CASE REPORT

Niger J Paed 2014; 41 (1):70 –73

Ahmed PA

Ulonnam CC

Undie NB

Recurrent Respiratory

Papillomatosis: A Report of two

cases and review of literature

DOI:http://dx.doi.org/10.4314/njp.v41i1,13

Accepted: 3rd September 2013

Abstract Background: Recurrent

Respiratory Papillomatosis (RRP)

is a non-cancerous tumour of the

upper airway caused by the

human papilloma virus, present-

ing as “wart-like” growth, which

could be anywhere from the nose

to the lungs commonly in the lar-

ynx.

Design and Setting: Review of

two cases at the National Hospital

Abuja (NHA).

Objectives: To highlight the chal-

lenges in the management of

RRP.

Subjects: Two patients diagnosed

with RRP were referred to the

paediatric respiratory clinic be-

tween 2009 and 2012. Case one is

a four year old female who pre-

sented with persistent hoarseness

of voice, breathing difficulty and

noisy breathing of one year dura-

tion. She was born at term by

spontaneous vertex delivery to a

mother who had vaginal warty

lesion excised during pregnancy.

A neck X-ray showed opacities

around the laryngeal region with

total obliteration of air column

with histological confirmation of

squamous papilloma. She had

eight excision surgeries within a

two years period with treatment

with oral acyclovir, interferon, and

methotrexate and tracheotomy

tube in situ. Case two, a six year

old female presented with persis-

tent hoarseness of voice that pro-

gressed to loss of voice, noisy and

difficulty in breathing, snoring and

frequent arousal from sleep of 1½

years. Histology was diagnostic of

laryngeal Papillomatosis and she

had two excisions surgeries and

treatment with oral acyclovir and

tracheotomy tube in place.

(

)

Ahmed PA

Ulonnam CC

Department of Paediatrics,

Undie NB

Department of Otorhinolaryngology,

National Hospital Abuja.

Nigeria.

Email: ahmedpatience@yahoo.com

Conclusion: RRP though a slow

growing tumour, presently has no

definitive cure. Excision surgeries

provide temporal relief and antivi-

ral agents adjuvant therapies. Pre-

vention with vaccination is desir-

able.

Keyword: Recurrent respiratory

Papillomatosis, Human papilloma

virus.

Introduction

RRP is categorized into juvenile onset RRP (JORRP)

and adult onset RRP (AORRP) depending on the presen-_,

2

Recurrent respiratory Papillomatosis (RRP) is caused by

a viral agent –the Human papilloma virus (HPV) of

which serotype six and 11 are the most common types.

tation before and after the age of 12 years, respectively.

4

, 5

The prevalence of the disease is variable depending

1

on the age of presentation, country and socioeconomic

status of the population being studied, but generally₂ ac-

RRP is characterized by exophytic wart–like growth that

could be found anywhere from the nose to the lungs₂,

with the larynx as most common site of occurrence.

Although the condition is a common benign neoplasm of

the larynx among children and a frequent cause of child-

hood hoarseness, the course is variable in expression

with some patients experiencing spontaneous regression

and others suffering aggressive papilloma growth requir-

ing multiple surgical procedure and medication for

cepted to be between one and four per 100 000.

A

prevalence 2.59/100 000 and 1.6/100 000 was found

among paediatric population in two ₆United States cities

(Atlanta and Seattle) respectively. Mgbor NC et al

from Enugu, Nigeria reviewed 54 cases of laryngeal

Papillomatosis, over an eleven year period (1988 – 98)

of which 64% were children (≤15 years), with most pre-

senting as upper airway emergency that necessitated

2

7

relief. The morbidity and mortality of RRP are attribut-

emergency tracheotomies. The child₇ren required multi-

able to the tendency of the tumour growth to recur and

ple surgeries than the adult group. Despite the low

prevalence of RRP, it has been shown to have signifi-

cant economic and emotional burden on the patients₁ as

they go through the cycle of recurrence and surgeries.

spread throu_,g₃hout the respiratory tract causing airway

2

obstruction. It is associated with a less than one

2

, 3, 4

percent risk of malignant transformation.

7

1

This report therefore aims to highlight the challenges in

management of RRP in a resource poor setting.

has no hearing loss or otalgia, no fever, no night sweats,

but with some weight loss. Other systemic review was

essentially normal. She had a course of antibiotics to

relief the cough.

Case 1

Miss TJ, is a four years old female resident with her

parent in Nyanya, Nasarawa state (a border town to

Abuja- Nigeria). She was first seen in the paediatric res-

piratory clinic in July 2009 on referral from the ENT

clinic. Her complaints were that of persistent hoarseness

of voice, noisy and difficulty in breathing of one year

duration. Her hoarseness of voice has been progressive

since first noticed by the parents. She had no history to

suggestive voice abuse, foreign body inhalation, cough

or catarrh. She had worsening difficulty in breathing

with fast breathing, but no cyanosis, orthopnea or leg

swelling.

Her pregnancy was not adversely eventful and was de-

livered by spontaneous vertex with an uneventful neona-

tal period. She is the first child in a monogamous family

setting with two other females and a male sibling, all

alive and well. Her father is 48 years civil servant with

tertiary level education, while the mother a 36 years old

housewife also with tertiary level education. No history

of warty lesion was reported in either of the parents.

On examination she was an underweight child with a

tracheostomy tube in insitu. She had an inaudible voice

and was not in respiratory distress. Other examination

findings were essentially normal. Histology report

grossly showed greyish white tissue aggregating

3x2x1cm; and microscopy was hyperplastic and papillo-

matos stratified epithelium overlying a fibrovascular

tissue, with the epithelium koilocytic atypia. Diagnosis

was recurrent laryngeal Papillomatosis. She has had two

excisions surgeries for laryngeal polyps within a one

year period and was commenced on oral acyclovir.

She was born at term, by spontaneous vertex delivery.

Mother had vaginal warty lesions which were excised

during pregnancy. Her immunization was routine NPI

vaccines and she’s had a normal developmental history.

Her father is a 42 years old Taxi driver with tertiary

level education, and her mother is a 38 years old house-

wife with secondary level education. She is the youngest

child in the family with two elder sisters and a brother,

all doing well.

Examination revealed a well nourished young child with

a functional tracheostomy tube in situ. She had no respi-

ratory distress. Further evaluation by indirect laryngo-

scopy showed a wart- like lesion on the vocal cord,

while a neck X-ray showed opacities around the laryn-

geal region with total obliteration of air column. Histol-

ogy report grossly was of multiple pieces of whitish soft

tissue aggregating 2.1 x 1.5 cm in the glottis and epiglot-

tis; while microscopy was hyperplastic stratified

squamous epithelium overlying a loose fibrovascular

stroma; the epidermis tends to have finger-like projec-

tions into the core, with several cell of superficial epi-

dermis of koilocytic atypia. Retroviral screening was

nonreactive. Diagnosis was recurrent laryngeal Papillo-

matosis.

Discussion

RRP was first described by Sir Morrell Mackenzie in

1800s; he recognized it as a distinct lesion of the larynx

in children. It was with modern genetic technology in

2

, 4

1990s that HPV was confirmed as the causative agent.

Over a 100 serotype of HPV have been identified, with

serotypes sometimes classified by anatomical sites;

namely anogenital, non- genital cutaneous and non-

genital mucosal. The HPV six and 11 can cause both

genital warts and laryngeal Papillomatosis. Some are

also classified as ‘high risk’ type when it is associated

with malignant transformation or ‘low risk’ type mani-

5

festig as warts (Condylomatosis), with low risk for ma-

5

lignancy. The low risk serotypes six and 11 are the

most common₂t_,y₅p_,₈es found to be involved as causative

She’s had eight excision surgeries ranging from two

months to eight months interval from recurrence. Drug

treatments given were oral acyclovir for two year, inter-

feron and lately methotrexate. Her tracheostomy tube

has been in place for over two years.

agent of RRP.

The aetiology of JORRP is gener-

ally agreed to be vertical transmission either in preg-

nancy or at child delivery, especially when a mother has

frank condylomatosis or is act_,i₅vely shedding disease

3

from a recent HPV infection. The two patients, had

symptoms before age five, which is common presenta-

tion in the juvenile form of the disease, mo_,₉stly transmit-

Case 2

5

ted vertically during gestation or delivery. The mother

Miss AF, a six years female was first seen at the ENT

department and referred to the paediatric respiratory

clinic of the hospital. Her complaints started 1½ yrs

earlier when she developed persistent hoarseness of

voice that progressed to loss of voice. There was associ-

ated noisy and difficult breathing, snoring while asleep

and frequent arousal from sleep. Later in the course of

the illness she developed cough that was productive of

yellowish sputum. She had no history of sore throat,

dysphagia, and odynophagia or globus sensation. She

of case number one had a history of anogenital wart

which was excised in pregnancy, a risk for JO₃_,R₅RP es-

pecially when its present at time of delivery.

Some

reports have showed that about 30- 60 percent of moth-

ers with geni₉t_,a₁l₀papilloma had their children affected

with JORRP.

Three major risk factors that have been

identified for development of JORRP in₃c_,₉l_,u₁d₀e; teenage

mother, vaginal delivery and first born. The two

mothers of the cases in this series were well over

twenty, while the second case was the first child of the

7

2

10, 11

sibility.

family. No other members of the family manifested the

warty- lesions in the second case. Both of the patients

were delivered vaginally. The relative risk of developing

RRP after vaginal delivery ranges from two to seven in

Patients with asthma, bronchiolitis or allergies tend to

have recurrent coughs and wheezes and a possible

family history atopy. Most RRP are diagnosed via laryn-

goscope or bronchoscopy as a cauliflower-like warty

growth. It is necessary that viral typing is done to deter-

mine the prognosis where the facility is available. Chest

and neck radiograph may reveal intratracheal densities.

Other findings in chest radiograph include segmental or

lobar atelectesis and post obstructive pneumonia.

CT scan of the upper airway may be helpful to reveal

tumor-like papillomatous growth. Histological findings

in biopsied lesion show growth of keratinized squamous

epithelium overlying a fibrovascular core. Koliocyte,

vacuolated cells with clear cytoplasmic inclusion are

seen₁₀, with variable degrees of dysplasia and metapla-

sia.

1

000, corresponding to odd ratio of 231 to 400 com-

pared with children born vaginally wi₁t_,h₈out condylomata

showing a low risk of transmission. The HPV DNA

has been identified in the upper airways of as many as

8

5% of normal unaffected children. This has fuelled

2

debate on the benefit of offering caesarean section rou-

tinely to mothers with anogenital condylomata. JORRP

8

occur in one of 109 children delivered via caesarean

section to mother with HPV infection of the anogenital

region. This suggests other modes of transmission,

among which is the haematogenous spread of HPV to

the fetus while in- ut₁e₁ro as HPV have been demon-

strated in cord blood.

Postnatal contact with₁infected

1

mother is also a possible mode of transmission. In con-

trast, the risk for AORRP has been associated with

sexual transmission especially in pers₁₀o_,n₁₁s with multiple

sexual partners and frequent oral sex.

Several staging methods have been put forwarded for

RRP, but none is uniformly accepted. Attempts are to

standardize the evaluation of RRP patients, based on

area of involvement, severity of involvement, and obser-

vation data such as the₁₁_,p₁₃atient voice quality and extent

of respiratory distress.

1

0

JORRP affects male and females in equal proportions,

although the two cases presented were fe₁₀males, while

the males are mostly involved AORRP. The age of

occurrence reported ranges from one day to 84 years;

however a bimodal distribution is seen with the peak age

range of juvenile form at two to four years and that of

At present, there is no cure for RRP and no single treat-

ment has consiste₁ntly been shown to be effective in

eradicating RRP. Surgery is the mainstay of treatment,

with several surgical methods that include direct resec-

tion with operating microscopes, endoscopic debulking

1

2

the adult at 20 to 40 years. The two cases in this re-

view had onset of the disease within the peak age for the

juvenile form. RRP most often involves the larynx b₂ ut

with microdebriders, laser ablative surgery using CO

Nd: YAG laser, pul₁s_-₃e_,₉d_-₁y₁e laser and most recently the

Shaver technology. Surgical techniques aim to

2

,

, 11

can be seen in any part of the aero digestive tract.

Extra- laryngeal spread₁o₁ f RRP occurs in 30% of chil-

dren and 16% of adult,

which is an indication of pro-

remove papillomatous lesion, maintain safe airway and

3

gressive disease common with the JORRP type. The

two patients in this report had progressive hoarseness,

stridor and respiratory distress. Most reviews show

that hoarseness of voice is the pr₁i₀n_, c₁₁ipal presenting

normal airway anatomy. Despite successful removal,

recurrence after surgery is common with complications

1

like dysphonia, excessive airway scarring and stenosis.

The case one in this report has had eight surgeries with

intervals from two months to eight months, which is a

great burden for the family. Serotype 11 has being

shown to be more likely associated with development of

aggressive disease requiring frequent surgical procedure,

adjuvant medical thera₁pies and sometimes tracheostomy

to keep airway patent.

symptoms among paediatric patients.

Stridor which

is the second common sympto₁m begins as inspiratory,

1

and then progress to biphasic. Other symptoms identi-

fied includes, chronic cough, paroxysms of choking,

recurrent pneumonia, failure to thrive, dyspnoea,

dysphasia and acute life threatening event which are

demonstrated in the two cases. At time of presentation it

is important to identify respiratory distress for immedi-

ate transfer of patient to emergency room or operating

room to ensure that a safe airway is established. A laryn-

goscopic examination should be performed on stable

patient. This is challenging in children and requires ex-

amination under anaesthesia in operating room.

Adjuvant medical therapy is indicated as surgery does

4

not eradicate the disease. Several adjuvant therapies

have been employed; unfortunately, most of these meth-

8

ods have not been rigorously tested. The criteria for

commencement of adjuvant therapy are the necessity for

more than four surgical procedures annually, rapid re-

growth of papillomata with airway compromise and

3

The natural history of RRP is highly variable; patient

may experience a lifelong remission after initial disease

whereas some will require periodic surgeries ranging

from days to weeks in addition to adjuvant medical

remote multisite spread of the disease. The list of adju-

vant medical therapy include; antiviral agents (acyclovir,

ribavarin, cidofovir); interferon, retinoid (oral metabo-

lite or analogue of vitamin A), photodynamic therapy,

zinc, antireflux medication, cyclooxygease -2- inhibitor,

methotrexate, preventive vaccine (mumps, MMR,

quad₂r_-₄i_,v₉_-a₁l₂ent HPV, heat shock protein E7) and gene ther-

1

, 2, 4

The clinical features of RRP are often

therapies.

mistaken as asthma, croup, allergy, laryngitis, vocal

nodules, bronchitis, foreign body aspiration, gastroe-

sophaeal reflux disease, and malingering. Stridor present

since birth may be diagnosed as laryngomalacia, sub-

glottis stenosis, or a vascular ring, but RRP is still a pos-

apy.

These treatment focus on several mechanisms

like immunomodulation, disruption of molecular signal-

ling cascade or HPV replication resulting in apoptosis,

7

3

inhibition of proliferation, growth arrest and/or prom₃ o-

tion of normal differentiation in HPV infected cells. In

both of the cases, acyclovir was employed as first line

adjuvant medication. This is for reason of availability

and documented evidence of usage for treatment of

RRP. Activity of acyclovir is dependent on the presence

of virally encoded thymidine kinase, an enzyme that is

not known to be encoded by HPV. Acyclovir, however

have been found effective in some cases when a concur-

rent viral infection or viral co- infection with herpes

simplex virus, cytomegalovirus and Epstein - Barr virus

occur. Patient with co-infe₁ction appear to have more

aggressive clinical course. Interferon has been exten-

sively investigated for treatment of RRP. They are class

of protein that are manufactured by cells in response to a

variety of stimuli including viral infection. The exact

mechanism of action is unknown; however, they modu-

late immune system and epithelial development by in-

creasing production of protein kinase and endonucleases

which inhibit viral protein synthesis. Interferon has

adjuvant therapies with interferon and acyclovir in addi-

tion to surgeries.

The economic and medical burden of RRP makes pre-

vention of paramount importance. There are two HPV

R

vaccines available fo_Rr usage. These are Gardasil from

5

Merck, and Cervirix from GlaxoSmithKline (GSK).

Both vaccines were developed with virus-like particle

(VLP) that stimulates the surface of HPV. The Cervirix

contains VLP to stimulate response to serotype 16 and

18, while Gardasil is a quadrivalent vaccine with VLP

for serotypes 6, 11, 16 and 18. Successful stage II₅trials

have been conducted with these two vaccines. Al-

though the usage is targeted at young age group before

commencement of sexual activities for the prevention of

cervical cancers, with a future hope for the decline of

RRP also.

Conclusion

1

shown to reduce severity of growth of papilloma. Com-

mon interferon side effect includes acute reactions

RRP is a chronic disease caused by HPV characterized

by cauliflower-like warty growth in the aerodigestive

tract. The lesion is commonly found in the larynx.

Hoarseness of voice is the commonest symptom and

patient can present with acute life threatening airway

obstruction. Surgery is mainstay of treatment but does

not provide cure. Several adjuvant medical treatments

are required for frequent relapse, lesions with rapid re-

growth causing airway obstruction and those in remote

site. RRP cause substantial emotional and economic

burden in patient and the family as well as create man-

agement challenge to the medical practitioner. The

greatest promise for future prevention rest with the de-

velopment of an HPV vaccine, and hence reduced man-

agement challenges for HPV- associated diseases.

(

fever, generalized flu-like symptoms, chills, headache,

myalgia and nausea) and chronic reactions ( reduced

growth, increased liver transaminase level, lecopenia,

diplegia, febrile convulsion, rash, thrombocytopenia,

1

alopecia, dry skin, generalized pruritis and fatigue). For

2

children, the dosage for treatment of RRP is 5MU/m

subcutaneous daily dose for 28 days; then three days

per week for six month. With good response the dosage

2

is reduced to 3MU/m 3 days per week followed by slow

1

weaning. If no clinical response is seen at 6 month, it is

advised to discontinue with the treatment as in the first

patient, with Methotrexate employed as alternate medi-

cation. It is an antimetabolite that inhibits DNA synthe-

9

sis and repair by affecting folate metabolism. There are

reports of cases where the uses have demonstrated a

marked improvem₉e_,₁n₂t in both severity of the disease and

Conflict of interest: None

Funding: None

surgical interval.

Both cases in this reporthave had

References

5

6

. Freed GL, Derkay CS. Prevention

9. Quin FB, Ronald W et al. Recurrent

respiratory papillomatosis. Grand round

presentation at UTMB, department of

otolaryngology. April 1999. Web link:

www.otohns.net/default.asp?id=14631.

1

. Derkay CS, Wiatrak B. Recurrent

respiratory papillomatosis: a re-

view.The Laryngoscope. The

American Laryngological, rhi-

nological and Otological Society,

Inc. 2008; 118: 1236-1247.

. Larson DA, Derkay CS. Epidemiol-

ogy of recurrent respiratory papillo-

matosis. APMIS. 2010; 118: 450-

of recurrent respiratory papillomato-

sis: role of HPV vaccination. Inter-

national Journal of pediatric otorhi-

nolaryngology. 2006; 70: 1779-

1

0. Harman EM, Mosenifar Z, Sarma S et al.

Recurrent respiratory papillomatosis.

Medscape reference. 2011. Web link:

emedicine.medscape.com/

1

803.

. Armstrong LS, Preston EJ, Reichert

M et al. Incidence and prevalence of

recurrent respiratory papillomatosis

among children in Atlanta and Seat-

tle. Clin infect dis. 2009; 31(1): 107

2

3

article/302648.

11. Quin FB, Ryan MW et al. Recurrent

respiratory papillomatosis. Grand round

presentation at UTMB, department of

otolaryngology. 2003. Web link:

www.utmb.edu.otoref/grnds/

papillomatosis-2003-0625/

4

54.

. Katsenos S, Berker HD. Recurrent

respiratory papillomatosis: a rare

chronic disease, difficult to treat

with potential to lung cancer trans-

formation: apropos of two cases and

brief literature review. Case Rep

Oncol. 2011; 4(1): 162-171. ISSN

-109.

7

8

. Mgbor NC, Dahilo EA, Mgbor S.

Laryngeal papillomatosis: an eleven

year review of 54 cases in Enugu.

Nigerian journal of otorhinolaryn-

gology. 2005; 2(2): 64-69

. Lee JH, Smith RJ. Recurrent respi-

ratory papillomatosis: pathogenesis

to treatment. Current opinion in

otolaryngology & head and neck

surgery. 2005; 13: 354-359.

papillomatosis 2003-0625.htm.

12. Avidano MA, Singleton GT. Adjuvant

drug strategies in treatment of recurrent

respiratory papillomatosis. Otolaryngol

head and neck surg. 1995; 112 (2): 197-

1

662–6575 www.karger.com/cro

4

. Strong MS. Recurrent respiratory

papillomatosis. Internet publication.

Weblink:http://famona.sezampro.rs/

medifiles/otohns/scott/scott631.pdf.

2

02. (abstract) [PubMed - indexed for

MEDLINE

1

3. Derkay CS. Recurrent Respira-

tory Papillomatosis. Laryngoscope.

2

001;111:57-69.