Condyloma Acuminatum

INTRODUCTION
Background: The viral nature of genital warts was first
recognized in 1907 when Ciuffo induced warts after
autoinoculation of cell-free wart extracts (Ciuffo, 1907).
With the development of molecular biology techniques, the
human papillomavirus (HPV) was identified as the virus
responsible for condyloma acuminatum. In the mid-1970s,
zur Hansen proposed that HPV was likely important in the
etiology of genital tract neoplasias (zur Hansen, 1976).
The DNA of the first genital wart was characterized in
1980. Today, over 80 distinct HPV subtypes have been
identified. This group of viruses is strongly linked to the
development of cervical dysplasia, cervical cancer, and
vulvar dysplasia.
Genital warts are spread by sexual contact. Approximately
two thirds of individuals who have sexual contact with an
infected partner develop genital warts. The exact
incubation time is unknown, but most investigators believe
the incubation period is 3 months (Becker, 1987).

Pathophysiology: HPV is a group of double-stranded
DNA viruses. The genome encodes 6 early open reading
frames (E1, E2, E4, E5, E6, E7) and 2 late open reading
frames (L1, L2). The E genes encode proteins important in
regulatory function, and the L genes encode for viral
capsid proteins. This group of viruses can infect many
different sites, including the larynx, skin, mouth,
esophagus, and the anogenital tract.
Approximately 20 different types of HPV can infect the
anogenital tract. Infection caused by the HPV virus results
in local infections and appears as warty papillary
condylomatous lesions. HPV infections in the genital area
are sexually transmitted (Gissmann, 1980).
HPVs associated with genital tract lesions have been
divided into low risk and high risk based on each
Most genital condylomata are due to infection by HPV-6 or
HPV-11. These HPV types replicate as an episome and
rarely incorporate their genetic material into the host DNA.
In contrast, HPV-16 and HPV-18 can be recovered in
approximately 70% of squamous cell carcinomas of the
cervix. These high-risk HPV types, along with types 31,
33, and 45, incorporate a portion of their genetic material
into the host DNA. The E6 and E7 genes can produce
oncoproteins that alter cell growth regulation. Specifically,
E6 oncoprotein inactivates the tumor suppressor gene
p53, and the oncoprotein produced by E7 inactivates pRB
(retinoblastoma) (Koutsky, 1997).

Frequency:
In the US: Frequency of HPV infection in the population
is difficult to estimate accurately. Studies reporting
the diagnosis of HPV by visual inspection of genital
condyloma report the lowest prevalence rates. Not
surprising, the highest prevalence rates are reported
by studies typing HPV from exfoliated genital tract
cells. Regardless of the conflicting prevalence
figures, HPV is a major sexually transmitted disease
(Koutsky, 1988; Nuovo, 1994). Condyloma
acuminata are clinically apparent in 1% of the
sexually active population. Molecular studies indicate
10-20% of men and women aged 15-49 years have
been exposed to HPV. Prevalence of HPV is higher
in certain populations. Data from sexually transmitted
disease clinics indicate a prevalence rate of 4-13%.
Based on clinical observations, incidence of HPV
infection clearly has increased in the last 35 years.
Data from the National Disease and Therapeutic
Index, which is a random survey of private
physicians, indicate that, in 1966, 169,000 people
consulted a physician about genital warts. By 1984,
this number had risen to 1,150,000 consultations.
Today, researchers believe at least 1 million new
cases of genital warts are diagnosed each year.
Genital HPV infection now is the most common
sexually transmitted disease (Bosch, 1995).
Several investigators report an increased
prevalence of anogenital HPV infections during
pregnancy. During pregnancy, the prevalence of
condyloma increases from the first to third trimester
and decreases significantly in the postpartum period.
The risk of condyloma acuminata in pregnancy is 2-
fold. First, the lesions can become large enough to
obstruct labor. Secondly, with an abdominal delivery,
the virus can be transmitted to the infant, resulting in
laryngeal papillomas (Peng, 1990; Rando, 1989;
Schneider, 1987; Shah, 1986).
Internationally: Outside of the United States, HPV
infections are common (Syrjanen, 1990). A study in
Finland in the mid-1980s demonstrated an annual
incidence of cytologic cervical HPV infection of 7%
(Kjaer, 2000). A study of Finnish males found 6.5%
had evidence of HPV in exfoliative cells obtained
from the urethra and genital epithelium (Hippelainen,
1993).
Mortality/Morbidity: Condyloma acuminatum often is
asymptomatic.
Pruritus or occasional bleeding may lead the patient to
seek medical care.
Patients who do not develop immunity to HPV can
develop potentially serious sequelae.
HPV infection of the vulva can result in the development
of vulvar intraepithelial neoplasia (dysplasia) or
squamous cell carcinoma of the vulva. Most research
indicates that HPV infection is strongly associated
with the development of cervical dysplasia and
cervical carcinoma. Vaginal dysplasia also is
associated with exposure to HPV.
Race: No racial predilection exists.
Sex: The prevalence of condyloma acuminata seems to
be similar in men and women. One study from a sexually
transmitted disease clinic in the state of Washington found
13% of men and 9% of women had condyloma acuminata
(US Department of Health and Human Services 1996,
Koutsky, 1988).
Age: The highest rates of genital HPV infection are found
in sexually active women younger than 25 years, even
after correcting for the number of lifetime sexual partners.
Most of these infections seem to be transient (Ho, 1998;
Burk, 1996; Figueroa, 1995).
A cytologic screening of the cervix in over 400,000
women supports the higher incidence of HPV in
young women. This study found that the rate of HPV
infection is twice as frequent in women younger than
30 years as it is in women older than 30 years
(Meisels, 1992).
The reason for the higher prevalence in younger women
is not completely understood. Some investigators
hypothesize that older women have fewer sexual
partners and, consequently, less exposure to the
HPV. An alternative theory is that by age 30 years,
women have acquired immunity to HPV (Evander,
1995).
The presence of genital condyloma in the pediatric
population presents a diagnostic and therapeutic
challenge. Vertical transmission of HPV can occur via
in utero exposure to amniotic fluid or transmission of
HPV from the maternal genital tract. An incubation
period of several months usually is required between
virus infection at delivery and clinical manifestations
in the infant. The average latency period is 3 months,
but periods as long as 20 months have been reported
(Davis, 1989). Unfortunately, most cases of
childhood condylomata outside a reasonable
incubation period after vertical transmission should
arouse the suspicion of child abuse. Treatment of
condyloma in the infant would include excision under
general anesthesia or the use of podophyllin
(Shelton, 1986).
CLINICAL
History:
Most patients seek medical care when they notice
area.
These lesions generally are not painful, but they can be
associated with pruritus.
Bleeding can be observed if the lesions become
confluent and are irritated by clothing.
Physical:
Inspection of the female genital area requires good
lighting.
On gross inspection, typical condyloma usually is a
discrete papillary growth that may arise from a
single stalk.
Condyloma acuminata can involve a large area in a
sessile fashion.
Subclinical infection is another common presentation of
condyloma. Tiny, slightly raised areas can be
felt or visualized on the vagina or cervix.
These flat warts are best visualized using 3-5% acetic
acid and a colposcope. Areas infected with HPV
appear acetowhite.
Often, a biopsy is needed to distinguish these lesions
from cervical squamous intraepithelial lesions or
vaginal intraepithelial lesions.
The sexual partner(s) of a woman with condyloma
should be examined by a physician and treated if
indicated. Often the examination of the male fails to
reveal any visible condyloma.
Causes: Approximately 20 different types of HPV can
infect the anogenital tract.
Infection caused by the HPV virus results in local
infections and appears as warty papillary
condylomatous lesions.
HPV infections in the genital area are sexually
transmitted.
WORKUP

Lab Studies:
Patients who present with condyloma acuminata do not
necessarily need other laboratory studies; however,
patients who are diagnosed with condyloma are at an
increased risk for other sexually transmitted
diseases.
Consider testing for chlamydia, gonorrhea, syphilis,
hepatitis B, hepatitis C, and HIV depending on
the clinical situation.
These patients need a Papanicolaou (Pap) test of the
cervix if a Pap test has not been performed in
the last 12 months.
The need to determine the HPV type is controversial
(Kaufman, 1999).
HPV typing has been proposed to supplement Pap test
screening (Cuzick, 2000).
This typing can be used as a secondary triage of
patients with atypical squamous cells of
undetermined significance (ASCUS) on Pap
tests (Cox, 1996).
Other clinicians have proposed to use HPV typing in
primary screening as an adjunct to Pap tests
(Goodman 2000).
In both of these scenarios, HPV typing can detect low-
risk and high-risk HPV types found in the cervix.
Histologic examination of the vulvar lesions to detect
vulvar condyloma sometimes is difficult.
Non-HPV conditions, such as vestibular papillomatosis
and inflammatory squamous metaplasia, may be
difficult to distinguish from condyloma with light
microscopy.
The pathologist may issue a pathology report
suggesting the microscopic features of a vulvar
biopsy are changes suggestive but not
diagnostic of HPV.
When the histologic diagnosis of condyloma is
questionable, HPV testing may be useful.
A wide variety of methods to detect HPV have been
used since 1983.
Currently, the 2 most accurate methods use 2
consensus primer polymerase chain reaction
(PCR) systems. The commercially available
system is the Hybrid Capture system with
differential testing for 9 high-risk HPV types and
5 low-risk HPV types.
Testing for HPV confirmation of equivocal vulvar
histology results provides an objective method
for confirming a diagnosis of condyloma.
Imaging Studies:
No imaging studies are indicated.
Procedures:
Patients who present with typical appearing condyloma
acuminata do not need a vulvar biopsy.
If clinical doubt about the diagnosis exists, perform a
biopsy.
The base of the lesion is injected with 1% lidocaine.
A biopsy can be performed easily with an alligator
mouth biopsy forceps.
Silver nitrate applied to the base of the biopsy site
controls any bleeding.
Rarely, a suture is required to obtain hemostasis.
Histologic Findings: Biopsy of the vulvar skin associated
with condyloma shows evidence of hyperkeratosis,
acanthosis, and parakeratosis. A chronic inflammatory
infiltrate often is observed within the dermis. Koilocytosis,
which is perinuclear cytoplasmic halos, commonly is
observed in the superficial epithelial cells. Other
microscopic findings include basilar hyperplasia with
binucleated and multinucleated cells and enlarged
parabasal cells with a foamy nuclear chromatin.
Staging: No staging system exists for condyloma
acuminata.
TREATMENT
Medical Care: A variety of medical treatments exists for
condyloma acuminata, and no single treatment regimen is
superior.
The treatment strategy is to eliminate as many of the
visible lesions as possible until the host immune
system can control viral replication.
Because most HPV infections spontaneously regress
when the immune system controls viral replication,
the need to treat subclinical or mild disease is
controversial.
Treatment usually is reserved for patients with visible
vulvar condyloma.
The type of treatment is influenced by previous
therapies, sexual behavior, immune status, and the
patient's willingness to comply with therapy.
Patients who are HIV positive or immunosuppressed due
to immunosuppressive drugs usually require more
than one treatment method. Often, the condyloma in
these patients is refractory to therapy.
Regardless of the mode of therapy chosen, recurrence
rates are high for any patient with condyloma
acuminata. This can result in a high level of
frustration for the patient and the physician.
For most patients, medical therapy should be the first
option. These different medical treatment modalities
can by performed in the physician's office or at home.
Morbidity is low. Surgery should be reserved to treat
condyloma resistant to medical therapy. Most
patients should not need surgical therapy unless the
condylomatous lesions are too large to treat
medically or if the lesions would interfere with an
abdominal delivery.
Surgical Care: Surgical treatment of condyloma
acuminata usually is reserved for patients in whom local
therapy has failed. Several options are available, including
local excision, laser therapy, cryotherapy, and
electrosurgical excision.
Simple excision
Simple excision usually is performed in an outpatient
surgical suite.
After general or regional anesthesia is administered, the
individual lesions are removed with a knife.
This procedure is reserved for refractory cases or
extensive disease.
Reports in the literature indicate that within one year of
surgery, complete wart clearance occurs in 35-
72% of individuals treated with surgical excision.
One report found surgical excision as effective
as laser surgery (Duus, 1985).

Patients with a few small lesions can have vulvar
condyloma removed in the office. The underlying skin
should be anesthetized with 1% Xylocaine and the
condyloma removed with a #15 knife blade. One or 2
sutures may be needed to reapproximate the healthy
skin.
Carbon-dioxide laser therapy (Duus, 1985; Reid, 1992)
Laser treatment of vulvar condyloma acuminata
effectively destroys the condyloma while sparing
adjacent healthy tissue.
This procedure is performed in outpatient surgery with
general or regional anesthesia.
The amount of energy needed to remove a
condylomatous lesion with the laser will depend
on parameters controlled by the surgeon. These
parameters include the setting of the machine in
watts, the length of time the beam is fired, and
the spot size on the tissue. Some researchers
calculate the power density, which equals the
power (watts)/area (cm
2
). No exact power
density is needed to remove vulvar or vaginal
condyloma. The surgeon needs to be flexible in
the application of the laser for each patient. If
the laser is calibrated to 20 watts, continuous
mode, the spot size can be adjusted easily to
provide the proper power density (Lopow,
1986).
Most patients experience significant discomfort
beginning 24 hours after surgery and require
narcotic analgesia.
Laser therapy should be reserved for recalcitrant cases
of condyloma or extensive disease.
Complete wart clearance after laser surgery has been
reported to occur in 23-52% of patients within 3
years of surgery.
The recurrence rates are similar to surgical excision.
Electrosurgery (Simmons, 1981)
For isolated lesions unresponsive to topical therapy,
electrosurgical techniques can be performed in
the office with local anesthesia.
The most popular method is to use a loop electrode that
removes the lesion(s).
Pain after surgery is common and can be treated with
narcotic analgesics. Topical analgesics, such as
lidocaine jelly, can be beneficial to some
patients.
A recurrence rate in one trial was 22% compared to
44% for podophyllin resin.
Cryotherapy (Godley, 1987)
Cryotherapy should be limited to small lesions that can
be treated with small cryoprobes.
Data from several clinical trials report a 63-88%
clearance 3 months after therapy.
The recurrence rate of 22% is similar to electrosurgery.
This therapy is safe to use in pregnancy.
The primary drawbacks are discomfort, ulceration, or
scabbing at the treatment site.
Activity:
The patient should refrain from sexual contact after any
surgical procedure for condyloma acuminata.
Soaking the genital area in warm water or sitz baths
usually offers excellent pain relief.
The genital area should be dried gently with a towel or a
hair dryer.
Loose fitting cotton underwear is helpful to avoid chafing.
No other activity restrictions exist, although patients
often have trouble sitting for long periods of time in
the first week after surgery.
Patients who have condyloma removed from the
periurethral area may experience dysuria. Sitz baths
and topical analgesics are beneficial.
MEDICATION
No one superior treatment exists for condyloma acuminata
(Auborn, 2000). Simple topical therapies are the initial
treatments of choice for most patients. They are cost-
effective and result in minimal toxicities. Most result in a
30-90% success rate in eliminating visible condyloma;
however, many clinical studies using topical therapies are
not well designed, making comparisons between therapies
difficult.
Drug Category: Antimitotics -- Arrests dividing cells in
mitosis, resulting in death of proliferating cells.
Drug Name

Podophyllin (Podocon-25, Podofin) -- Treatment results in necrosis of
visible wart tissue. Exact mechanism of action is unknown. Great
variability exists in the potency of podophyllin between batches.
American podophyllum contains one-fourth the amount of the Indian
source. Warts visible after 6 treatments usually do not respond to
further therapy (Hellberg, 1995).
Adult Dose
Apply concentration of 25% sparingly onto lesions; wash treatment area
4 h after application; repeat q1-2wk until eliminated
Pediatric Dose Apply as in adults
Contraindications
Documented hypersensitivity; diabetes; impaired peripheral circulation;
avoid use on mucous membranes, eyes, bleeding warts, moles,
birthmarks, or unusual warts with hair
Interactions None reported
Pregnancy X - Contraindicated in pregnancy
Precautions
Powerful caustic and severe irritant; do not use if surrounding tissue is
swollen or irritated; do not use large amounts; avoid contact with
cornea; should be applied by a physician or trained nurse; redness or
burning of the skin can occur 6-24 h after treatment
Drug Name

Podofilox (Condylox) -- Topical antimitotic that can be synthesized
chemically or purified from plant families Coniferae and Berberidaceae
(eg, species of Juniperus and Podophyllum).
Active agent of podophyllin resin and is available as a 0.5% solution.
Can apply solution to warts at home.
Adult Dose Apply 0.5% solution to warts bid for 3 d; repeat qwk for up to 4 wk
Pediatric Dose Apply as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions
Avoid contact with eyes; if eye contact occurs, immediately flush eye
with copious quantities of water and seek medical advice; not for use on
mucous membranes of genital area, including urethra, rectum, and
vagina; do not exceed frequency of application or duration of usage
Drug Category: Antineoplastic agents -- Topical
preparation containing the fluorinated pyrimidine, 5-
fluorouracil. Antineoplastic and antimetabolite agent.
Drug Name

Fluorouracil (Efudex) -- Interferes with DNA synthesis by blocking
methylation of deoxyuridylic acid, inhibiting thymidylate synthetase and,
subsequently, cell proliferation. Limited data exist concerning the
efficacy of this therapy for genital warts. Three case series indicate wart
clearance in 10-50% of participants (Krebs, 1990). Experimental
treatments injecting 5-FU with epinephrine and bovine collagen
currently are in trials.
Adult Dose Apply 5% solution to warts 1-3 times per wk; wash off after 8 h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; potentially serious infections
Interactions None reported
Pregnancy X - Contraindicated in pregnancy
Precautions
Incidence of inflammatory reactions may occur with occlusive dressings;
porous gauze dressing may be applied for cosmetic reasons without
increase in reaction; adjacent healthy skin around warts should be
coated with a protective gel before application; reproductive age group
should use adequate contraception during therapy
Drug Category: Desiccants -- These are acids that are
most effective when applied to moist warts. They are
nontoxic and can be used in pregnancy.
Drug Name

Trichloroacetic acid (Tri-Chlor) -- Cauterizes skin, keratin, and other
tissues. Although caustic, causes less local irritation and systemic
toxicity than others in the same class; however, response often is
incomplete and recurrence occurs frequently (Abdullah, 1993).
Adult Dose
Apply 50-85% solution to warts q1-2wk in physician's office; wash off
after 4-6 h
Pediatric Dose Administer as in adults
Contraindications
Documented hypersensitivity; not for use on premalignant or malignant
lesions
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions
External use only; restrict use to treatment areas only; skin adjacent to
warts needs to be protected; severe burning may occur
Drug Category: Immune response modifiers --
Stimulates production of cytokines and has demonstrated
strong antiviral activity.
Drug Name

Imiquimod (Aldara) -- Induces secretion of interferon alpha and other cytokines.
Mechanism of action unknown (Edwards, 1998).
Adult Dose
Apply 5% cream 3 times per wk hs; leave on skin for 6-10 h; treatment period
not to exceed 16 wk
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions
Not recommended for treatment of rectal, cervical, intravaginal, urethral, and
intra-anal human papilloma infection; following surgery or drug treatment, do not
use topical imiquimod until genital/perianal tissue is healed; local skin erythema,
erosion, or abrasion can occur
Drug Name

Interferon alfa 2b (Intron) -- Interferons have been used in the United States for
the treatment of genital warts in various doses and preparations. Topical,
intralesional, and systemic therapy have been used. Currently, no convincing
evidence suggests that topical or systemic therapy is better than placebo (Eron,
1986; Monsonego, 1996; Welander, 1990; Bornstein, 1997).
Adult Dose
1 million U per lesion administered directly into the wart 3 times per wk for 3 wk;
no more than 5 warts should be treated at once
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions
Theophylline may increase toxicity; cimetidine may increase antitumor effects;
zidovudine and vinblastine may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions
Depression and suicidal ideation may be adverse effects of treatment; flulike
symptoms (eg, fever, dizziness, malaise, myalgia, headache) may occur
FOLLOW-UP

Further Outpatient Care:
Patients who complete therapy for condyloma acuminata
should have a clinical examination 3 months and 6
months after treatment.
Most patients who develop recurrent or persistent
disease are diagnosed within 6 months of
therapy.
If the patient appears disease free at the 6-month visit,
yearly visits are recommended.
The sexual partner(s) of a woman with condyloma
should be examined by a physician and treated if
indicated. Often the examination of the male fails to
reveal any visible condyloma.
Deterrence/Prevention:
Because genital warts are sexually transmitted, the risk
of acquiring HPV primarily is dependent on several
factors related to sexual activity.
These factors include the number of sexual partners,
frequency of sexual intercourse, and the
presence of genital warts on the sexual
partners.
Latex condoms offer some, but not complete, protection
in the transmission of HPV.
Women should avoid skin-to-skin contact with partners
if genital warts are visible.
Complications:
The major complication from exposure of the vulva,
vagina, or cervix to HPV is the development of
dysplasia.
Patients who develop condyloma acuminata usually
have been exposed to low-risk HPV types such
as HPV-6 and HPV-11. These HPV infections
are associated with mild dysplasia that often is
transient in nature.
Many patients with mild dysplasia of the vulva, vagina,
or cervix experience spontaneous regression of
these lesions.
Patients who are exposed to high-risk HPV types, such
as HPV-16 or HPV-18, are at risk for developing
high-grade dysplasias or carcinomas. The
development of cancer occurs in a small percentage
of these patients who do not have therapy for
dysplasia.
Prognosis:
The prognosis of immunocompetent women diagnosed
with condyloma acuminata is excellent.
HPV infections are transient in the vast majority of
these women.
Unless the woman constantly is exposed to different
HPV types, the infection eventually abates when
the host immune system stops viral replication.
Women who are immunocompromised due to
immunosuppressive drugs or HIV infection are at
higher risk of developing persistent disease. These
women have a higher incidence of developing
dysplasia of the vulva, vagina, or cervix.
Patient Education:
Inform patients that genital HPV is a sexually transmitted
disease.
The only way to prevent HPV infection is to avoid direct
contact with the virus, which is transmitted by
skin-to-skin contact.
If the sexual partner has visible genital warts, sexual
contact should be avoided until treatment is
completed.
Latex condoms offer some, but not complete, protection
from transmission.
Condoms should be used with vaginal, anal, or oral sex,
because the virus may be found in the semen in
the absence of visible warts.
MISCELLANEOUS

Medical/Legal Pitfalls:
Patients who appear to have classic condyloma
acuminata and do not respond to therapy should
have a biopsy of one of the lesions. This will avoid
continued treatment of lesions that are not HPV-
related.
Postmenopausal women who present with condyloma-
appearing lesions should have a biopsy before
initiation of therapy. These women have a greater
chance of having vulvar dysplasia or vulvar cancer
than younger women.
Special Concerns:
Many investigators report higher rates of HPV infections
in pregnant women. If condyloma develops, rapid
growth can be observed. Factors responsible include
suppression of immunity during pregnancy and
hormonal changes (Meisels, 1992).
Small asymptomatic lesions do not need to be treated.
Larger lesions can be treated with bitrichloroacetic
acid or cryotherapy (Bergman, 1984). Occasionally,
condyloma in pregnant women becomes large and
macerated, requiring surgical excision after the first
trimester. Interferon, podophyllin, and 5-fluorouracil
should not be used in pregnancy.
Pregnant women with genital warts can transmit the
virus to the newborn.
Infants can develop laryngeal papillomatosis in the first
5 years of life.
The method of transmission is unknown.
Approximately 60% of mothers with infants with
laryngeal papillomatosis report having genital
warts.
Based on the frequency of HPV infection in this country,
approximately 5% of all births are at risk for
neonatal HPV exposure.
The frequency of childhood laryngeal papillomatosis is extremely low,
approximately 2000 cases per year in the United States. This would
imply the transmission rate from mother to infant is low and does not
warrant recommending a cesarean delivery for prevention of laryngeal
papillomatosis. If the mother has huge condyloma that interferes with
labor or delivery, a cesarean delivery may be needed.