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.

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)

7. 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

9. 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

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

13. 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

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 < 5 procedures over their lifetime as opposed to <25% 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

20. 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

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/endoscopic 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 won�t cooperate)

30. 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

33. Treatment Modalities Surgical Microlaryngoscopy with cups forceps removal Microdebrider CO2 laser Phono-Microsurgical KTP/Nd:YAG 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

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.

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

46. 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 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.

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 can�t be determined due to lack of controlled studies

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

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

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

58. 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

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

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 500�g subQ monthly for 3 doses over 60 days Primary endpoint was comparing the pretreatment intersurgical interval with the posttreatment intersurgical interval.

67. 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)

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.

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.

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.