GOOD AFTERNOON

DIAGNOSIS AND MANAGEMENT OF

JUVENILE-ONSET LARYNGEAL PAPILLOMATOSIS

SCIENTIFIC ADVISORDR. I GDE ARDIKA NUABA,SP.THT-KL [K]

PUTU DEWI PRAMUSITA

INTRODUCTION

A common proliferative benign tumor in children

It is also known as respiratory papillomatosis It is also known as respiratory papillomatosisor recurrent respiratory papillomatosis

Divided into 2 categories :

• Juvenile-onset laryngeal papillomatosis

• Adult-onset laryngeal papillomatosis

INTRODUCTION

Donalus (17th Century) : warts in the throat

McKenzie (19th Century) : laryngeal papilloma McKenzie (19th Century) : laryngeal papilloma

Ullman (1923) : virus as the etiology

1982 : HPV is identified

Most often : HPV types 6 & 11

INTRODUCTIONjuvenile-onset laryngeal papillomatosis

The most common laryngeal neoplasm identified in children

♂ : ♀ = 1: 1 ♂ : ♀ = 1: 1

Diagnosis is based on anamnesis, physical examination, biopsy, and other ancillary services

Management modalities are surgery and adjuvant therapies

INTRODUCTIONjuvenile-onset laryngeal papillomatosis

obstruction of the airway, high recurrent rate, no single effective modality of therapy &

complications

potential for morbid consequences

acknowledgement of

diagnosis & management is a necessity

EMBRIOLOGY OF LARYNX

Basic Otorhinolaryngology : A Step by Step Learning Guide, 2006

ANATOMY OF LARYNX

Basic Otorhinolaryngology : A Step by Step Learning Guide, 2006

EPIDEMIOLOGY

The most common laryngeal neoplasm & second most frequent cause of hoarseness in children

Diagnosed at 2-4 years old ( 75% are Diagnosed at 2-4 years old ( 75% are diagnosed before 5 years old), with a 1-year delay in diagnosis

Estimated 1500-2500 new cases/year in USA

Incidence (USA ): 4,3/100.000 children whom requires over 15.000 surgeries & US $ 100 million per year

EPIDEMIOLOGY

♂ : ♀ = 1: 1

A mean number of 19,7 surgeries/children (4,4/year) in USA

Children diagnosed before 3 years old are :

• 3,6 times more likely to require more than

4 surgery/year

• 2,1 times more likely to have 2/more

anatomic sites affected after 4 years old

EPIDEMIOLOGY

younger children whom affected & diagnosed

are often :

• with disease progression

• have persistent disease

• experience increased number of surgeries

in the 1st year following diagnosis

ETIOPATHOGENESIS

HPV type

6 & 11

lesions on respiratory tract

ETIOPATHOGENESIS

HPV

• Non enveloped icosahedral capsid• Non enveloped icosahedral capsidvirus

• Double stranded circular DNA 7900 base pair long

• 3 regions : upstream regulatory, early and later

ETIOPATHOGENESIS

ETIOPATHOGENESIS

lesions on respiratory tract

• Sessile / exophytic• Sessile / exophytic• Pink / white• Pedunculated masses with fingerlike

projections of non-keratinized stratified squamous epithelium

• Supported by a core of highly vascularized connective tissue stroma

ETIOPATHOGENESIS

lesions on respiratory tract

• Basal layer normal / hyperplastic with mitotic figures

• Basal layer normal / hyperplastic with mitotic figures

• Cellular differentiation is abnormal• Degree of atypia sign of premalignant

tendency• HPV type 11 more obstructive airway

early in the disease & greater need for tracheotomy

ETIOPATHOGENESIS

common anatomic sites

where ciliated & squamous epithelium are juxtaposed

• Limen vestibuli• Nasopharyngeal surface of soft palate• Midline laryngeal surface of epiglottis• Upper & lower margins of the ventricle• Undersurface of vocal folds• Carina• Bronchial spurs

ETIOPATHOGENESIS

Laryngeal Papillomatosis

ETIOPATHOGENESIS

Histopathology of Laryngeal Papillomatosis

TRANSMISSION

Remains unclear

Several studies linked juvenile-onset laryngeal Several studies linked juvenile-onset laryngeal papillomatosis to mothers with genital HPV infection (vertically through birth canal)

Kashima : more likely to be first born & vaginally delivered

PREDISPOSITION FACTORS

Child whose mothers are with genital condylomatascondylomatas

Child with bronchopulmonary dysplasia who needs prolonged endotracheal intubation

DIAGNOSIS

• History of the patientAnamnesis

• Signs and symptoms• Indirect laryngoscopy

Physical examination

• Histopathology• Identification of HPV &

extention of lesions

Biopsy and Other ancillary

services

DIAGNOSIS

ANAMNESIS & PHYSICAL EXAMINATION

triad of progressive hoarseness, stridor, and respiratory distress

other symptoms :

hoarseness + obstructive

airway symptoms laryngoscopy

inspiratory stridor biphasic

other symptoms :

chronic cough, recurrent

pneumonia, failure to thrive,

dyspnea, dysphagia

DIAGNOSIS

ANAMNESIS & PHYSICAL EXAMINATION

• when respiratory distress is absent : careful history of onset, possible airway trauma, history of onset, possible airway trauma, characteristic of the cry

• Subglottic lesion : low/high-pitched, coarse, fluttering voice

• Glottic lesion : high-pitched, cracking voice, aphonia

• Neonatus with stridor consider papillomatosis

DIAGNOSIS

PHYSICAL EXAMINATION & BIOPSY

• Thorough & organized examination • Thorough & organized examination • Frequent visits to establish agressiveness• Evaluation of : signs of respiratory distress, level of

obstruction, level of oxygenation• Clinic setting / operating room setting• With indirect laryngoscopy : rigid / flexible (flexible

is considered superior to rigid)• Biopsy is the gold standard

DIAGNOSIS

OTHER ANCILLARY SERVICES

• Identification of HPV on lesions : IHC, isolation of DNA virus, in situ hybridisation, PCR

• Chest X-Ray & CT Scan of neck & chest : will demonstrate extent of the lesions

STAGING

Most clinicians find that tracking a child’s disease progression in a uniform protocol is necessarynecessary

A such universal yet simple protocol is not yet accepted

Coltrera & Derkay have proposed a staging system to overcome the issue

STAGING ASSESSMENT FOR RECURRENT LARYNGEAL PAPILLOMATOSIS

Patient initials__ Date of Surgery__ Surgeon__ Patient ID#___Institution__

1. How long since the last papilloma surgery? __days,__weeks,__months,__years,__don’t know,__this is the child first surgery

2. Counting today’s surgery, how many papilloma surgery in the past 12 months? ___

3. Describe the patient’s voice today:Normal__ (0), abnormal__ (1), aphonic__ (2)Normal__ (0), abnormal__ (1), aphonic__ (2)

4. Describe the patient’s stridor today:Absent__ (0), present with activity__ (1), present at rest__ (2)

5. Describe the urgency of today’s intervention: Scheduled__(0), elective__ (1), urgent__ (2), emergent__ (3)

6. Describe today’s level of respiratory distress: None__ (0), mild__(1), moderate__(2), severe__(3), extreme__(4)

Total score for questions 3-6=_______________

FOR 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 folds right__ left__True vocal folds right__ left__Arytenoids right__ left__Anterior commisure ___Anterior commisure ___Posterior commisure ___Subglottis ___

TRACHEA: Upper one-third ___Middle one-third ___Lower one-third ___Bronchi right__ left__Tracheotomy stoma___

FOR EACH SITE, SCORE AS 0=NONE, 1=SURFACE LESION, 2=RAISED LESION, 3=BULKY LESION

OTHER:Nose ___Palate ___Pharynx ___Esophagus ___Esophagus ___Lungs ___Other ___

TOTAL SCORE ALL SITES :_____

TOTAL CLINICAL SCORE :_____

DIFFERENTIAL DIAGNOSIS

Laryngotracheobronchitis

Asthma

Laryngomalacia

Vocal fold paralysis

Vocal fold nodules

Congenital laryngeal cyst

MANAGEMENT

No single effective modality of therapy

Recent modalities: surgery & adjuvant therapies

When respiratory distress is present When respiratory distress is present tracheotomy probably necessary to secure the airway

Several experts : tracheotomy should be avoided & decannulation as soon as the disease is managable by endoscopic procedures

MANAGEMENT

SURGERY

• Goals : optimal erradication of papillomatosis, preservation of normal structures, maintain voice qualityquality

• In aggressive disease : reducing disturbances due to tumor, reducing extention rate, maintain patency of airway, increasing time interval between procedures

• Modalities : forceps, CO2 laser, phonomicrosurgical, KTP/Nd:YAG laser, flash scan laser, microdebrider

MANAGEMENT

Forceps

Early modality

CO2 laser

Favored over cold instruments

Emission wave length of 10.600 nm

Controlled destruction of pathologic tissue & hemostasis

Convert light to thermal energy vaporizes the lesions

Several procedures & intervals

Beware of potential post op scar formation

MANAGEMENT

Phonomicrosurgical

Cold steel excision + principles of phonomicrosurgery, submucosal infusion & phonomicrosurgery, submucosal infusion & microinstrumentation minimize the risk of scar formation

KTP/Nd:YAG laser

532 nm wave

Found to be safe & effective

MANAGEMENT

Flash scan laser

Good early result

Microdebrider Microdebrider

Quickly debulking laryngeal papilloma

Smaller shaver blades (< 2 mm)

Reduced laryngeal scarring, adding safety compare to CO2 laser, shorter operating time, less expense

MANAGEMENT

ADJUVANT

> 4 surgeries/year, distal multisite spread &/or rapid regrowth with airway compromise

• Cidofovir• Cidofovir• Interferon α

• Photodynamic• Indole-3-carbinol• Acyclovir• Chemoterapy & hormon therapy

MANAGEMENT

Cidofovir

Most commonly recommended

Apoptosis induction on HPV-positive cellsApoptosis induction on HPV-positive cells

Improve airway & increase interval period

Nefrotoxicity & carcinogenesis

Repetitive procedures increase risk of airway compromise, cost, and morbidity

MANAGEMENT

Interferon αProteins manufactured by cellsEnzymes block DNA & RNA virus

replication + altering cell membrane less susceptible to viral penetrationsusceptible to viral penetration

The exact mechanism remains unclearSide effects : acute & chronic reactionsDose: 5 million unit/m2 (s.c) for 28 days 3

days/week for at least 6 months if excellent response, severe side effects 3 million unit/m2 days per week & slow weaning afterward

MANAGEMENT

Photodynamic

Transfer of energy to a photo-sensitive drug (dyhematoporphyrin ether/DHE)

Dose : 4,25 mg/kg (iv) prior to photoactivationwith argon pump dye laser

Significant decrease of disease growth

Drawback : markedly photosensitive for 2-8 weeks

MANAGEMENT

Indole-3-carbinol (I3C)

dietary supplement (high concentration in cabbage,brocoli, cauliflower)cabbage,brocoli, cauliflower)

inhibit papilloma formation in mice

dosage of active drug in human is still a controversy

MANAGEMENT

Acyclovirdependent on the precense of thymidine

kinase coded by virus still unknown for HPV, but conflicting clinical still unknown for HPV, but conflicting clinical

results in several studies (+) may be effective when there are codisease

factors

Chemoterapy & hormonal therapy not yet proven to be effective

MANAGEMENT

VACCINE

• Quadrivalent vaccine (HPV type 6,11,16,18) is undergoing phase III clinical studies

• Goal : a reduction in the susceptibility of neonates to the virus among vaccinated mothers

COMPLICATIONS

MORBID CONCEQUENCES

AIRWAY OBSTRUCTION

PROGRESSION TO SCC

COMPLICATIONS

• Distal spreading to trachea (±26%)

• Distal spreading to bronchi & lungs (±5%)

AIRWAY OBSTRUCTION

lungs (±5%)

• Rare• Commonly with lungs involvement• Etiology of progression is still

unknown

PROGRESSION TO SCC

COMPLICATIONS

COMPLICATIONS DUE TO SURGERY

• Pneumothorax• Pneumothorax• Tracheal or lung injury• Posterior glottic stenosis• Anterior glottic stenosis• Subglottic stenosis• Tracheal stenosis

PROGNOSIS

Is unpredictable

Significance recurrence rate (70%)

Most children require surgical procedures as often as 1 every 2-4 weeks (total of average 150 times before adolescent)

PROGNOSIS

Most children whom severely affected are with complications

Laryngeal papillomatosis in neonatus has a poor prognosisa poor prognosis

Death is often associated with complications caused by surgical procedures and distal course of disease’ spreading

PROGNOSIS

careful & sequential inspections are necessary to establish

the disease’ aggressivenessthe disease’ aggressiveness

• Some clinicians conduct it at their clinic• Others suggest early routine bronchoscopy in

operating theatre with 4-6 weeks interval in children with presumably aggressive disease

DISCUSSION

Proliferative benign tumor

Age 1 day to 84 years old

Quite common in children Quite common in children

Synonim : respiratory papillomatosis or recurrent respiratory papillomatosis

Divided into 2 categories :

• Juvenile-onset laryngeal papillomatosis

• Adult-onset laryngeal papillomatosis

DISCUSSION

JUVENILE- ONSET LARYNGEAL

PAPILLOMATOSIS

• 2-4 years old

ADULT-ONSET LARYNGEAL

PAPILLOMATOSIS

• 20-40 years old• 2-4 years old• ♂:♀ = 1:1• No apparent

differencies in surgical frequencies

• More common & aggressive

• <25% < 5x surgeries

• 20-40 years old• ♂>♀• Less aggressive• 50% < 5x surgeries

DISCUSSION

AGENT

• HPV type 6 & 11• Transmission is presumably vertically through birth

canal from mothers with genital HPV infection• More likely to be first born & vaginally delivered

because of long second stage of labor (Kashima)

DISCUSSION

AGENT

• Risk of a child contracting the disease from a mother with active condylomatous lesion & vaginally delivered = 1/400 (Shah, et al)

• In utero process & SC not yet proven to be effective to overcome the issue

NEEDS FURTHER RESEARCH

DISCUSSION

Hallmark of anamnesis : triad of progressivehoarseness, stridor, respiratory distress

Thorough, organized, frequent examination in clinical / operating room setting clinical / operating room setting

Examination with indirect laryngoscopy : flexible is considered superior to rigid

Biopsy is the gold standard

Coltrera & Derkay staging system : unified protocol to evaluate disease progression

DISCUSSION

Frequently detected after signs of respiratory distress are present need for tracheotomy

Prolonged tracheotomy + subglottic papilloma Prolonged tracheotomy + subglottic papilloma higher risk for distal spreading

Therefore tracheotomy should be avoided

DISCUSSION

When tracheotomy can not be avoided decannulation as soon as disease is managed by endoscopic proceduresby endoscopic procedures

Other studies : tracheotomy do not lead the spread

Other extralaryngeal structures which most affected : oral cavity, trachea, bronchi

DISCUSSION

THERAPY

• No single effective modality of therapy• No single effective modality of therapy• Surgery procedures requires skilled team &

properly equipped facility• Primary goals : optimal erradication of

papillomatosis, preservation of normal structures, & maintain voice quality

• Recently microdebrider is more favorable to CO2 laser

DISCUSSION

THERAPY

• Adjuvant therapy is required in ± 20% of all cases

• Frequently recommended : cidofovir & interferon-α

• Consideration on adjuvant therapy : indication & side effects

CONCLUSION

Juvenile-onset laryngeal papillomatosis is a disease with potential morbid consequences

No single effective modality of therapy

On-progress current modalities of therapy are On-progress current modalities of therapy are surgery and adjuvant therapies

Future research on its clinical course and predisposition factors are still needed

Alert, supportive, and educated parents or family is invaluable to the child’s safety

THANK YOU