Treatment

35. Conclusion HPV types 6 and 11 Lesions common at squamo-ciliary junction RRP does not regress with puberty Malignant transformation: rare but universally fatal Prophylactic C-section is NOT routinely recommended, but should be strongly considered in young, primiparous mothers with recent HPV infection and genital warts

36. Conclusion Treatment: palliative surgery while awaiting natural disease remission Latest developments: the microdebrider and intralesional cidofovir Microdebrider safer, cheaper, and faster than laser Cidofovir highly effective, but no long-term data regarding tumorigenicity or remission Hope for the future: HPV vaccine