peggy e. kelley - papilloma_copy

7/29/2019 Peggy E. Kelley - Papilloma_copy

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Laryngeal

Papillomas and The

Papilloma VaccinePeggy E. Kelley MD

Associate Professor of OtolaryngologyUniversity of Colorado, Denver


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Outline

Human Papilloma Virus Mechanism of Action

Recurrent Laryngeal Papillomatosis (Recurrent

Respiratory Papillomatosis) Epidemiology

Diagnosis

Treatment options

Quadravalent Human Papillomavirus Vaccine


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12

HPV in Head and Neck Cancers

Syrjnen S.J Clin Virol. 2005;32:S59S66.

Based on meta-analyses


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Summary

HPV depends on the differentiation of the epithelium toregulate its replication and complete its life cycle.

The natural immune response to HPV infection is slow andweak because of the ability of HPV to evade immuneresponses.

Humoral immunity prevents infection by forming typespecific neutralizing antibodies. Cell mediated immunitymay help eliminate established HPV infections and has notbeen demonstrated to be type specific.


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Laryngeal Papillomatosis

Also known as Recurrent RespiratoryPapillomatosis (RRP)

Infection by Human Papilloma Virus in theairway.


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HPV Types 6 and 11 AssociatedWith RRP

RRP is rare; in the United States1,2:

4.3 per 100,000 children

1.8 per 100,000 adults

Age distribution is bimodal withpeaks at3:

2 to 4 years of age (juvenile onset)

20 to 40 years of age (adult onset)

HPV 6 and 11 cause ~100% of bothjuvenile- and adult-onset RRP.4

1. Zacharisen MC et al. Pediatrics. 2006;118:19251931. 2. Derkay CS et al.Ann Otol Rhinol Laryngol.

2006;115:111. 3. Derkay CS. Laryngoscope. 2001;111:5769. 4. Lacey CJN et al. Vaccine. 2006;24:S35S41.

Image reprinted with permission from Glikman D.,

et al. N Engl J Med. 2005; 352:e22. Copyright

2005 Massachusetts Medical Society. All rights

reserved.


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Diseases Caused by HPV Types 6 and 11

Have a Significant Financial Impact1

The principal costs associatedwith HPV 6 and 11 result fromtreatment of genital warts andRRP.1

In countries with cervical cancerscreening programs, includingthe United States, there are alsosignificant costs associated with

HPV 6

and 11

associated CIN1 and other abnormal cytologyand consequent procedures.13

1. Lacey CJN et al. Vaccine. 2006;24:S35S41. 2. Insinga RP et al.Am J Obstet Gynecol. 2004;194:114120. 3.

Clifford GM et al. Cancer Epidemiol Biomarkers Prev. 2005;14:1157

1164. 4. Derkay CS.Arch OtolaryngolHead Neck Surg. 1995;121:13861391. 5. Insinga RP et al. Pharmacoeconomics. 2005;23:11071122.

Genital Warts$200 million5

RRP

$151 million4

Estimated US Annual Cost

CIN 1$113 million2,3

Note: The cost for CIN 1 is based on an estimated incidence of 1.1 million cases per year, of which 10% are dueto HPV 6 and HPV 11.


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Presentation and Diagnosis

Progressive hoarseness about age 2-4 years

Diagnose with flexible fiberoptic laryngoscopy in office

Relook for nodules not responding to treatment

Airway obstruction, stridor or abnormal cry in infants ortoddlers

Younger age predictor of higher severity of disease

Diagnosis in office with flexible or if in distress rigid inoperating room

Aphonia

Atypical presentation Differential diagnosis, laryngeal web


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RRP Is an Important Disease ThatIs Often Misdiagnosed

RRP is often misdiagnosed, with the most common diagnosesbeing asthma, croup, laryngeal hemangioma, andtracheomalacia.1

The duration of symptoms prior to definitive diagnosis rangesfrom 2 months to >2 years.1

Although histologically benign,RRP causes significant morbidityand mortality owing to its recurrent nature.2

Papilloma masses can obstruct theairway if not removed.

Could require surgery under generalanesthesia as frequently as everyfew weeks

Although rare, it has been shown thatlaryngeal papillomas may convert spontaneously to carcinomas atrates of 3% to 19%. These carcinomas have

been shown to contain HPV 6 and 11.3 1. Zacharisen MC et al. Pediatrics. 2006;118:19251931. 2.

Abramson AL et al.J Med Virol. 2004;72:473

477. 3.Steinberg BM et al. Cancer Metastasis Rev. 1996;15:91112.

Vocalcords

Papillomas

Airway

Photos courtesy of Craig S. Derkay, MD

Eastern Virginia Medical School


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Disease Course

Derkay Severity Score Scores clinical symptoms and anatomic locations

Can compare patients treatment course and patients from

different sites. Variable but fairly regular for the individual

Every 2 weeks to every 6months.

Most common in larynx but concern for spread to trachea

Distal disease can be fatal

Greatest concern for malignant degeneration into squamouscell carcinoma


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Laryngoscopic and ClinicalAssessment Scale for RRP

A. Clinical Score

1. Describe the patients voice today: normal___(0),abnormal___(1), aphonic___(2)

2. Describe the patients stridor today: absent___(0), present withactivity___(1), present at rest___(2)

3. Describe the urgency of todays intervention: scheduled___(0),elective____ (1), urgent___(2), emergent___(3)

4. Describe todays level of respiratory distress: none___(0),mild___(1), moderate___(2), severe___(3), extreme___(4)

Total Clinical Score (Questions 1 through 4) = __(0-11)____


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B. Anatomical ScoreFor each site, score as: 0=none, 1=surface lesion, 2=raised lesion, 3=bulky lesion

LARYNX:

Epiglottis: Lingual surface___ Laryngeal surface___

Aryepiglottic folds: Right___ Left___

False vocal cords: Right___ Left___

True vocal cords Right___ Left___ Arytenoids: Right___ Left___

Anterior commissure______

Posterior commissure___

Subglottis______

TRACHEA

Upper one-third_____

Middle one-third______

Lower one-third_______

Bronchi: Right___ Left____

Tracheotomy stoma____


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Anatomic Sites


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B. Anatomic Score (continued)

OTHER:

Nose_______

Palate_______ Pharynx_____

Esophagus___

Lungs_______

Other________ Total Anatomical Score __(0-75)________

C. Total Score = Total Anatomical Score plus Total ClinicalScore (0-86)


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Treatment Options

Medical

Interferon

-interferon given intravenously decreased disease immediately

but had no lasting effect To be avoided secondary to side effects such as spastic diplegia

Cidofivir intralesional injections

Antiviral to DNA viruses

promising but no placebo controlled trials yet concern formalignant transformation potential

Mumps vaccine- used to induce remission

Indole 3-carbinaol given orally

Cimetidine or proton pump inhibitor may improve course


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Treatment of RRP

Surgical

Maintain a safe airway with debulking procedures

Cup forceps

Biopsy at least once for typing

CO2 laser

Micromanipulator

fibers

Microdebrider

KTP laser following debulking to effect the blood vessels

Used to treat anterior commissure disease

Pulse dye laser following debulking


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RRP Is a Costly Disease

In the United States, there are an estimated 15,000procedures each year to treat RRP cases.1

The US approximate annual cost of juvenile- and adult-

onset RRP is >$150 million.1

Juvenile-onset RRP is the most frequent1 and the mostcostly2:

At birth, the cost of a single case of juvenile-onset RRP is

estimated at $201,724.2

The annual estimated cost for a single case of juvenile-onset RRPis $57,996.2

Some children require >100 lifetime surgical interventions tomanage their airways.3

1. Derkay CS et al.Ann Otol Rhinol Laryngol. 2006;115:1

11. 2. Bishai D et al.Arch Otolaryngol Head NeckSurg. 2000;126:935939. 3. Freed GL et al. Int J Pediatr Otorhinolaryngol. 2006;70:17991803.


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Preventing not treating

Vaccine to prevent viral infection from

beginning

Vaccine to treat active disease


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Efficacy and Antibody Response

toHuman Papillomavirus (HPV)

Vaccines


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Infectious Virus Particle of HPV1,2

Capsid proteins:L1L2

Viral DNA

Viral exterior Viral interior

1. Baker TS, et al. Biophys J. 1991;60:1445

1456.2. Chen XS, et al. Mol Cell. 2000;5:557567.


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HPV Infection and Productive Life Cycle

Adapted from Doorbar J.J Clin Virol. 2005;32S:S7S15.

Virus introducedthrough microabrasion

Viral DNA replicationVirion assembly

Infectious virions shed

Virusinfection

Late HPV protein

productionL1 & L2

Early HPV protein

production

E1, E2, E4, E5, E6, & E7


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HPV L1 Protein Self-Assembles Into VLPs13

1. Berzofsky JA, et al.J Clin Invest. 2004;114:450462.

2. Kirnbauer R, et al. Proc Natl Acad Sci USA. 1992;89:12180

12184.

3. Modis Y, et al. EMBO J. 2002;21:47544762.


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L1 VLPs Mimic the HPV Virion14

Viral DNA

Infectious HPVNoninfectious HPV VLP

Capsid proteins:

L1

L2

Lacks viral DNA

Lacks

L2 protein

1. Stanley M. Vaccine. 2006;24(Suppl 1):S16S22.

2. Berzofsky JA, et al.J Clin Invest. 2004;114:450

462.3. Baker TS, et al. Biophys J. 1991;60:14451456.

4. Chen XS, et al. Mol Cell. 2000;5:557567.


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Side view Top view

Antibody Binding Region

L1 Surface Loops: Immune Targets

Chen XS, et al. Mol Cell. 2000;5:557567.


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Humoral Vaccine

Prophylactic HPV vaccines are based on L1 VLPs.

Antibody produced to virus-like particle (VLP)

Prevents disease by memory cells attacking the viralparticle before it can infect a cell.

GARDASIL is a vaccine indicated in girls and women 9 to

26 years of age for the prevention of cervical cancer,precancerous or dysplastic lesions, and genital wartscaused by HPV Types 6, 11, 16, and 18.

f


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American Academy of PediatricsPolicy Statement

Girls between 11-26 should get 3 vaccine series

Time to the 2nd vaccination is 2 months

Time to the 3rd vaccination is 6 months

Consistent with recommendations of the Centers forDisease Control (CDC)

The goal is to prevent cervical cancer but the

secondary goal is to eliminate the carrierstate so that RRP disappears.


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Conclusion

JRRP is a scary challenging frustrating disease process

Treatment is currently limited to control of the disease

It is hoped that by vaccinating all female children beforeexposure to HPV JRRP will disappear.

Future areas of research are to develop vaccines against

active disease using cellular immunity and involving theearly region proteins.

peggy e. kelley - papilloma_copy

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