C in the Pediatric Population The Management of Condyloma Acuminata E

CM E
The Management of Condyloma Acuminata
in the Pediatric Population
Donna A. Culton, MD, PhD; Dean S. Morrell, MD;
and Craig N. Burkhart, MD
CM E
EDUCATIONAL OBJECTIVES
1. Discuss the routes of transmission of
condyloma acuminata in the pediatric population.
2. Determine which factors may
suggest a route of transmission for
condyloma acuminata in children
other than sexual abuse.
3. Outline the available treatment
options for condyloma acuminata in
children.
Donna A. Culton, MD, PhD, is Resident
Physician, Department of Dermatology,
University of North Carolina at Chapel Hill.
Dean S. Morrell, MD, is Associate Professor
and Residency Training Program Director, Department of Dermatology, University of North Carolina at Chapel Hill. Craig
N. Burkhart, MD, is Assistant Professor and
Director of Medical Student Education,
Department of Dermatology, University of
North Carolina at Chapel Hill.
Address correspondence to: Donna A.
Culton, MD, PhD, 3100 Thurston-Bowles
Building, Campus Box 7287, Chapel Hill, NC
27599; fax: 919-966-3898; or e-mail [email protected], [email protected],
or [email protected]
Dr. Culton, Dr. Morrell, and Dr. Burkhart
have disclosed no relevant financial relationships.
doi: 10.3928/00904481-20090622-05
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PED0709Culton.indd 368
C
ondyloma acuminata, more
commonly known as genital
warts, are caused by infection
with human papillomavirus (HPV).
Prevalence is increasing in adults, as
well as in the pediatric population.
Management of condyloma in the pediatric population can be difficult given
the possibility of sexual abuse as a mode
of transmission. Moreover, the available
treatment options are only moderately
efficacious and associated with significant rates of recurrence. Treatment can
be quite painful, and multiple office
visits are typically required. Finally, no
large studies have been conducted in the
pediatric population, and none of the
medical treatments available is approved
by the Food and Drug Administration
(FDA) for use in children younger than
12 years. Each of these factors complicates management and treatment decisions in children with genital warts.
EPIDEMIOLOGY
Condyloma acuminata is quickly becoming the most frequently diagnosed sexually transmitted disease (STD) in the adult
population, with 10% of adults having
clinically evident lesions.1 Strikingly, more
than half of sexually active women have
been shown to harbor HPV virus, even in
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© iStockphoto.com
younger than 5 years of age showed that
41% were due to HPV type 2, whereas
only 3% of vulvar warts in adult women
were caused by HPV type 2.11
The incubation time following infection
may last months; HPV can also remain in
a latent phase. Therefore, the time from
exposure to clinically evident lesions can
range from months to years.12 The potential for unpredictable durations of latency
make determination of the mode of transmission problematic.
the absence of symptoms.2-4 Pediatric cases are also increasing,5 which is thought to
reflect the increase in adult cases; however,
little is known about the epidemiology of
condyloma in the general pediatric population. Among children presenting to an STD
clinic, 14.2% were diagnosed with condyloma, second only to syphilis (including
congenital syphilis).6,7 Girls are more often
affected than boys by a ratio of 3:1.7
PATHOGENESIS
HPV is a non-enveloped, double-stranded DNA virus with more than 100 reported
subtypes causing both clinical and subclinical infection of the skin and mucous membranes.5,8 Basal keratinocytes are the target
cell infected and as cells become cornified,
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the virion is maintained. As these cornified cells are shed, so is the virion, thereby
spreading potential disease-bearing particles into the environment, onto fomites,
or onto the skin of another person.9
Although not specific in their clinical
manifestations, HPV types 6 and 11 are
predominantly associated with genital
warts, and HPV types 16 and 18 are more
commonly associated with cervical neoplasias. Common warts (verruca vulgaris) are caused by many HPV types, but
most often types 1-4. Although certain
viral subtypes are typically associated
with site-specific clinical presentations,
overlap is common, especially in the
pediatric population.10 For example, a
study of 29 cases of genital warts in girls
CLINICAL PRESENTATION
Condyloma most often presents as 1to 5-mm fleshy, skin-colored, verrucoussurfaced papules, which can coalesce into
large plaques. They may be sessile or pedunculated and may even become quite
exophytic forming cauliflower-like masses.
They are typically asymptomatic, but may
bleed or become painful or pruritic due to
larger size or local trauma with toileting.8
In prepubertal boys the most common
site of involvement is the perianal area,
while adult males often have lesions on the
penile shaft.7,10 In girls, the perianal region
and vulva are commonly involved.7,10
MODES OF TRANSMISSION
In adults, sexual transmission is the
most common route of inoculation. Although the possibility of sexual abuse
must be considered for each individual
case of condyloma occurring in a child,
other routes of transmission should be
considered as well, particularly in children younger than 4 years, a demographic
where non-sexual transmission is more
likely.13,14 Perinatal exposure may occur
in utero via ascending HPV infection. In
a study of HPV-infected pregnant women,
24 of 37 had detectable HPV genome in
the amniotic fluid.15 Cases of congenital
condyloma have been reported,16,17 further
supporting ascending infection as a mode
of transmission. Perinatal exposure can
also occur as the neonate passes through
the birth canal of an HPV-infected mother.10,18 Accordingly, the healthcare pro-
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vider should attempt to elicit a maternal
gynecologic history including any history
of condyloma or abnormal pap smears.
Another potential mode of transmission
is auto- or heteroinoculation from nongenital warts of the child, parent, or other
care provider.10,19,20 A thorough physical
examination should be performed on any
child with condyloma, inspecting for other
non-genital warts, and parents should be
questioned regarding personal history of
verrucae as well. The long latency from
exposure to clinical presentation must be
considered, as exposure may precede development of condyloma by months to
years.12,16 As mothers of pediatric HPV-infected patients may have subclinical cervical HPV infection (especially mothers of
those who acquired HPV via in utero or
perinatal exposure), physicians should advise potential carriers to seek medical attention from their primary care physician.
should be initiated. However, there are no
FDA-approved treatments of genital warts
in children younger than 12 years.
Treatment of condyloma can be divided
into surgical and non-surgical approaches.
All surgical approaches rely on nonspecific tissue destruction. Many non-surgical
approaches also utilize nonspecific tissue
DIAGNOSIS
The diagnosis of condyloma is most
often made clinically. Biopsy is rarely
necessary, but histology shows typical hyperkeratosis and viral cytopathic change.
HPV subtyping may be performed if clinical and histologic features are non-diagnostic but is not typically necessary.21 As
site-specific subtypes are not as reliable
in children as they are in adults, HPV
subtyping has not been shown to be useful in making a case for or against sexual
abuse as a mode of transmission.20,22
The diagnosis of condyloma is
most often made clinically.
TREATMENT
Approximately 75% of untreated or
treatment-resistant condyloma spontaneously resolve within months to a few years
in children and adolescents with healthy
immune systems.7,23,24 Therefore, active
nonintervention is an option in children
with asymptomatic lesions. However, studies suggest that lesions present for longer
than 2 years are less likely to undergo
spontaneous resolution.24 In these cases
and in cases where the condyloma are
symptomatic or affect function, treatment
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destruction, but treatments have expanded
to include immunomodulatory agents
as well. It is important to remember that
no treatment has been shown to result in
complete clearance of disease, that recurrences are common, and that multiple
treatment modalities used in combination
are often necessary to achieve significant
improvement.25 In addition, many of the
available treatments have not been studied
in children, and in general no one treatment has been shown to be most efficacious. Therefore, treatment must be tailored to the individual patient.
Surgical Approaches
Cryotherapy in the form of liquid
nitrogen is the most commonly utilized
surgical approach to treatment. Complete
clearance rates in the adult population
range from 62% to 86%.25 Longer freeze
time and multiple freeze/thaw cycles are
associated with a higher clearance rate.26
This modality is useful when treating a
limited number of small lesions. Side effects include local pain and burning during treatment, which may persist for a
few hours, and blistering, which is typically asymptomatic and heals within a
week. Scarring is unusual but may occur
with aggressive treatment, particularly
in children with heavily pigmented skin.
Although no studies using treatment
with cryotherapy have been performed
in children, these side effects often limit
its use in the pediatric population.
Electrodessication is another method
of nonspecific tissue destruction. Complete clearance rates in the adult population range from 57% to 94% with
recurrence in one fourth of patients.25
Anesthesia is required, and side effects
include the possibility of scarring and
pain following treatment. Given the need
for anesthesia, this method of destruction is not often utilized in children.
Carbon dioxide laser ablation can be
effective in children. Complete clearance
rates in adults range from 27% to 100%
but varies widely based on the experience
of the surgeon.25,27 Johnson et al published a retrospective review of a single
surgeon’s case series of 17 consecutive
pediatric patients.28 Following one treatment, complete clearance was achieved
in 16 patients with a recurrence rate of
23% at 1-year follow up. Only one patient
(6%) had persistent disease. The authors
argue that carbon dioxide laser ablation
is safe, relatively atraumatic, and effective in the pediatric population. However,
postoperative pain can be severe and general anesthesia is necessary. These factors
should be taken into consideration.
Pulsed-dye laser is another alternative that has been shown to be effective in
treating flat, plantar, and periungal warts.29
Treatment has been extended to genital
warts in adults with one study showing
complete resolution in all of 22 patients
after an average of 1.59 (1-5) laser ses-
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sions without evidence of scarring.30 In 13
patients, a single treatment was sufficient,
whereas in the remaining nine patients up
to five treatments were necessary with an
average treatment interval of 14 to 21 days.
Tuncel and colleagues found that treatment with pulsed-dye laser is also safe,
effective, and well-tolerated in children.31
Postoperative pain and scarring are infrequent, making this an attractive option for
children with condyloma.
Surgical excision is also an option for
limited disease or single large lesions.
Local or general anesthesia is required,
and the procedure is usually performed
in the office or outpatient surgical suite.
In adults population, complete clearance
rates range from 35% to 72% at 1-year
follow up.27 If shave removal is performed, electrocautery to the base of the
wound may add additional destruction
of any remaining virally infected tissue.
The use of this technique in children
must be carefully considered given the
need for general anesthesia.
Nonsurgical Approaches
Podophyllin is a resin that is derived
from the rhizome of the Podophyllum
species. The active agent of podophyllin resin is podophyllotoxin, which has
antimitotic properties. Podophyllin is
available as a 10% to 25% resin typically applied by the physician every 1
to 2 weeks until clearance is achieved.32
The resin should be washed off 4 hours
after application to minimize local side
effects such as redness and burning. In
order to increase efficacy, the treatment
is often combined with other destructive
treatment options such as cryotherapy.33
Podophyllotoxin (podofilox) is available
as a 0.5% solution or 0.15% cream and
has increased purity and stability compared to podophyllin.32 It is applied by
the patient or caretaker at home once or
twice daily for several days per week as
tolerated, and it is associated with slightly
higher clearance rates in adults compared
with podophyllin (56% to 79% compared
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with 41% to 47%).25,32 Moresi et al reported 15 of 17 children (88%) treated
with podofilox experienced clearance of
lesions over a duration of treatment ranging from 1 week to 4 months without significant side effects, suggesting that it is
safe and effective for use in children.34
Imiquimod 5% cream (Aldara) is a
synthetic immune modulator that acts
through the enhancement of both innate and cellular immune responses
via extensive cytokine activation. It has
been shown to be efficacious in treating
external genital warts and is FDA-approved for use in children 12 and older.
No large studies have been published
on the safety and efficacy in children
below 12 years of age, but case reports
suggest that the compound is both safe
and highly effective in the treatment of
genital warts in children as young as 6
months, with clearance rates of 75%.34-36
Treatment typically involves application
of imiquimod 5% cream overnight three
times weekly with improvement within
weeks to months. Side effects, which are
usually mild and well-tolerated, include
local pain, pruritus, and irritation.34 Because of the ease of application and the
favorable side effect profile, imiquimod
is quickly becoming first line treatment
for condyloma in children.
Case reports of other topical agents
have been reported. For example, cidofovir is an acyclic nucleoside phosphonate
that acts as a DNA polymerase inhibitor.
It is used primarily to treat cytomegalovirus retinitis in AIDS patients. Calisto
et al reported improvement in condyloma of the glans penis in a 3-year-old boy
using compounded topical cidofovir 1%
cream applied daily for 5 consecutive
days per week for 2 weeks.37 A second
cycle was initiated after a 30-day pause
and resulted in complete clearance without local or systemic side effects. There
was no recurrence after 12 months.
Cimetidine is a histamine receptor
antagonist that is often used to treat peptic ulcer disease. However, cimetidine
also possesses immunomodulatory effects and has been reported to be useful
in treating other conditions including
verruca vulgaris. Although randomized
controlled trials failed to show a significant benefit in non-genital warts in
adults, Franco reported a case series of
four children with condyloma treated
with oral cimetidine.38 In two children,
cimetidine was given as primary treatment, while in the other two children
cimetidine was given to prevent recurrence. Dosing was initiated at 30 to 40
mg/kg/day divided into three doses and
given for 3 months. All patients had complete clearance at 24-month follow-up.38
Cimetidine may be useful for primary
and adjunctive therapy for condyloma in
children, but more studies are needed.39
CONCLUSION
When presented with a case of pediatric condyloma, a thorough physical
examination and history (particularly
of genital or non-genital warts in the
mother or other care providers) must be
performed. The American Academy of
Pediatrics (AAP) recommends that all
school-aged children presenting with
condyloma for the first time should
undergo a medical evaluation for child
abuse including interview of the child
and caretakers and testing for other
sexually transmitted diseases. They
also state that condyloma in children
suggests sexual abuse if the lesions
were not acquired perinatally. Regardless of the child’s age, sexual abuse
must be considered in all children with
condyloma. Given the difficulty in determining time of inoculation because
of the long latency period, we advocate
that in children younger than 4 years,
non-sexual transmission is more likely
and an alternative route of inoculation
should be explored.13 When there is any
concern by the parents or health care
provider for sexual abuse, referral to an
agency skilled in handling such cases
should be made.
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