CONTINUING MEDICAL EDUCATION
Human papillomaviruserelated genital disease in the
immunocompromised host
Part I
Rachel H. Gormley, MD,a and Carrie L. Kovarik, MDa,b
Philadelphia, Pennsylvania
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4. Completion of the Journal CME Evaluation
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Learning Objectives
After completing this learning activity, participants should be able to identify,
diagnose, and triage HPV-related anogenital disease.
Date of release: June 2012
Expiration date: June 2015
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867.e1
867.e2 Gormley and Kovarik J AM ACAD DERMATOL
JUNE 2012

Human papillomavirus (HPV) is responsible for common condyloma acuminata and a number of
premalignant and malignant anogenital lesions. These conditions are of particular concern in immunocom-
promised individuals who have higher risk of malignant transformation and are more difficult to treat. This is
part I of a two-part review that will highlight the cutaneous features of condyloma acuminata and vaginal,
vulvar, penile, and anal intraepithelial neoplasias, with an emphasis on presentation of these HPV-mediated
diseases in the immunocompromised host. Counseling patients about these conditions requires a thorough
understanding of the epidemiology, natural history of HPV, transmission and infectivity, risk of malignancy,
and the role of the host immune response in clearing HPV lesions. Part II will provide an updated review of
available treatments, with a focus on recent advances and the challenges faced in successfully treating HPV
lesions in immunocompromised patients. ( J Am Acad Dermatol 2012;66:867.e1-14.)

Key words: AIDS; anal intraepithelial neoplasia; BuschkeeLowenstein tumor; condyloma acuminata; HIV;
human papillomavirus; organ transplant; penile intraepithelial neoplasia; vulvar intraepithelial neoplasia.

Human papillomavirus (HPV) infections are the
most common sexually trans-
mitted disease and have been
shown to cause both anogen-
ital warts and anogenital ma-
lignancy. Immunosuppressed
patients are at increased risk
for developing multiple HPV-
iatrogenic immunosuppression. This presents impor-
tant implications for screening
CAPSULE SUMMARY and surveillance in the immu-
nocompromised patient
Human papillomavirus causes both
d population.
benign condyloma acuminata and In all patients, HPV can
anogenital malignancies. lead to both benign neopla-
sia and frankly malignant
Immunosuppressed patients, including
d

related benign and malignant anogenital lesions of the cer-

patients with HIV infection and organ
anogenital tumors. Among vix, vulva, anus, and, rarely,
transplant recipients, are at increased risk
immunocompetent patients, the penis. The following re-
for developing these conditions.
cell-mediated immunity can view will discuss benign con-
control latent HPV infection Patients with HIV infection and organ
d
dyloma acuminata (CA), the
and mediate the regression transplant recipients require heightened most common cutaneous
of HPV-induced lesions. screening and aggressive treatment. manifestation of anogenital
Patients who are immuno- HPV infection. The review
compromised because of a will also discuss intermediate
decrease in cell-mediated immunity are therefore at malignancy or premalignant conditions, including
increased risk of developing and failing to clear HPV- giant CA, also called BuschkeeLowenstein tumor
related disease. Such patients include but are not (BLT), anal intraepithelial neoplasia (AIN), penile
limited to organ transplant patients receiving chronic intraepithelial neoplasia (PIN), and vaginal or vulvar
immunosuppressive treatment and individuals with intraepithelial neoplasia (VIN). Finally, we will dis-
HIV infection. Since the introduction of highly active cuss frankly malignant lesions, including invasive
antiretroviral therapy (HAART), there has been a anal, penile, or vulvar carcinoma. This review will
dramatic reduction in mortality and morbidity in focus on the more common CA but will also address
HIV/AIDS patients. As HIV/AIDS has become a the rare, but clinically important, malignant forms of
chronic disease, patients with HPV coinfection have HPV-related anogenital disease.
a prolonged period in which HPV-related anogenital
disease can progress from premalignant to malignant
lesions. Similarly, organ transplant patientswho are IMMUNOCOMPROMISE AND HUMAN
living longer, healthier lives with the advent of ad- PAPILLOMAVIRUS INFECTION
vanced immunosuppression and improved antirejec- Key points
tion therapiesare at increased risk of developing d Immune status has a significant impact on

HPV-mediated anogenital neoplasia because of their HPV disease course and response to treatment

From the Departments of Dermatologya and Internal Medicine,b 3600 Spruce St, Philadelphia, PA 19104. E-mail: Carrie.
Division of Infectious Diseases, University of Pennsylvania Kovarik@uphs.upenn.edu.
School of Medicine. 0190-9622/$36.00
Funding sources: None.
Reprint requests: Carrie L. Kovarik, MD, Department of
Dermatology, University of Pennsylvania, 2 Maloney Bldg,
J AM ACAD DERMATOL
VOLUME 66, NUMBER 6
Abbreviations used:
AIN: anal intraepithelial neoplasia
BLT: BuschkeeLowenstein tumor
CA: condyloma acuminata
DRE: digital rectal examination
HAART: highly active antiretroviral therapy
HPV: human papillomavirus
MSM: men who have sex with other men
PIN: penile intraepithelial neoplasia
VIN: vulvar intraepithelial neoplasia
d Reduced cytotoxic T-lymphocyte reactivity
to HPV oncoproteins E6 and E7 leads to
impaired ability to clear HPV
d Organ transplant patients and patients with
HIV/AIDS suffer from increased rates of HPV
infection with increased severity and dura-
tion of disease
d These patients are frequently infected with
multiple HPV types and have been found to
have a higher prevalence of HR HPV-16
d It remains to be seen whether prophylactic
HPV vaccination will be therapeutic in these
patients, many of whom have previously
established HPV infections
The immune status of the host has a significant
impact on the HPV disease course and response to
treatment. In general, patients who are immunosup-
pressed are more likely to be infected with HPV,
often have high-risk (HR) HPV infections, and may
have larger or more numerous warts that do not
respond as well to treatment. Studies examining HPV
carriage have shown that skin samples of plucked
hairs are positive for HPV DNA in close to 100% of
immunocompromised patients, compared with only
50% of immunocompetent volunteers.1,2
Smoking has also been linked to an increased risk
of anogenital warts.3,4 Cigarette smoking has been
strongly linked to the risk of anogenital warts in men,
with a dose-dependent response in which smokers
of more than 10 cigarettes per day have been shown
to be twice as likely to have anogenital warts as
nonsmoking men.5 In a study by Wen et al,5 the
baseline prevalence of HPV DNA was similar in
smokers and nonsmokers, and the authors suggested
that the increased rate of progression of exophytic
anogenital warts in smokers reflects immune modu-
lation effects induced by cigarettes.5 Similar results
have been found in women, with a three-fold
increase in the incidence of anogenital warts in
women who are smokers.4 In both of these studies,
it is important to note that smoking may act as a
confounder rather than actually acting as a risk factor
for the development of warts.
Gormley and Kovarik 867.e3
While any patient with suppression of the im-
mune system is at increased risk for HPV-related
anogenital disease, this review will focus specifically
on transplant patients and patients with HIV/AIDS.
HIV patients suffer from increased rates of HPV
infection (a prevalence as high as 31-57%6), with
increased duration and persistence of disease.6,7 It
should be briefly noted that showing a direct corre-
lation between HIV/AIDS-induced immunosuppres-
sion and acquiring HPV infection is difficult, given
that HIV-infected persons may also be more likely to
have sexual behavior, age characteristics, and other
shared risk factors for HPV infection.8 Patients with
HIV commonly present with larger or more numer-
ous warts that may not respond as well to treatment,
have a higher HPV viral load within their warts, and
have a higher prevalence of coinfection with HR
HPV, particularly HPV-16.9-12
While there are more data examining HPV inci-
dence, prevalence, and disease course in patients
with HIV, it is important to be aware of similarly
increased risk in transplant patients. Viral infections,
including several potentially oncogenic viruses, such
as EpsteineBarr virus, HPV, human herpesvirus-8,
and human T-cell lymphoma virus-1, are known
complications in transplant recipients. This in-
creased risk is related to immune system suppression
from the use of immunomodulatory, antirejection
medications that are necessary after organ transplan-
tation. The incidence of anogenital HPV infection
specifically is increased 17-fold in immunosup-
pressed renal transplant patients.13 Allograft recipi-
ents, therefore, should be screened like HIV-positive
patients for anogenital malignancy and carefully
followed. Both transplant recipients and HIV pa-
tients are frequently infected with multiple HPV
types and have been found to have a higher prev-
alence of HR HPV-16 found within condylomata than
the prevalence of HR HPV found in condyloma of
immunocompetent patients.9-12 Many of the most
successful treatments for HPV-mediated disease in-
volve the activation of the host immune response
(see discussion of imiquimod and intralesional in-
terferon in part II of this review). While stimulating
the immune response in an HIV patient is clearly
advantageous, these forms of treatment raise the
concern for the theoretical risk of inducing rejection
in transplant patients.
Whether increased HPV infection in immunocom-
promised patients is related to the increased reacti-
vation of latent HPV infection or related to the
acquisition of new HPV infections remains unclear.9
In the case of immunosuppression from HIV, alter-
ations in cytokine expression within epithelial cells
allows for the increased reactivation of latent HPV
867.e4 Gormley and Kovarik
virus in keratinocytes and hastens the course of
already established HPV infections.14 As HIV/AIDS
progresses, there is reduced cytotoxic T-lymphocyte
reactivity to HPV oncoproteins E6 and E7, leading to
impaired ability to clear HPV and allowing for
relatively undisturbed epithelial proliferation.14,15
Some authors have suggested that in fact immuno-
compromised patients and control subjects do not
really differ in the presence versus absence of HPV,
but rather they differ in the extent of HPV replication,
and therefore, quantitative HPV viral load.16 This
increased carriage and quantitative level of HPV in
HIV patients results in a higher incidence in a variety
of conditions, both benign and malignant, but most
commonly CA.11 The treatment of CA in HIV pa-
tients, which will be discussed later in detail, is often
less effective, with frequent recurrences after treat-
ment, and higher number of required treatment
visits, sometimes necessitating a combination of
medical and surgical procedures.17
One of the most promising and clinically exciting
developments in HPV-mediated disease is the intro-
duction of prophylactic vaccines directed against
HPV. There are two currently in clinical use: Gardasil
(Merck and Co. Inc, Whitehouse Station, NJ), a
quadrivalent vaccine that protects against HPVs-6,
-11, -16, and -18; and Cervarix (GlaxoSmithKline,
London, United Kingdom), a bivalent vaccine that
protects against HPVs-16 and -18.18 Clinical trials for
all commercially available vaccines enrolled primar-
ily healthy young women, and studies addressing
efficacy in immunosuppressed patients (either HIV-
positive or solid organ transplant recipients) are
lacking.18-20 These vaccines are likely to be safe in
both populations given that they are not live vac-
cines; however, other side effects and toxicities must
be formally assessed in immunocompromised pa-
tients. Efficacy and appropriateness in this popula-
tion of prophylactic vaccines aimed at reducing the
number of new HPV infections presents a greater
issue because these patients are often already
infected with HPV. It remains to be seen whether
vaccination will have therapeutic effect in patients
with previously established HPV infections.21
CONDYLOMA ACUMINATA
Key points
d Anogenital warts are caused by low-risk
types of human papillomavirus (HPV), most
commonly types -6 and -11
d Even after the eradication of warts, patients
may continue to harbor the latent virus in
their anogenital epithelium
d Patients with anogenital warts are also at
risk for coinfection with oncogenic high-risk
J AM ACAD DERMATOL
JUNE 2012
Fig 1. Condyloma acuminata. Dark brown, verrucous
papules on the penile shaft of an African American patient.
HPV types and require monitoring and
screening for HPV-mediated malignancies
d Immunosuppressed patients have a higher
prevalence of coinfection with high-risk
HPV, particularly HPV-16
As previously mentioned, CA are the most com-
mon presentation of anogenital HPV infection. CA,
commonly referred to as genital warts, are esti-
mated to affect 1% to 2% of all sexually active
individuals in the United States, with the incidence
increasing steadily since the 1950s.22-25 In North
America, there is an annual rate of 100 cases per
100,000 individuals, making anogenital warts more
common than breast and prostate cancer; this is an
incidence that translates to a lifetime cumulative risk
approaching 10%.22 Low-risk (LR) HPV types 6 and
11 are most commonly associated with anogenital
warts, with 70% to 100% of anogenital warts con-
taining one or both of these subtypes.9 However, at
least 18 other HPV types have been associated with
CA, including -16, -18, -31, -33, -35, -39, -41 to -45,
-56, and -59.26 HPV-6 appears to be the most com-
monly associated subtype, even when compared to
HPV-11.27,28
Clinical presentation and diagnosis
CA have a variety of clinical presentations, but
most commonly appear on areas of the anogenital
mucosa that are vulnerable to microtrauma during
intercourse (introitus, perianal skin, and intraanal
muscosa) as papular or pedunculated lesions, with
granular papillations over their surfaces, resulting in
a verrucous appearance (Fig 1).29 Lesions generally
start as small growths ranging from 2 to 5 mm in
diameter but may grow to form bulky, confluent
clusters or nodules up to several centimeters in
diameter.17 Warts are frequently multifocal and may
extend into the rectum, urethra, vagina, and cervix.
While many cases are asymptomatic, some patients
J AM ACAD DERMATOL
VOLUME 66, NUMBER 6
may experience pruritus, mild burning, bleeding, or
irritation in addition to psychological distress, anxi-
ety, shame, and embarrassment.24,29,30 When bleed-
ing occurs, it is an indication that the wart has eroded
into the dermal papillae.17 Genital warts may also
become traumatized from friction caused by either
intercourse or clothing, with a subsequent risk of
secondary bacterial infection,17 as well as an in-
creased risk of infecting sexual partners. The diag-
nosis of CA is made primarily on clinical grounds
based on visual inspection. Clinical impression may
be confirmed by biopsy in special circumstances,
including when the diagnosis is uncertain, when the
lesions fail to respond to or become more severe
during therapy, or when warts have unusual fea-
tures, including pigmentation, excessive bleeding, or
ulceration.
Transmission and infectivity
Studies of the transmissibility of genital warts have
found that 60% to 85% of unaffected sexual partners
of patients with warts subsequently developed ano-
genital warts within 6 weeks to 8 months, suggesting
a high transmissibility for the subtypes of HPV that
cause anogenital warts.31-33 Patients are frequently
surprised by the development of anogenital warts,
and may question the diagnosis of a sexually
transmitted infection when they have not recently
been sexually active. Clinicians treating anogenital
warts should be aware that there may be a long
incubation period, with detection of incident HPV-6
or -11 infection leading to appearance of clinically
visible warts only after an average of 2.9 months.28 In
addition to contributing to the emergence of disease
in patients who are not currently sexually active, this
latency period also provides a potential window
during which transmission may occur to new part-
ners in the absence of visible lesions.34
The protective effect of condoms in preventing
the transmission of HPV is not entirely clear. There
are data to suggest that consistent condom use
provides some protection against the development
of external anogenital warts.5,35 The level of protec-
tion appears to be somewhat lower for women than
for men.35 Winer et al36 found that consistent con-
dom use reduced the risk of cervical and vulvovag-
inal HPV infection (level IIB evidence). However,
multiple studies, including a large metaanalysis by
Manhart et al,35 have found that condoms do not
provide protection against the transmission of HPV
(level IA evidence),29,37 presumably because sub-
clinical HPV infections may occur at epithelial sites
outside of the area covered by a latex condom (ie,
the scrotum and vulva and the suprapubic and
perianal areas).35
Gormley and Kovarik 867.e5
HPV DNA viral load increases from the latent, to
the subclinical, to the clinically overt state in which
warts are present.34 The exact infectivity of each of
these states is unclear, and clinicians cannot tell
patients definitively whether they are more infec-
tious when warts are present or whether treatment
results in a reduction in risk for the transmission of
HPV to sex partners.34 Infectivity of HPV is associ-
ated with detectable viral load,31,32,38 and the treat-
ment of warts has been shown to reduce tissue viral
load. Many clinicians have therefore hypothesized
that treating anogenital warts decreases infectivity.39
However, there is no direct evidence to date that
treatment of visible lesions reduces the risk of HPV
transmission or development of disease in sexual
partners.34 The duration and relative degree of
infectivity after treatment with complete clearance
of clinically apparent lesions also remains unclear.
Even after the eradication of warts, patients may
continue to harbor latent virus in their anogenital
epithelium, and it is not known whether HPV is
sufficiently infectious to allow transmission in this
state. Overall, the natural history of HPV infection,
patterns of viral load, and how this impacts infec-
tiousness remains to be understood in both men and
women.
Natural history of HPV infection
HPV infections are usually transient and tend to
undergo spontaneous regression. It is generally
accepted that in immunocompetent patients, most
anogenital HPV infections are cleared spontaneously
by the immune system. Data for spontaneous clear-
ance of HPV infection come primarily from studies
looking at natural history of HR HPV infections in
female patients with cervical infection. Data on the
natural history of HPV infections in men, as well as
LR HPV infections in anogenital warts, are limited. In
women with HR infections, the evidence for spon-
taneous regression of HPV infection includes first the
decreasing frequency of HPV DNA isolated from
women with increasing age31,40 and second more
direct evidence from longitudinal studies showing a
loss of ability to detect cervicovaginal DNA in most
women 1 to 2 years after initial DNA detection.22,28,37
In a landmark study by Ho et al,37 approximately
70% of women became HPV DNA undetectable at 12
months after incident HPV infection detection, and
more than 80% were clear at 18 months. Similar
results from multiple studies show that HPV can be
detected in only a small proportion of subsequent
cytologic samples of young women who were
initially positive for HPV.41-43 Initial data suggest
that HR HPV infections seem to persist longer than LR
HPV infections,22,37,42 and among HR types, it
867.e6 Gormley and Kovarik
appears that HPV-16 may persist longer than other
types.42 As previously discussed, the bulk of avail-
able data on HPV transmission and persistence is for
women; however, in general, in populations that are
of similar age, the prevalence of specific HPV types
seems to be lower in men than in women.9 It has yet
to be determined whether this is related to the lower
incidence or shorter duration of infection in men
versus women.9
Knowledge of the natural history of HPV infection
in relation to anogenital warts has been considerably
improved over the past 20 years because of the
publication of an increasing number of relevant
studies (recently reviewed by Insigna et al44).
However, understanding of the natural history of
genital warts remains severely limited, in part be-
cause of a selection bias of patients with anogenital
warts who seek physician care. In mild cases,
patients with anogenital warts may be unaware of
their presencesurprisingly, the self-reporting of
anogenital warts is not a sensitive tool for diagno-
sis.44-46 For example, Wiley et al46 found that only
38% of men who had external anogenital warts
diagnosed by a trained examiner using bright light
and visual inspection also self-reported having ano-
genital warts.46 In practice, patients with a low wart
burden and a higher likelihood of natural clearance
may not seek physician care, while individuals with
the largest and most extensive warts are more likely
to seek treatment.44
What is known about the development of ano-
genital warts in relation to initial infection and
duration of HPV-6 or -11 infection comes primarily
from data by Winer et al.28 They estimated the rate of
development of anogenital warts after incident HPV-
6 or -11 infection to be approximately 66% within
38.8 months,28 translating to an annual risk of pro-
gression of 28.5%.44 The median time between
detection of incident HPV-6 or -11 infection and
detection of anogenital warts was 2.9 months.28
Left untreated, approximately 20% to 38% of
episodes of anogenital warts will resolve.47-50 Most
studies to date showing the regression of warts in
patients taking placebo treatment have been flawed
in that they have used a follow-up of 3 months or less
and included high proportions of patients with
extensive, recalcitrant, and previously treated
warts.44,47,51 In the single available analysis using
longer-term data (20 weeks of follow-up), previously
untreated anogenital warts cleared in 37.5% of cases,
with a 12-month clearance probability of 71%.48 In a
study by Winer et al28 with 8 months of follow-up,
75% of women with anogenital warts achieved
clearance with therapy, with a median time to
clearance of 5.9 months.28
J AM ACAD DERMATOL
JUNE 2012
Coinfection with multiple HPV types
Coinfection with more than one HPV type is
common, and the concurrent acquisition of multiple
types occurs more often than expected by chance
alone.52 However, there is no evidence to suggest
that any two types are more likely to be acquired
together.52 It is unclear as to whether the natural
history of anogenital warts containing multiple HPV
types differs from that of warts with single HPV-6
or -11 infection.34 There are data to suggest that
coinfection increases the duration of infection. Che
et al53 found that infection with multiple subtypes
was associated with persistence of infection;
Woodman et al42 revealed that simultaneous coin-
fection with HPV-16 along with another subtype
resulted in longer duration of HPV-16epositivity as
compared with HPV-16 infection alone. Multiple
natural history studies show an increased risk of
acquisition of new HPV types in women who already
have cervical HPV infections, compared to those
who are HPV-negative54,55; however, these same
studies show the persistence of HPV infection to be
independent of coinfection with other subtypes. In
most cases, it is impossible to determine whether
having an HPV infection confers risk for acquisition
of an infection with a different type or whether HPV
subtypes were transmitted simultaneously.42 It is also
nearly impossible to determine whether having per-
sistence of infection with a single HPV type is related
to true persistence or rather reinfection and new
infection with the same HPV type.
Regardless of the effect of coinfection on natural
history, it is critical to determine how often patients
with anogenital warts may also be harboring HR
HPV. While HPV-6 and/or -11 account for the vast
majority of anogenital warts (70-100%), some warts
also contain HR HPV types. A study by Che et al53
documented HPV-16 or -18 coinfection in 11% of
anogenital warts. This raises the potential for the
development of anogenital malignancy related to the
oncogenic potential of HR HPV. In female patients, if
HPV-16, -18, or other HR HPV is detected within the
lesions of the external genitalia, this may predict the
presence of this HPV type in lesions of the cervix,
with implications for the patients risk of cervical
cancer.10 It has yet to be determined definitively
whether patients who are coinfected with HR HPV
within their warts have the persistence of HR HPV
after effective CA therapy.53
Patients with HIV or other forms of immunosup-
pression commonly have a higher viral load within
their warts and a higher prevalence of coinfection
with HR HPV, particularly HPV-16.9-12 It is still
unclear whether the natural history of anogenital
warts containing multiple HPV types, commonly
J AM ACAD DERMATOL
VOLUME 66, NUMBER 6
detected in HIV patients, differs from that of warts
with single HPV-6 or -11 infection.34 Data regarding
the effects of coinfection on persistence of infection
are conflicting. If coinfection confers some mutual
survival benefit, then the elimination of one HPV
type could have an unexpected beneficial effect on
the natural history of other coinfecting subtypes.42
However, multiple studies show the persistence of
HPV infection to be independent of coinfection with
other subtypes.54,55
HUMAN PAPILLOMAVIRUSeMEDIATED
ANOGENITAL MALIGNANCY
Key points
d Anogenital warts are benign lesions with a
minimal risk of malignant degeneration
d BuschkeeLowenstein tumor is a human pap-
illomaviruserelated lesion of intermediate
malignant potential
d Patients with high-risk HPV infections are at
risk for the development of multiple ano-
genital malignancies, including anal intraep-
ithelial, penile intraepithelial, and vaginal or
vulvar intraepithelial neoplasias, along with
frankly malignant conditions, including in-
vasive anal, penile, or vulvar carcinoma
d All of these malignancies are more common
and may be clinically more severe in the
immunosuppressed
Risk of malignant transformation of CA
Genital warts are generally considered benign
lesions, but in rare cases, malignant degeneration
with the subsequent development of invasive squa-
mous cell carcinoma (SCC) has been described.29 In
addition, there is an epidemiologic association be-
tween condyloma and cancer, likely because con-
dyloma act as a marker for HPV exposure and
possible coinfection with HR HPV types. As previ-
ously discussed, LR HPV types -6 and -11, which
account for the vast majority of cases of CA, represent
a very low risk for carcinoma because these viruses
do not integrate into the chromosomes of infected
host cells. Carcinoma is generally associated with HR
HPV, chiefly types -16 and -18. A small study in
Uganda found that nearly 30% of vulvar carcinomas
were associated with or preceded by condylomata.56
In addition, men who have sex with other men
(MSM) who have anal condylomata have been found
to carry a 50-fold relative risk for developing anal
cancer.57 There is also an established association in
women between having vulvar and perianal CA and
developing cervical dysplasia. This increased risk
for carcinoma may simply be related to coinfection
with HR HPV types, but it is still an important
Gormley and Kovarik 867.e7
Fig 2. BuschkeeLowenstein tumor in a young woman.
Large verrucous erythematous and hyperpigmented tumor
extending from the vulva. Photograph courtesy of Joseph
Magina.
consideration when counseling and treating patients
with anogenital warts.
Intermediate skin disease: Giant CA (BLT)
While common CA represent benign HPV-
associated tumors with a very low potential for
malignant transformation, giant CA, also called
BLT, is classified as a distinct entity between benign
condyloma and SCC.58 BLTs do not metastasize and
have benign histology; however, they have the
potential for expansive and invasive growth.59
Malignant transformation occurs in up to 50% of
cases of BLT, with an average time to transformation
of approximately 5 years.60,61 These tumors present
clinically as disfiguring, exophytic, cauliflower-like
masses on the penis, vulva, or anus (Fig 2).58,59
Symptoms result from invasive, deeply infiltrative
growth of these tumors with the subsequent destruc-
tion of underlying tissues, and include pain, bleed-
ing, itching, and fistulae formation.58,59 Obstructive
symptoms, including ileus and problems with defe-
cation, may eventually result in patients minimizing
their food intake with resulting cachexia.59 Fistulae
may become colonized with bacteria, forming ab-
scesses and occasionally resulting in sepsis.59 Such
local tissue destruction can have fatal consequences
even before malignant transformation occurs.59,60
Overall, the risk of mortality is estimated to be as high
as 21%.60
Histologically, BLTs and ordinary CA are very
similar, both showing vacuolization of cells in the
superficial layer of the epidermis, marked acantho-
sis, and parakeratosis, with infrequent mitotic figures
and maintenance of epithelial stratification.58,60 BLT
can be distinguished from common CA by its ten-
dency to infiltrate deeper tissue layers,62 with a
pushing rather than infiltrating pattern of invasion,63
resulting in the compression and displacement
of underlying tissues, sometimes involving the
867.e8 Gormley and Kovarik
musculature of the pelvis.58,60,61 Malignant transfor-
mation to SCC is determined by the presence of more
frequent mitotic figures, a loss of intact basement
membrane, a more infiltrative pattern of growth,
and, occasionally, the development of metastases.63
BLT is an exceedingly rare tumor. Even so, clini-
cians treating patients with HIV/AIDS should be
aware of this entity, because BLTs occur most com-
monly in patients with immunodeficiency including
HIV infection, posttransplantation, hematologic ma-
lignancy, prolonged steroid use, diabetes, during
pregnancy, and in persons with alcohol abuse.59,64-66
Ten cases have been reported in immunosuppressed
HIV-positive individuals in the English language
literature.59,65,67-69 It remains unclear as to whether
decreased cell-mediated immunity plays a role at the
time of initial HPV infection and allows for the
development of more severe, extensive disease, or
whether immune dysfunction allows for worsening
of preexisting HPV infection.59 In either case, when
BLT is diagnosed in an HIV-infected or otherwise
immunosuppressed patient, it is critical that these
patients be treated early and aggressively for this
locally invasive tumor.59,62
Premalignant and malignant HPV-induced
anogenital disease
Premalignant and malignant anogenital
disease. While the most common manifestation of
HPV infection in all patients, including the immuno-
suppressed, is CA, HPV is also responsible for
multiple premalignant and malignant lesions of the
anogenital region. Anogenital HPV can cause intra-
epithelial neoplasias, each named for the affected
site: AIN, PIN, and VIN, as well as frankly malignant
conditions, including invasive anal, penile, or vulvar
carcinoma, all of which have increased prevalence in
immunosuppressed patients.
VIN and vulvar cancer. Vulvar/vaginal neopla-
sia is a rare condition, but the incidence of both VIN
and vulvar carcinoma has been increasing.70 A his-
tory of CA, along with a history of genital herpes and
infection with HIV, are particularly common in
women with VIN.71,72 Presenting symptoms are
generally nonspecific (pruritus, pain, ulceration,
and dysuria); however, many patients are entirely
asymptomatic and seek clinical care only after find-
ing an abnormal appearing vulvar area on self-
examination (22% of patients).73 In all cases of vulvar
lesions of uncertain significance, or atypical warts,
with persistent vulvar irritation or itching, a biopsy
specimen of the vulva should be obtained to deter-
mine a definitive histopathologic diagnosis.72 An
optimal biopsy specimen should be taken from the
most suspicious part of the lesion, preferably taken
J AM ACAD DERMATOL
JUNE 2012
Fig 3. Invasive vulvar cancer. Verrucous white plaque
with underlying erythema, focal ulceration, and macera-
tion arising on nonehair-bearing vulvar skin in a white
patient. Photograph courtesy of Christopher J. Miller, MD.
from the edge of the lesion to include a small portion
of normal tissue.72 A punch or small incisional
biopsy specimen may be used, but in either case, a
minimal size of 4 mm is advisable for a reliable
diagnosis.72
VIN is categorized according to the updated
International Society for the Study of Vulvar
Disease classification, based on morphologic criteria
as either (1) usual type, the more common form of
VIN, which encompasses older terms (Bowen dis-
ease, bowenoid papulosis, and carcinoma in situ), or
(2) the less common differentiated type (2-10% of
cases70), which is generally not HPV-associated.21,74
The more common usual type (HPV-induced VIN)
presents clinically as raised, well demarcated, asym-
metric lesions, ranging from bulky whitish or ery-
thematous plaques, to verruciform, polypoid, or
papular lesions either with or without pigment
(Fig 3).70,72
HIV-positive women have increased rates of inci-
dence and prevalence of both VIN and vulvovaginal
carcinoma,14,75-77 with VIN occurring 29 times more
frequently in HIV-infected compared to noneHIV-
infected women.78 High grade VIN and vulvar car-
cinoma resulting from HPV infection is presenting in
increasing numbers of young women (\45 years of
age) with immunosuppression from HIV/AIDS, and
can even present in childhood.79 Patients taking
immunosuppressant drugs to prevent rejection after
transplantation or to treat a chronic autoimmune
disease are also at increased risk for development of
VIN, and have a 10- to 30-fold increased risk of
cancer of the vulva.80,81 This increased risk seen in
transplant recipients receiving iatrogenic immune
suppression is even greater than in HIV/AIDS pa-
tients, with a standardized incidence ratio of 22.76
compared to 6.45.82 The degree of immunosuppres-
sion directly correlates with risk of developing vulvar
J AM ACAD DERMATOL
VOLUME 66, NUMBER 6
Fig 4. Penile intraepithelial neoplasia. Bowen disease
presenting as a well-defined, erythematous, nontender
plaque on the shaft of the penis in a white patient.
Photograph courtesy of Christopher J. Miller, MD.
neoplasia. Multiple studies have shown that having
CD4 counts \200 cells/uL is an independent risk
factor for developing VIN.75-77,83
VIN in immunosuppressed patients often presents
as multifocal (in [40% of cases70), extensive disease
with a tendency to recur after treat-
ment.21,75,76,78,79,84-86 The multicentric nature of
HPV-induced VIN includes a risk of concurrent
cervical intraepithelial neoplasia. In some cases, it
may be unclear whether vulvovaginal lesions are
arising as an extension of cervical disease or whether
the lesions represent a separate HPV infection local-
ized to the vulvovaginal skin.87 In either case, if
vulvar neoplasia is confirmed by a biopsy specimen,
referral for colposcopic evaluation is indicated,88 and
these women should continue to receive careful
cervical cancer screening and follow-up throughout
their lives (level IV evidence).
PIN and penile cancer. A history of anogenital
warts in men is associated with a five- to six-fold
increased risk of penile SCC.89 The precursor to
penile SCC, PIN, can present with a variety of clinical
forms, including bowenoid papulosis, erythroplasia
of Queyrat, and Bowen disease (Fig 4).58 While
Bowen disease and erythroplasia of Queyrat share a
similar histologic appearance and biologic behavior,
and premalignant, bowenoid papulosis is probably
better considered a separate entity, with a lower
likelihood of progression to full-thickness in situ or
invasive carcinoma.90,91
Penile cancer (Fig 5) appears to develop along two
separate pathways, only one of which is mediated by
HPV infection. PIN is clearly associated with HPV,
with the detection of HPV DNA reported in 100% of
high-grade PIN lesions.92,93 However, detection in
invasive penile carcinoma is significantly lower, with
only 29% to 81% of all penile cancers containing HPV
Gormley and Kovarik 867.e9
DNA (most commonly types -16 and -18; HPV-16
[60.23%]; HPV-18 [13.35%]94).90,92,93,95-100 Micali
et al91 recently provided an excellent review of penile
carcinoma, its risk factors, clinical and histologic
presentations, and treatment.
Again, the immune system clearly plays an im-
portant role in the clearance and persistence of HPV
infection and in the development of PIN and penile
carcinoma. HIV-positive men have a two- to three-
fold increased risk for penile cancer compared to
their HIV-negative counterparts,14,92,101-105 along
with higher rates of high-grade PIN than HIV-
negative men.105,106 Transplant recipients receiving
iatrogenic immune suppression have an even greater
risk of developing carcinoma of the penis, with a
standardized incidence ratio of 15.79, compared to
4.42 in HIV/AIDS patients.82
AIN and anal cancer. AIN and anal carcinoma
are also examples of HPV-induced genital disease.
AIN is the precursor lesion to anal SCC. Anal cancer is
a rare malignancy that accounts for \1.5% of all
gastrointestinal cancers107; however, it is more com-
mon than either vulvar or penile carcinoma.
Clinicians should be aware that in immunocompro-
mised patients, including transplant recipients and
HIV/AIDS patients, there is a significantly increased
risk for anal cancer.14,103,108-110
Anal HPV infection, AIN, and anal cancer are
some of the most important and most common HPV-
related skin diseases affecting HIV patients, and
treatment options have recently been reviewed by
Palefsky et al.111 Rates of anal HPV infection are
extremely high in HIV-positive patients, particularly
in MSM.112 This increased prevalence of anal infec-
tion with HR HPV (particularly HPVs -16 and -18)
results in extremely high rates of both AIN and anal
cancer in the HIV-positive population.14,103,109,110
The relative risk for developing anal cancer is 37
times greater among HIV-positive MSM than that of
the general population.14 Clinicians had initially
hoped that the introduction of HAART therapy might
lead to regression of AIN or decreased rates of anal
cancer, because the risk for AIN increases with the
degree of immunosuppression from HIV infection
(as measured by CD41 counts).109 However, this has
disappointingly not been the case, and no regression
of AIN has been observed after the introduction of
HAART.113-115 On the contrary, there is concern that
the incidence of AIN and progression to anal cancer
may in fact increase as patients live longer lives with
the initiation of HAART. Sexual health clinics
throughout the United States have begun to initiate
screening programs to detect AIN in HIV-positive
patients who practice anal intercourse. The authors
of this review urge that this become standard practice
867.e10 Gormley and Kovarik J AM ACAD DERMATOL
JUNE 2012

Fig 5. Invasive penile squamous cell carcinoma in an uncircumcised patient. A, The patients
unremarkable physical examination when the foreskin is unretracted highlights the necessity
for a thorough examination of the entire anogenital area when screening for dysplasia. B, Two
lesions of penile squamous cell carcinoma appearing as an erythematous, raised, ulcerated
plaque with heaped borders and a white verrucous plaque with surrounding erythema.
Photographs courtesy of Christopher J. Miller, MD.

in this population given the high rate of morbidity
and mortality caused by HPV-induced AIN and anal
cancer in the HIV-positive population (level III
evidence). Palefksy et al11 have proposed an anal
cancer screening program modeled in part after
successful cervical cancer screening programs.116
Research into anal cancer and precancer in
immunosuppressed groups has mainly concentrated
on the HIV population, with a particular focus on
MSM; however, while more moderate in transplant
patients, the risk for AIN and anal cancer is also
significantly increased.108 In transplant recipients,
the overall prevalence of anal HPV infection is 23%
and that of HR types is 15%.117 In renal transplant
recipients specifically, the relative risk for anal can-
cer is 10.80,108 While the rates of AIN and anal cancer
are clearly increased in iatrogenically immunosup-
pressed transplant patients, the case for screening in
this population is less convincing than for HIV/AIDS
patients (level IV evidence).108 Nevertheless, clini-
cians treating transplant patients should be aware of
the heightened risk for HPV-induced anal dysplasia
and should have a low threshold for the biopsy of
suspicious lesions of the anal region (level IV
evidence).
While it is clear that immunocompromised pa-
tients are at increased risk of developing both AIN
and anal cancer, and that this population warrants
careful surveillance and screening, there are no
national or international practice guidelines for
screening patients for anal dysplasia to date. No
randomized clinical trials have yet been performed
to document the value of screening for AIN; instead,
the rationale for screening has been extrapolated
from the success of cervical cytology screening
programs in the reduction of cervical cancer inci-
dence.118 For dermatologists, it is critical to first be
aware of the increased risk of AIN and anal cancer in
immunocompromised patients, and second, based
on this awareness, to conduct a simple visual in-
spection of the external anal area in order to identify
lesions. Dermatologists should counsel patients
about their increased risk and recommend an annual
digital rectal examination (DRE).119 While there are
no formal studies on the performance of DRE to
detect anal cancer, given the ease of performing this
assessment, it is recommended that all at-risk indi-
viduals have this procedure annually, in order to
detect masses suspicious for anal cancer, with the
goal of identifying these cancers at a treatable
stage.119 Patients with worrisome findings on visual
examination or DRE should be referred to clinicians
trained to perform high-resolution anoscopy with a
biopsy of any visible lesions to determine the level of
histologic changes and to rule out invasive cancer.119
Eventually, anal Papanicolaou tests and cytology-
based screening programs may be useful. Studies of
cost effectiveness have projected that anal cytology
screening would be a cost effective preventive strat-
egy if performed every 2 to 3 years in both HIV-
positive and -negative MSM populations.118,120,121
While this modeling has only been performed in
MSM, the need for increased AIN and anal cancer
screening can logically be extrapolated to other
populations at high risk for HR HPV infection,
including men and women with anogenital warts.
J AM ACAD DERMATOL
VOLUME 66, NUMBER 6
While anal Papanicolaou tests may one day prove to
be a preventive strategy with substantial life expec-
tancy benefits, additional study is still needed before
definitive recommendations for anal cytology
screening can be made.122
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