By Mildred West,2014-07-06 13:59
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Laryngeal papillomatosis and current treatment R3 林世倉


     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)


    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

    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


    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


     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


     Malignant transformation:

    - rare event, 3% to 7% of the patients

    - potential cofactor: irradiation therapy, smoking


     Surgical management

    - The mean number of surgical procedures per child is 4.4 per year in

    juvenile-onset RRP

    - The CO (λ=10600 nm) laser utilizing the micromanipulator: mainstay 2

    of surgical management of pediatric RRP since 1970s

    ~ superficial vaporization

    ~ 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

    (HPV-infected basal cells), lower rate of recurrence, more precise

    treatment, less smoke and effective suction (less infectious laser


    ~ 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

    - Retinoic acid

    ~ potentially affects epithelial maturation and the ability of the viral HPV DNA to stimulate papillomatous growth

    ~ efficacy in selective patients

    ~ 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

     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


    ~ 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


    1. Katherine A. Kendall: Current treatment for laryngeal papillomatosis. Current

    Opinion in Otolaryngology & Head and Neck Surgery 2004, 12:157-159 2. Leena-Maija Aaltonen; Heikki Rihkanen; Antti Vaheri: Human Papillomavirus in

    Larynx. Laryngoscope 112:700-707, 2002

    3. Brian J. Wiatrak: Overview of recurrent respiratory papillomatosis. Current

    Opinion in Otolaryngology & Head and Neck Surgery 2003, 11:433-441 4. De Clercq E, Holy A, Rosenberg I, et al.: A novel selective broad-spectrum

    anti-DNA virus agent. Nature 1986, 323:464-467

    5. Van Custem E, Snoeck R, VanRanst M, et al.: Successful treatment of a

    squamous papilloma of the hypopharynx-esophagus by local infections of

    (S)-1-(3-hydroxy-2-phonylmethoxypropyl) cytosine. J Med Virol 1995,


    6. W. Peyton Shirley, Brian Wiatrak: Is cidoforvir a useful adjunctive therapy for

    recurrent respiratory papillomatosis in children. International Journal of Pediatric

    Otorhinolarygology (2004) 68, 413-418.

    7. Pransky SM, Magit AE, Dearns DB, et al: Intralesional Cidofovir for recurrent

    respiratory papillomatosis in children. Arch Otolaryngol Head Neck Surg 1999,

    125: 1143-1148

    8. Snoeck R, Wellens W, Desloovere C, et al.: Treatment of severe laryngeal

    papillomatosis with intralesional injections of Cidofovir. J Med Virol 1998,


    9. Philip J, Andreas L, Ronald S, et al.: Preliminary report of enolaryngeal and

    endotracheal laser surgery of juvenile-onset respiratory papillomatosis by

    Nd:YAG laser and a new fiber guidance instrument. Otolaryngol Head Neck Surg

    2004; 131:44-9

    10. Pashley NR: Can mumps vaccine induce remission in recurrent repiratory

    papilloma? Arch Otolaryngol Head Neck Surg 2002, 128: 783-786 11. Sethi N, Palefsky J: Treatment of human papillomavirus (HPV) type 16-infected

    cells using herpes simplex virus type 1 thymidine kinase-mediated gene therapy

    transcriptionally regulated by the HPV E2 protein. Hum Gene Ther 2003,


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