papillomatosis current status
Dr. T. Balasubramanian M.S.
Recurrent respiratory papillomatosis is a
disorder of viral origin. It is associated with multiple exophytic
lesions present in the airway. It is a benign disorder, but can
cause airway complications with risk of malignant conversion. This
disease is difficult to treat because of its tendency to
recur. Some patients may experience spontaneous
regression of the disease, while others may suffer from aggressive
papillomatous growth requiring multiple surgical interventions. The
reasons for this extremes in behaviour are not clearly understood.
Etiology: Human papilloma
virus has been attributed as the causative organism. Viral particles
have never been consistently demonstrated in the papilloma lesions
even with electron microscopy. Use of viral probes have demonstrated
papilloma virus DNA in all the papilloma lesions studied.
Human papilloma virus: is a
small DNA containing non enveloped icosahedral (20 sided) capsid
virus. The DNA is double stranded and circular.
Depending on viral genetics 100 different
types of human papilloma viruses have been identified. Among the
types affecting the aerodigestive and genital tracts human papilloma
virus types 6 and 11 have been associated with the lowest malignant
potential, where as human papilloma virus types 16 and 18 have the
greatest malignant potential. Children infected
with human papilloma virus 11 have more obstructive airway early in
The human papilloma virus infects the basal
layer of the mucosa. The viral DNA enters the cells and gets
transcribed into RNA. This RNA is translated into viral proteins.
After infection the viral DNA can either be actively expressed or
can exist as latent infection in the mucosa. In latent infections
the mucosa remains clinically and histologically normal. During
latency, very little viral RNA is present inside the cells.
Reactivation of the virus can occur at any time leading to symptoms.
The viral genome has 3 regions:
1. The upstream regulatory region
2. E region / Early region: The E genes are
involved in oncogenes responsible for active replication of the
3. L region / Late region genes encode viral
Genome of Human papilloma virus
Human papilloma virus must have a means to
reactivate the necessary host replication genes to facilitate its
own DNA replication. One growth factor known to be associated with
proliferation of epithelial cells is the epidermal growth factor
receptor. Papilloma virus induce epithelial proliferation by
increasing the level of expression of epidermal growth factor or its
ligands. It may also increase cell proliferation by interacting with
p53 or other tumor suppressor proteins inhibiting their normal
Host immune plays an important role in the
pathogenesis of papilloma virus infections. The patient's
immunocompetence may influence the clinical course of the disease.
Both humoral and cellular immune responses may be compromised in
children with recurrent respiratory papillomatosis.
Recurrent respiratory papillomatosis may have
its clinical onset either during childhood or adulthood. Juvenile
onset respiratory papilloma is more aggressive, and adult onset
disease may be little bit less aggressive. In children recurrent
respiratory papillomatosis is the most common benign neoplasm of the
Incidence may be very variable ranging from 2
- 3 / 100,000 population. Observations suggest that most of these
patients are first born child to young primi gravida mothers. Primi
gravida mothers are more prone for prolonged second stage of labor
causing increased exposure to the virus. It is common in patients
among low socioeconomic status. It is worthwhile to
aggressively manage genital papillomatous infections to prevent
vertical transmission of the infection from mother to child.
Transmission: The mode of transmission of
human papilloma virus is unclear. Studies have demonstrated the link
between childhood onset recurrent respiratory papillomatosis to
mothers with genital papilloma virus infections; in adults evidence
suggests that it could be associated with oro genital contact.
Histology: It appears as
sessile or pedunculated masses. It may be pink or whitish in color.
The masses consist of finger like projections of non keratinised
stratified squamous epithelium supported by a core of highly
vascularised connective tissue stroma. The basal layer may be either
normal or hyperplastic and mitosis is generally limited to this
of respiratory papilloma
Recurrent respiratory papilloma lesions occur
often at anatomic sites in which cilitated and squamous epithelium
are juxtaposed. Common locations are:
1. Limen vestibuli of nose
2. Nasopharyngeal surface of soft
3. Laryngeal surface of
4. Upper and lower margins of
5. Under surface of vocal folds
7. Bronchial spurs
seen involving the vocal cord
Areas of transition from ciliated respiratory
eithelium to native or metaplastic squamous epithelium are commonly
involved as seen in patients with tracheostomies. Papilloma is seen
at the stoma and in the mid thoracic trachea. Children with broncho
pulmonary dysplasia, in whom prolonged endotracheal intubation may
result interruption of the continous respiratory mucosal surface
causing increased incidence of respiratory papillomatosis.
Injury to respiratory mucosa caused by
prolonged gastro oesophageal reflux may also increase the risk of
respiratory papillomatosis. Iatrogenic implantation of papilloma may
be prevented by avoiding injury to non diseased squamous or ciliated
epithelium adjacent to areas of frank papilloma.
Hoarseness: of voice may occur depending on
the position of the papilloma. It is worse if the lesion is present
in the vocal cord.
Stridor: occurs if the mass occludes the
laryngeal inlet. Commonly inspiratory becoming
Dysphonia: Children with respiratory
papillomatosis always present with certain degree of dysphonia
Affected children should undergo complete
physical examination. Airway compromise if any must be given top
priority. Tracheostomy will have to be performed in cases of acute
airway obstruction. Definitive diagnosis is possible only after
flexible fibre optic bronchoscopic examination.
Coltera and Derkay have evolved a staging
system to stage recurrent papillomatous lesions involving the
Coltera-Derkay method of staging
1. Voice: Normal - 0,
Abnormal - 1, Aphonia - 2
2. Stridor: Absent - 0, Present on activity -
1, Present at rest - 2
3. Respiratory distress - None - 0, Mild - 1,
Moderate - 2, Severe - 3, Extreme - 4.
For each site - 0 = none, 1=surface lesion, 2=
raised lesion, 3=bulky lesion.
Total score = Anatomical score + Total
Surgical: Microlaryngeal excision of the
lesion is performed. Laser excision is preferred in recurrent cases,
and for cases where tracheal mucosa is involved.
Adjuvant treatment: Most commonly adopted
criteria for initiating adjuvant therapy is the requirement of more
than 4 surgical procedures during a calender year, distal
multispread of disease.
Cidofovir: is a nucleoside analog that has
antiviral activity against herpes family of virus. This drug has
been shown to induce apoptosis in human papilloma virus infected
Interferons: are manufactured by cells in
response to a variety of stimuli, including viral infection.
Interferons when administered produce a blocking effect on viral
replication of RNA and DNA. It also alters the cell membrane causing
it become impervious to viral penetration. Hence interferon can be
adminstered as adjuvant.
Side effects of interferons
1. Flu like symptoms
2. Decreased growth rate of child
4. Spastic diplegia
Is based on the transfer of energy to a
photosensitive drug. The drug used is dihematoporphyrin ether (DHE).
This drug has a tendency to concentrate within papillomas more than
in surrounding normal tissue. Patients are typically treated
intravenously with 4.25mg /kg of DHE before
photoactivation with an argon pump dye laser.
Ribavirin: is an antiviral drug used to treat
pneumonia in infants caused by respiratory syncytial
virus has shown some promise in the treatment of
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