Laryngeal papillomatosis and current treatment
R3 林世倉
Introduction
‧ Recurrent respiratory papillomatosis (RRP): Three clinical subgroups, including
pediatric cases, adults-onset cases, pediatric cases persist into adulthood.
‧ Most common sites of involvement: within the larynx
‧ Extralaryngeal sites: trachea, esophagus, lungs parenchyma, oropharynx, oral
cavity, nasal cavity, and other head and neck sites
‧ The most common benign laryngeal neoplasm to occur in children
‧ Defy most medical and surgical treatments
‧ Caused by human papilloma virus (HPV):
a. Double-stranded DNA with an icosahedral-shaped virion protein capsid with a
diameter 55 nm.
b. Genome consists of three regions: upstream regulatory region (URR), early (E,
E1-7, replication of viral genome) and late (L, L1-2, structural proteins)
regions
c. Infect basal cells of epithelium
d. More than 90 subtypes of HPV are known:
- Only viral subtype 6, 11 and, rarely, 16 and 18 have been noted in cases
of RRP
- High-risk subtypes 16 and 18: malignant transformation in the
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laryngotracheal airway in cases of RRP ( high risk: subtype 31, 45)
Cutaneous warts: types 2 and 3
Condylomas: HPV types 6 and 11
Cervical cancer: HPV types (80%)16, 18, 31 and 45
‧ Laryngeal and genital HPV infection
a. The relationship between maternal genital condyloma acuminata in children
with RRP was first noted in 1956
b. A history of maternal condyloma was found in more than 30% of mother
bearing children with juvenile-onset laryngeal papillomatosis
c. In 1982, Mounts, et al. implicated HPV types 6 & 11 in the pathogenesis of
laryngeal RRP
d. Both caused by HPV subtypes 6 & 11 – vertical transmission in most of cases
(vaginal)
e. Rare in cesarean-delivered children
f. Adult-onset laryngeal papillomatosis- orogenital spread (clear evidence is
lacking). Junctional areas of cuboidal and cylindrical epithelium in both the
larynx and the uterine cervix may favor the existence of HPV infection.
‧ Milestones in the history of laryngeal human papillomavirus infection.
‧ Prevalence of HPV by PCR testing in the larynx
Histologic Features
‧ Pedunculated masses of slender projection of nonkeratinizing stratified squamous
epithelium supported by a core of highly vascular connective tissue stroma
‧ Cellular differentiation has been noted to be abnormal, with altered expression and
production keratins
‧ Histologically benign. Dysplasia and malignant changes may occur
Epidemiology
‧ The incidence: 4.3 per 100,000 people in the United States, 3.6 per 100,000 from
study in Denmark
‧ Bimodal age distribution
- the first peak: children younger than 5 years of age, 25% presenting
during infants
- the second peak: between the ages of 20 and 30 years
‧ Sex ratio
- juvenile-onset: equal
- adult-onset: M:F =2:1 to 4:1
‧ HPV 6 and HPV 11 are most commonly found in laryngeal papilloma lesions
‧ Typical site of infection at diagnosis: vocal folds
‧ Silverberg et al. (Danish): 7/1000 births to women with a maternal history of
genital warts resulted in RRP in their offspring
‧ Delivery times > 10 hours: Twofold of risk
Clinical appearance
‧ Initially hoarseness or aphonia, subsequently airway obstruction, stridor
‧ Less commonly, chronic cough, recurrent pneumonia, failure to thrive, dysphagia,
or acute life threatening events
‧ Tracheostomy may predispose children to distal tracheobronchial spread
Clinical course
‧ The course of the disease is unpredictable
- some patients recover after one laryngeal procedure
- in others the disease runs a relapsing course
‧ Two risk factors for frequent laryngeal procedures
a. young age at the onset of papilloma
b. a lesion extending to the anterior third of the vocal folds
‧ Children whose disease was diagnosed before the age of 3 years had a worse
prognosis
‧ Malignant transformation:
- rare event, 3% to 7% of the patients
- potential cofactor: irradiation therapy, smoking
Treatement
‧ Surgical management
- The mean number of surgical procedures per child is 4.4 per year in
juvenile-onset RRP
- The CO2 (λ=10600 nm) laser utilizing the micromanipulator: mainstay
of surgical management of pediatric RRP since 1970s
~ superficial vaporization
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-
~ Scarring with subsequent airway obstruction, webbing, hoarseness,
possibility of endolaryngeal tube ignition, thermal injury to
surrounding tissue.
Pulsed dye laser (λ=577 and 585 nm): effective in vascular tissue
~ Franco et al.: pilot study on 41 adult cases (2002), most effective for
smaller, sessile lesions.
~ Less effective for larger, more exophytic lesions owing to the limited depth
of penetration of the laser
Fiber-guided Nd:YAG laser (λ=1064 nm):
~ Philip et al. (2003), 5 patients (4-8 y/o): deep penetration
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(HPV-infected basal cells), lower rate of recurrence, more precise
treatment, less smoke and effective suction (less infectious laser
plume)
~ Sullivan et al. and Dagidin: damaging vocal cord mobility, scarring, or
acute postoperative edema with consecutive dyspnea
Microdebrider
~ Pasquale et al.(2003), Petel et al. (2003), El-Bitar et al.(2002): more
rapid improvement in voice quality, shorter procedure times, and lower
overall procedure costs, no soft tissue complication
‧ Medical treatment
- Numerous adjuvant medical therapies are available: none of these
demonstrated a curative result
- Interferon (Interferon-α2a)
~ the most commonly accepted adjuvant medical therapy for pediatric RRP
~ a family of nonspecific regulatory proteins associated with a variety of
antiviral, antiproliferative and immunomodulating activities
~ given systemically by subcutaneous injection
~ eradication of disease in 30%-50% of patients
~ potential side effects and toxicities related to interferon:
a. neuropsychiatric complications and bone marrow suppression
b. Neutropenia and thrombocytopenia may occur, along with exacerbation
of autoimmune disorders, renal dysfunction, cardiac dysfunction, liver
dysfunction, alopecia, and impaired hormone levels leading to
infertility among women
c. significant rebound phenomenon may occur with extensive regrowth of
lesions after cessation of interferon-α2a
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Retinoic acid
~ potentially affects epithelial maturation and the ability of the viral HPV
DNA to stimulate papillomatous growth
~ efficacy in selective patients
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-
-
~ clinical trials have not demonstrated consistent, significant response
rates
Photodynamic therapy
~ base on a selective uptake of hematoporphyrins by neoplastic cells and
subsequent exposure to specific wavelength laser light
~ Only variable results have been reported in the literature
Indo-3 carbinol/diindolylmethane (I3C/DIM)
~ derived from eating cruciferous vegetables ( broccoli, cabbage, and
cauliflower)
~ estrogen metabolites: potential antipapilloma effect
~ significant regression in cervical intraepithelial neoplasia
~ Rosen et al.(1998): safety and efficacy of pre I3C/DIM in 18 children
(a small series)
Cidofovir
~ nucleoside monophosphate analogue: inhibits viral DNA polymerase,
active against many DNA viruses such as herpes virus, EBV,
cytomegalovirus, adenovirus, and poxvirus
~ (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC)
~ FDA: cytomegalovirus retinitis in HIV-positive patients
~ injection after gross removal of the papillomas, max. doses: 5 mg/kg
~ treat papilloma at ant. commissure without risk of web formation
~ Van Custem et al. (1995): first report, Cidofovir in the treatment of
aerodigestive tract papillomas ( papillomatosis at upper esophagus and
hypopharynx ), disease free for 4 years
~ Snoeck et al. (1998): the use of Cidofovir in 17 adult patients with
laryngeal papillomatosis, 2.5 mg/mL every 2 weeks until a complete
clinical response
a. 10 patients remained disease free
b. 4 patients who relapsed responded to a repeat series of injections
and remained free of disease
c. 3 patients who were not cured of the papillomas required therapy
much less frequently than before
~ Pransky et al. (1999): 5 children who had required laser therapy more
frequently than once a month
a. one patient had complete remission
b. three pateintes had a significant decrease
c. one patient have had an “erratic” response
~ W. Peyton et al. (2003): 11 children who were requiring debridement of
papillomas at least every 6 weeks
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a. 3 patients had impressive improvement
b. 2 patients had a partial response
c. 6 patients: cidofovir was considered ineffective
d. Cidofovir (5mg/mL) did not decrease the severity or frequency of
operative intervention for RRP in the majority of children in this
study
~ Details regarding the best treatment protocol for Cidofovir infection are
yet to be worked out
Vaccine research
~ Pashley (2002): 11 patients with pediatric RRP underwent sequential
surgical debridement in the operating room with laryngeal injection of
mumps vaccine.
~ Remission occurred in 76% of patients
Gene therapy
~ Sethi et al.(2003): direct gene transfer of the HSV-1TK (herpes simplex
virus type 1 thymidine kinase) into HPV-16-infected cells expressing E2
protein may result in cell death
Reference
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anti-DNA virus agent. Nature 1986, 323:464-467
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squamous papilloma of the hypopharynx-esophagus by local infections of
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respiratory papillomatosis in children. Arch Otolaryngol Head Neck Surg 1999,
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