LITERATURE READING LARINGFARING

RECURRENT RESPIRATORY
PAPILLOMATOSIS
Presentant : Ichsan Juliansyah Juanda, dr.
Supervisor : Agung Dinasti Permana, dr., [Link].,
Sp. THT-KL (K)
1

Otorhinolaryngology
Head and Neck Surgery Departement
Faculty Of Medicine UNPAD
Dr. Hasan Sadikin General Hospital
2016

INTRODUCTION

Most
common
benign
neoplasm of the larynx among
children
2nd most common cause of
pediatric hoarseness
Disease of viral etiology and
May

involve

entire

aerodigestive tract
Benign disease, Morbidity due
to airway involvement and risk
Byron J. Bailey, Head & Neck Surgery-Otilaryngology, 5
of malignant
conversion
Wilkins, Philadephia,
2014

th

editon, Lippincot Williams &

INTRODUCTION

Diagnosed at 2 and 4 years of age

delay from onset of symptoms
averaging about 1 year

75% of the children have been

diagnosed before their 5th birthday

Childhood (juvenile onset recurrent

respiratory papillomatosis - JORRP)
more aggressive

Adulthood (adult onset recurrent

respiratory papillomatosis- AORRP)
Byron J. Bailey, Head & Neck Surgery-Otilaryngology, 5th editon, Lippincot Williams &
Wilkins, Philadephia, 2014

EPIDEMIOLOGY
4

CHILDHOOD ONSET
Often at 2-4 yrs old
Boys = Girls
No gender/ethnic
difference
More aggressive
19.7 surgeries per
child 4.4 per year

ADULT ONSET
Peaks 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

ETIOLOGY (HPV)
5
DNA containing virus - 7,900 base pairs long
dsDNA
Type 6 and 11
Also cause genital warts
Type

11

appear

to

have

more

obstructive airway course early in the

disease

and

greater

need

for

tracheotomy
Other types identified
Type

16

potential)

and

18

(most

malignant
Byron J. Bailey, Head & Neck Surgery-Otilaryngology, 5th editon,
Lippincot Williams & Wilkins, Philadephia, 2014

ETIOLOGY
6

HPV 11 Infection Associated with

Greater RRP Disease Severity
HPV 11 or HPV 6/11 Co-Inf required
more
surgical
intervention
suggesting
more
severe
manifestation

ETIOLOGY
7

HPV infection process initiates in basal layer

Viral DNA enters the cell
DNA then transcribed into RNA
RNA translated into viral proteins

Byron J. Bailey, Head & Neck Surgery-Otilaryngology, 5th editon, Lippincot Williams & Wilkins, Philadephia,
2014

ETIOLOGY
8

Host immune response compromised

Malfunction
response

Stealth like
surveillance

of

cell

effect

on

mediated
immune

HPV infection can be actively

expressed or latent
HPV DNA detected in the
normal mucosa of RRP
patients
Reactivation can occur at
any time
AORRP could be:
Activation of latent virus
acquired since birth
Activation of infection
contracted during adult life

HISTOLOG
Y9
Pedunculated
with
projections

masses
fingerlike

Non-keratinized stratified
squamous epithelium
Supported by a core of
highly
vascularized
connective tissue stroma

Sessile or pedunculated and irregular exophytic

clusters
10
MACROSCOPIC

Pinkish to white in coloration

TRANSMISSION
11

Exact mode of transmission unclear

Childhood onset linked to mothers with genital HPV infectio

Most likely to be first born, vaginally delivered to primigrav

Adult-onset RRP possibly associated with oral-genital conta

12

TRANSMISSION

Although there is close relationship between JORRP and maternal

condylomata, few patients exposed to genital warts at birth
manifest clinical symptoms
Not well understood
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
-- Patient immunity, Time/volume of virus exposure, Local tissue
trauma
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 101:645652

13

Immunodeficiency Increases
Severity of RRP

14

Lesion Characteristics

Any site along aero-digestive track, most often occur at sites

where ciliated and squamous epithelium are juxtaposed
Most common RRP sites:
Lumen vestibuli
Nasopharyngeal surface of soft palate
Laryngeal surface of epiglottis
Upper/lower margins of ventricle
Undersurface of vocal folds
Carina
Bronchial spurs

Lesion Characteristics
15

Viral DNA detected at normal mucosa recurrent after surgical

removal
Most common RRP condition:
Tracheostomized patient : stoma and mid thoracic trachea
(areas
where iatrogenic trauma to ciliated epithelium often induced
metaplasia)
Prolonged ETT used : alongside of the respiratory mucosa
GERD : risk factor for persistence of disease need additional
research

16

Pruess et al. Acta Oto-Laryngologica, 2007; 127: 11961201

17

SECONDARY FACTORS

Patient

immunity

(timing, length, and volume of virus

exposure)

Local traumas (intubation, extra esophageal reflux) must be

important in the development of RRP

Patients with AORRP had more lifetime sexual partners and

a higher frequency of oral sex than matched controls

CLINICAL FEATURES

18

Hallmark triad:
Progressive hoarseness
Stridor
Respiratory distress
Most often present with dysphonia
Stridor is usually 2nd symptom to manifest
Inspiratory biphasic
Chronic cough, recurrent pneumonia, failure to thrive,
dyspnea, dysphagia may be present
Sometimes undiagnosed until respiratory distress result

19

RRP THE GREAT

MASQUERADER

RRP often misdiagnosed

as :
Asthma
Croup
Tracheomalacia
Allergies
Vocal nodules
Bronchitis

20

CLINICAL FEATURES

Extralaryngeal spread of papillomas

13-30% children and 16% adults

Most frequent sites :
Oral cavity
Trachea
Bronchi
Pulmonary
Dissemination

21

PATIENT ASSESSMENT

Onset of symptoms?
Rate of progression?
Associated infection?
How is the cry?
Presence of respiratory distress?
Quality of voice change? Etiology
History :
Airway trauma/ previous intubation?
Perinatal period
STD history
Parental condylomata/HPV

22

Vocal cord nodules

Tracheomalacia (stridor since
birth)
Vocal cord paralysis

Subglottic cysts
Subglottic
hemangioma
Subglottic stenosis

Alternative Diagnosis to think

about:

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

23

PATIENT ASSESMENT

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 and possible tracheotomy is READILY
available (i.e. OR, ER, ICU)

24

PHYSICAL EXAMINATION

Auscultation of airway with stethoscope

Airway endoscopy needed for definitive diagnosis
Flexible fiberoptic (consider PATIENT
cooperation), smallest 1.9 mm, sequential
video
Exam under anesthesia (esp. if patient wont
cooperate)

25

EXAMINATION

Normal Respiratory cycle : Shorter inspiratory, longer

expiratory
Stridor of laryngeal origin Inspiratory, progress to
biphasic as airway narrowing progress
Placed on various position to elicit any chages on
stridor No changes RRP usually
Oxygen saturation should be observed
Pulmonary testing Where asthma is likely diagnosis
Blood gas analysis

26
MALIGNANT
TRANSFORMATION

1-7% of patients with RRP

Advanced disease, usually pulmonary extension
3rd or 4th decade of life
Lesions contain HPV type 11 and type 6
Gerien et al
Average duration to malignant transformation : 19-35 yrs
Pulmonary extension dx until malignant transformation :

9-21 yrs

27

TREATMENT MODALITIES
Adjuvant

Surgical

Microlaryngoscopy with
cups forceps removal

Microdebrider
CO2 laser
Phono-Microsurgical
KTP/Nd:YAG laser
Flash scan lasers

-Interferon
Indole-3-carbinol
Photodynamic therapy
Cidofovir
Acyclovir
Ribavirin
Retinoic acid
Mumps vaccine
Methotrexate
Hsp E7

28

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30

31

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

24 Hours post operative pain

Voice Quality post operative

32

Staging
RECURRENT RESPIRATORY
System
PAPILLOMATOSIS STAGING

Assess
functional
parameters,
Diagrammaticall
y catalogs
subsite
involvement
Assigns a final
numeric score
to the patient's
current extent
of disease

ADJUVANT THERAPIES
33

Approximately 20% need some form

of adjuvant therapy
Criteria :
> 4 surgical procedure/year
Distal or metastatic disease
Rapid re-growth of papilloma with
airway compromised

34

35

CIDOFOVIR

Effectiveness in intra-lesional route

Route :
Injection of 5mg/mL into papilloma bed
Microbedding total volume 2 mL
Repeating at 4-6 week intervals up to 6 months

Evidence :
Chadha : Complete vs Partial response (57% vs 35%)
McMurray : No statistical difference

Side Effect (Animal Studies) :

Malignant dysplasia of intra-lesional site
Nephrotoxicity and Mamary Adenocarcinoma
Lindsay : No Malignant transformation in human

36

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38

39

40

41

42

Hsp
E7

Recombinant fusion protein derived :

M. Bovis BCG heat shock protein 65
(Hsp65)
E7 protein of HPV 16

Activity has been demonstrated in genital wart

treatment
Clinical responses observed in HPV 16 - negative
lesions
Pediatric

patients

improving

clinical

course

(Derkay, 2005)
27 patients (13 F, 14 M) aged 2-18 years old
After baseline debulking

surgery HspE7

500g subsequently monthly for 3 doses over 60

days

43

HPV Vaccine

2 VACCINES AVAILABLE :
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

44

45

Highlights

RRP is a frustrating, captous disease with the potential

for morbid consequences due to its involvement of the
airway and the risk of malignant transformation.
No single modality of therapy shown effective, goals of
surgical therapy a safe airway
Many

adjuvant

therapies

supplementing

surgical

therapy, shown promise, but no adjuvant therapy cure

RRP
HPV vaccine may ultimately prevent transmission of this
disease eliminating it from the common practice

46

THANK YOU

HISTORY
47
Sir Morrell Mackenzie (1837-1892)
was the first to identify papillomas
as a lesion of the
laryngopharyngeal system in
children in the late 1800s

Sir Morrell Mackenzie

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

Chevalier Jackson

48

sexually
transmitted
disease in humans
14 million women,
or about 10% of
the female
population of childbearing age are
DNA positive but
have no visible
lesions while more
than 80 million
women, or 60% of
the at risk
population, are
HPV antibody
positive but DNA
negative
Clinically apparent
HPV infection has

49

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