respir-papill-recur-slides-080625

respir-papill-recur-slides-080625 - Recurrent Respiratory...

Info iconThis preview shows pages 1–11. Sign up to view the full content.

View Full Document Right Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: 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 Chevalier Jackson (1837-1892) was the first to identify papillomas as a lesion of the laryngopharyngeal 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. 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 replication & transcription Viral release Viral capsid proteins 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 stealthlike 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 Core of vascularized Connective tissue stroma Finger-like projections 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 midthoracic 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 Csection 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 vs Pasquale, et al. Microdebrider Versus CO2 Laser Removal of Recurrent Respiratory Papillomas: A Prospective Analysis. Laryngoscope 2003;113: 139-43 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. OtolaryngologyHead 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 coinfectors (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, Chadha and James. Otolaryngology-Head and headache, fatigue 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 Tasca and Clarke. Recurrent Respiratory unsustained 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 16negative 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. Bibliography Soma MA, Albert DM. Cidofovir: to use or not to use? Curr Opin Otolaryngol Head Neck Surg. 2008 Feb;16(1):86-90. Review. Goon P, Sonnex C, Jani P, Stanley M, Sudhoff H. Recurrent respiratory papillomatosis: an overview of current thinking and treatment. Eur Arch Otorhinolaryngol. 2008 Feb;265(2):147-151 Chadha NK, James AL. Antiviral agents for the treatment of recurrent respiratory papillomatosis: a systematic review of the English-language literature. Otolaryngol Head Neck Surg. 2007 Jun;136(6):863-9. Review. Zacharisen MC, Conley SF. Recurrent respiratory papillomatosis in children: masquerader of common respiratory diseases. Pediatrics. 2006 Nov;118(5):1925-31. Tasca RA, Clarke RW.Recurrent respiratory papillomatosis. Arch Dis Child. 2006 Aug;91(8):689-91. Review. McKenna M, Brodsky L. Extraesophageal acid reflux and recurrent respiratory papilloma in children. Int J Pediatr Otorhinolaryngol. 2005 May;69(5):597-605. Rosen CA, Bryson PC.Indole-3-carbinol for recurrent respiratory papillomatosis: longterm results.J Voice. 2004 Jun;18(2):248-53. Pasquale K, Wiatrak B, Woolley A, Lewis L. Microdebrider versus CO2 laser removal of recurrent respiratory papillomas: a prospective analysis. Laryngoscope. 2003 Jan;113(1):139-43. Pashley, Nigel R.T. Can Mumps Vaccine Induce Remission in Recurrent Respiratory Papilloma? Arch Otolaryngol Head Neck Surg. 2002; 128: 783-786 Silverberg MJ, Thorsen P, Lindeberg H, et al. Clinical course of RRP in Dan ish children. Arch Otolaryngol Head Neck Surg 2004; 130:711–7116. Derkay CS. Task force on recurrent respiratory papillomas. Arch Otolaryngol Head Neck Surg 1995;121:1386–1391. Wiatrak BJ, Wiatrak DW, Broker TR, Lewis L. RRP: a longitudinal study compari ng severity associated with HPV types 6 and 11 and other risk factors in a large pediatric population. Laryngoscope 2004;114:1–23 Rady PL, Schnadig VJ, Weiss RL, Hughes TK, Tyring SK (1998) Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53. Laryngoscope 108:735–740 Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, Shah KV (2003) Condyloma in pregnancy is strongly predictive of juvenile onset recurrent respiratory papillomatosis. Obstet Gynecol 101:645–652 Hallden C, Majmudar B (1986) The relationship between juvenile laryngeal papillomatosis and maternal condylomata acuminata. J Reprod Med 31:804–807 Kashima HK, Shah F, Lyles A, Glackin R, Muhammad N, Turner L, Van Zandt S, Whitt S, Shah K (1992) A comparison of risk factors in juvenile-onset and adult-onset recurrent respiratory papillomatosis. Laryngoscope 102:9–13 Holland BW, Koufman JA, Postma GN, McGuirt WF Jr. Laryngopharyngeal reflux and laryngeal web formation in patients with pediatric recurrent respiratory papillomas. Laryngoscope 2002;112:1926–1929. Healy GB, et al. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical study. N Engl J Med 1988; 319: 401-407. Derkay, Craig S. et al. HspE7 Treatment of Pediatric Recurrent Respiratory Papillomatosis: Final Results of an Open-Label Trial. Ann Otol Rhinol Laryngol 2005; 114: 730-7 Kjer JJ, Eldon K, Dreisler A (1988) Maternal condylomata and juvenile laryngeal papillomas in their children. Zentralbl Gynakol 110:107–110 Gerien, et al. Incidence, age at onset , and potential reasons of malignant transformation in recurrent respiratory papillomatosis patients: 20 years experience. Otolaryngol Head Neck Surg 2005; 132: 392-394. ...
View Full Document

Page1 / 78

respir-papill-recur-slides-080625 - Recurrent Respiratory...

This preview shows document pages 1 - 11. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online