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CONTINUING MEDICAL EDUCATION
Human papillomaviruserelated genital disease in theimmunocompromised host
Part I
Rachel H. Gormley, MD,a and Carrie L. Kovarik, MDa,b
Philadelphia, Pennsylvania
CME INSTRUCTIONS
Thefollowing isa journal-based CMEactivitypresented bythe AmericanAcademy of
Dermatology and is made up of four phases:
1. Reading of the CME Information (delineated below)
2. Reading of the Source Article
3. Achievement of a 70% or higher on the online Case-based Post Test
4. Completion of the Journal CME Evaluation
CME INFORMATION AND DISCLOSURES
Statement of Need:The American Academy of Dermatology bases its CME activities on the Academy’s
core curriculum, identified professional practice gaps, the educational needs which
underlie these gaps, and emerging clinical research findings. Learners should reflect
upon clinical and scientific information presented in the article and determine the
need for further study.
Target Audience:
Dermatologists and others involved in the delivery of dermatologic care.
Accreditation
The American Academy of Dermatology is accredited by the Accreditation Council
for Continuing Medical Education to provide continuing medical education for
physicians.
AMA PRA Credit Designation
The American Academy of Dermatology designates this journal-based CME activity
for a maximum of 1 AMA PRA Category 1 Credits . Physicians should claim only the
credit commensurate with the extent of their participation in the activity.
AAD Recognized Credit
This journal-based CME activity is recognized by the American Academy of
Dermatology for 1 AAD Credit and may be used toward the American Academy of
Dermatology’s Continuing Medical Education Award.
Disclaimer:
The American Academy of Dermatology is not responsible for statements made by
theauthor(s).Statementsor opinionsexpressedin this activityreflecttheviewsof the
author(s) and do not reflect the official policy of the American Academy of
Dermatology. The information provided in this CME activity is for continuing
education purposes only and is not meant to substitute for the independent medical
judgment of a healthcare provider relative to the diagnostic, management and
treatment options of a specific patient’s medical condition.
Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers
of this journal-based CME activity have reported no relevant financial relationships
with commercial interest(s).
Authors
The authors of this journal-based CME activity have reported no relevant financial
relationships with commercial interest(s).
Planners
The planners involved withthis journal-based CMEactivity havereportedno relevant
financial relationships with commercial interest(s). The editorial and education staff
involved with this journal-based CME activity have reported no relevant financial
relationships with commercial interest(s).
Resolution of Conflicts of Interest
In accordance with the ACCME Standards for Commercial Support of CME, the
American Academy of Dermatology has implemented mechanisms, prior to the
planning and implementation of this Journal-based CME activity, to identify and
mitigate conflicts of interest for all individuals in a position to control the content of
this Journal-based CME activity.
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
2011 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2011.12.050
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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 ispart 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-mediateddiseases 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 themost common sexually trans-mitted disease and have beenshown to cause both anogen-
ital warts and anogenital ma-lignancy. Immunosuppressedpatients are at increased riskfor developing multiple HPV-related benign and malignantanogenital tumors. Amongimmunocompetent patients,cell-mediated immunity cancontrol latent HPV infectionand mediate the regressionof HPV-induced lesions.Patients who are immuno-
compromised because of adecrease in cell-mediated immunity are therefore atincreased risk of developing and failing to clear HPV-related disease. Such patients include but are notlimited to organ transplant patients receiving chronicimmunosuppressive treatment and individuals withHIV infection. Since the introduction of highly activeantiretroviral therapy (HAART), there has been adramatic reduction in mortality and morbidity inHIV/AIDS patients. As HIV/AIDS has become achronic disease, patients with HPV coinfection havea prolonged period in which HPV-related anogenitaldisease can progress from premalignant to malignantlesions. Similarly, organ transplant patients—who areliving longer, healthier lives with the advent of ad- vanced immunosuppression and improved antirejec-tion therapies—are at increased risk of developingHPV-mediated anogenital neoplasia because of their
iatrogenic immunosuppression. This presents impor-tantimplications for screeningand surveillance in the immu-nocompromised patient
population.In all patients, HPV canlead to both benign neopla-sia and frankly malignantanogenital lesions of the cer- vix, vulva, anus, and, rarely,the penis. The following re- view will discuss benign con-dyloma acuminata (CA), themost common cutaneousmanifestation of anogenitalHPV infection. The review
will also discuss intermediatemalignancy or premalignant conditions, includinggiant CA, also called BuschkeeLowenstein tumor(BLT), anal intraepithelial neoplasia (AIN), penileintraepithelial neoplasia (PIN), and vaginal or vulvarintraepithelial neoplasia (VIN). Finally, we will dis-cuss frankly malignant lesions, including invasiveanal, penile, or vulvar carcinoma. This review willfocus on the more common CA but will also addressthe rare, but clinically important, malignant forms of HPV-related anogenital disease.
IMMUNOCOMPROMISE AND HUMANPAPILLOMAVIRUS INFECTIONKey pointsd Immune status has a significant impact on
HPVdisease course and response to treatment
CAPSULE SUMMARY
d
Human papillomavirus causes bothbenign condyloma acuminata and
anogenital malignancies.
d Immunosuppressed patients, including
patients with HIV infection and organ
transplant recipients, are at increased risk
for developing these conditions.
d Patients with HIV infection and organ
transplant recipients require heightened
screening and aggressive treatment.
From the Departments of Dermatologya and Internal Medicine,b
Division of Infectious Diseases, University of Pennsylvania
School of Medicine.
Funding sources: None.
Reprint requests: Carrie L. Kovarik, MD, Department of
Dermatology, University of Pennsylvania, 2 Maloney Bldg,
3600 Spruce St, Philadelphia, PA 19104. E-mail: Carrie.
0190-9622/$36.00
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d Reduced cytotoxic T-lymphocyte reactivity to HPV oncoproteins E6 and E7 leads toimpaired 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 diseased These patients are frequently infected with
multiple HPV types and have been found tohave a higher prevalence of HR HPV-16
d It remains to be seen whether prophylacticHPV vaccination will be therapeutic in thesepatients, many of whom have previously established HPV infections
The immune status of the host has a significantimpact on the HPV disease course and response totreatment. 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 notrespond as well to treatment. Studies examining HPV carriage have shown that skin samples of pluckedhairs 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 riskof anogenital warts.3,4 Cigarette smoking has beenstrongly linked to the risk of anogenital warts in men, with a dose-dependent response in which smokersof more than 10 cigarettes per day have been shown
to be twice as likely to have anogenital warts asnonsmoking men.5 In a study by Wen et al,5 thebaseline prevalence of HPV DNA was similar insmokers and nonsmokers, and the authors suggestedthat the increased rate of progression of exophyticanogenital warts in smokers reflects immune modu-lation effects induced by cigarettes.5 Similar resultshave been found in women, with a three-foldincrease 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 aconfounder rather than actually acting as a risk factor
for the development of warts.
While any patient with suppression of the im-mune system is at increased risk for HPV-relatedanogenital 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), withincreased duration and persistence of disease.6,7 Itshould be briefly noted that showing a direct corre-lation between HIV/AIDS-induced immunosuppres-sion and acquiring HPV infection is difficult, giventhat HIV-infected persons may also be more likely tohave sexual behavior, age characteristics, and othershared risk factors for HPV infection.8 Patients withHIV 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, andhave 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, suchas EpsteineBarr virus, HPV, human herpesvirus-8,and human T-cell lymphoma virus-1, are knowncomplications in transplant recipients. This in-creased risk is related to immune system suppressionfrom the use of immunomodulatory, antirejectionmedications 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-positivepatients 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 thanthe prevalence of HR HPV f ound in condyloma of immunocompetent patients.9-12 Many of the mostsuccessful 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 stimulatingthe immune response in an HIV patient is clearly advantageous, these forms of treatment raise theconcern for the theoretical risk of inducing rejectionin transplant patients.
Whether increased HPV infection in immunocom-promised patients is related to the increased reacti- vation of latent HPV infection or related to theacquisition 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
Abbreviations used:
AIN: anal intraepithelial neoplasiaBLT: BuschkeeLowenstein tumorCA: condyloma acuminataDRE: digital rectal examinationHAART: highly active antiretroviral therapy HPV: human papillomavirusMSM: men who have sex with other menPIN: penile intraepithelial neoplasia
VIN: vulvar intraepithelial neoplasia
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virus in keratinocytes and hastens the course of already established HPV infections.14 As HIV/AIDSprogresses, there is reduced cytotoxic T-lymphocytereactivity to HPV oncoproteins E6 and E7, leading toimpaired ability to clear HPV and allowing forrelatively undisturbed epithelial proliferation.14,15
Some authors have suggested that in fact immuno-compromised patients and control subjects do notreally differ in the presence versus absence of HPV,but rather they differ in the extent of HPVreplication,and therefore, quantitative HPV viral load.16 Thisincreased carriage and quantitative level of HPV inHIV patients results in a higher incidence in a variety of conditions, both benign and malignant, but mostcommonly CA.11 The treatment of CA in HIV pa-tients, which will be discussed later in detail, is oftenless 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 excitingdevelopments in HPV-mediated disease is the intro-duction of prophylactic vaccines directed againstHPV. There are two currently in clinical use: Gardasil(Merck and Co. Inc, Whitehouse Station, NJ), aquadrivalent vaccine that protects against HPVs-6,-11, -16, and -18; and Cervarix (GlaxoSmithKline,London, United Kingdom), a bivalent vaccine thatprotects against HPVs-16 and -18.18 Clinical trials forall commercially available vaccines enrolled primar-
ily healthy young women, and studies addressingefficacy in immunosuppressed patients (either HIV-positive or solid organ transplant recipients) arelacking.18-20 These vaccines are likely to be safe inboth populations given that they are not live vac-cines; however, other side effects and toxicities mustbe formally assessed in immunocompromised pa-tients. Efficacy and appropriateness in this popula-tion of prophylactic vaccines aimed at reducing thenumber of new HPV infections presents a greaterissue 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 pointsd 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, patientsmay 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
HPV types and require monitoring andscreening 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 activeindividuals in the United States, with the incidenceincreasing steadily since the 1950s.22-25 In North America, there is an annual rate of 100 cases per100,000 individuals, making anogenital warts morecommon than breast and prostate cancer; this is anincidence that translates to a lifetime cumulative riskapproaching 10%.22 Low-risk (LR) HPV types 6 and11 are most commonly associated with anogenital warts, with 70% to 100% of anogenital warts con-taining one or both of these subtypes.9 However, atleast 18 other HPV types have been associated withCA, 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 toHPV-11.27,28
Clinical presentation and diagnosis
CA have a variety of clinical presentations, butmost commonly appear on areas of the anogenitalmucosa that are vulnerable to microtrauma duringintercourse (introitus, perianal skin, and intraanalmuscosa) as papular or pedunculated lesions, withgranular papillations over their surfaces, resulting ina verrucous appearance (Fig 1).29 Lesions generally start as small growths ranging from 2 to 5 mm indiameter but may grow to form bulky, confluentclusters or nodules up to several centimeters indiameter.17 Warts are frequently multifocal and may extend into the rectum, urethra, vagina, and cervix.
While many cases are asymptomatic, some patients
Fig 1. Condyloma acuminata. Dark brown, verrucouspapules on the penile shaft of an African American patient.
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may experience pruritus, mild burning, bleeding, orirritation 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 erodedinto the dermal papillae.17 Genital warts may alsobecome traumatized from friction caused by eitherintercourse 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 groundsbased on visual inspection. Clinical impression may be confirmed by biopsy in special circumstances,including when the diagnosis is uncertain, when thelesions fail to respond to or become more severeduring therapy, or when warts have unusual fea-tures, including pigmentation, excessive bleeding, orulceration.
Transmission and infectivity Studies of the transmissibility of genital warts have
found that 60% to 85% of unaffected sexual partnersof patients with warts subsequently developed ano-genital warts within 6 weeks to 8 months, suggestinga high transmissibility f or the subtypes of HPV thatcause 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-6or -11 infection leading to appearance of clinically visible warts only after an average of 2.9 months.28 Inaddition to contributing to the emergence of diseasein patients who are not currently sexually active, thislatency period also provides a potential windowduring which transmission may occur to new part-ners in the absence of visible lesions.34
The protective effect of condoms in preventingthe transmission of HPV is not entirely clear. Thereare data to suggest that consistent condom useprovides some protection against the development
of external anogenital warts.5,35
The level of protec-tion appears to be some what lower for women thanfor 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 notprovide protection against the transmission of HPV (level IA evidence),29,37 presumably because sub-clinical HPV infections may occur at epithelial sitesoutside of the area covered by a latex condom (ie,the scrotum and vulva and the suprapubic and
perianal areas).
35
HPV DNA viral load increases from the latent, tothe 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 tellpatients definitively whether they are more infec-tious when warts are present or whether treatmentresults 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 viralload. Many clinicians have therefore hypothesizedthat treating anogenital warts decreases infectivity.39
However, there is no direct evidence to date thattreatment of visible lesions reduces the risk of HPV transmission or development of disease in sexualpartners.34 The duration and relative degree of infectivity after treatment with complete clearanceof clinically apparent lesions also remains unclear.
Even after the eradication of warts, patients may continue to harbor latent virus in their anogenitalepithelium, and it is not known whether HPV issufficiently infectious to allow transmission in thisstate. 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, mostanogenital HPV infections are cleared spontaneously by the immune system. Data for spontaneous clear-ance of HPV infection come primarily from studieslooking at natural history of HR HPV infections infemale patients with cervical infection. Data on thenatural history of HPV infections in men, as well asLR HPV infections in anogenital warts, are limited. In women with HR infections, the evidence for spon-taneous regression of HPV infection includes first thedecreasing frequency of HPV DNA isolated from women with increasing age31,40 and second more
direct evidence from longitudinal studies showing aloss 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 12months after incident HPV infection detection, andmore than 80% were clear at 18 months. Similarresults from multiple studies show that HPV can bedetected in only a small proportion of subsequentcytologic samples of young women who wereinitially positive for HPV.41-43 Initial data suggestthat HR HPV infections seem to persist longer than LR
HPV infections,
22,37,42
and among HR types, it
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appears that HPV-16 may persist longer than othertypes.42 As previously discussed, the bulk of avail-able data on HPV transmission and persistence is for women; however, in general, in populations that areof similar age, the prevalence of specific HPV typesseems to be lower in men than in women.9 It has yetto be determined whether this is related to the lowerincidence or shorter duration of infection in men versus women.9
Knowledge of the natural history of HPV infectionin relation to anogenital warts has been considerably improved over the past 20 years because of thepublication of an increasing number of relevantstudies (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 presence—surprisingly, 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 wartsdiagnosed by a trained examiner using bright lightand visual inspection also self-reported having ano-genital warts.46 In practice, patients with a low wartburden and a higher likelihood of natural clearancemay not seek physician care, while individuals withthe 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 andduration 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% within38.8 months,28 translating to an annual risk of pro-gression of 28.5%.44 The median time betweendetection of incident HPV-6 or -11 infection anddetection 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 inpatients taking placebo treatment have been flawedin that they have used a follow-up of 3 months or lessand included high proportions of patients withextensive, recalcitrant, and previously treated warts.44,47,51 In the single available analysis usinglonger-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 astudy by Winer et al28 with 8 months of follow-up,75% of women with anogenital warts achievedclearance with therapy , with a median time to
clearance of 5.9 months.
28
Coinfection with multiple HPV typesCoinfection with more than one HPV type is
common, and the concurrent acquisition of multipletypes occurs more often than expected by chancealone.52 However, there is no evidence to suggestthat any t wo types are more likely to be acquiredtogether.52 It is unclear as to whether the naturalhistory of anogenital warts containing multiple HPV types differs from that of warts with single HPV-6or -11 infection.34 There are data to suggest thatcoinfection increases the duration of infection. Cheet 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 subtyperesulted in longer duration of HPV-16epositivity ascompared with HPV-16 infection alone. Multiplenatural 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 samestudies show the persistence of HPV infection to beindependent of coinfection with other subtypes. Inmost cases, it is impossible to determine whetherhaving an HPV infection confers risk for acquisitionof an infection with a different type or whether HPV subtypes were transmitted simultaneously.42 It is alsonearly impossible to determine whether having per-sistence of infection with a single HPV type is relatedto 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 vastmajority of anogenital warts (70-100%), some wartsalso 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 thedevelopment of anogenital malignancy related to theoncogenic 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 thepresence of this HPV type in lesions of the cervix, with implications for the patient’s risk of cervicalcancer.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 withintheir warts and a higher prevalence of coinfection with HR HPV, particularly HPV-16.9-12 It is stillunclear whether the natural history of anogenital
warts containing multiple HPV types, commonly
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detected in HIV patients, differs f rom that of warts with single HPV-6 or -11 infection.34 Data regardingthe effects of coinfection on persistence of infectionare conflicting. If coinfection confers some mutualsurvival benefit, then the elimination of one HPV type could have an unexpected beneficial effect onthe natural history of other coinfecting subtypes.42
However, multiple studies show the persistence of HPV infection to be independent of coinfection withother subtypes.54,55
HUMAN PAPILLOMAVIRUSeMEDIATED ANOGENITAL MALIGNANCY Key pointsd 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 theimmunosuppressed
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 Inaddition, there is an epidemiologic association be-tween condyloma and cancer, likely because con-dyloma act as a marker for HPV exposure andpossible coinfection with HR HPV types. As previ-ously discussed, LR HPV types -6 and -11, whichaccountfor the vast majority of cases of CA, representa very low risk for carcinoma because these viruses
do not integrate into the chromosomes of infectedhost cells. Carcinoma is generally associated with HR HPV, chiefly types -16 and -18. A small study inUganda 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 foundto carr y a 50-fold relative risk for developing analcancer.57 There is also an established association in women between having vulvar and perianal CA anddeveloping cervical dysplasia. This increased riskfor carcinoma may simply be related to coinfection
with HR HPV types, but it is still an important
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 formalignant transformation, giant CA, also calledBLT, is classified as a distinct entity between benigncondyloma and SCC.58 BLTs do not metastasize andhave benign histology; however, they have thepotential for expansive and invasive growth.59
Malignant transformation occurs in up to 50% of cases of BLT, with an average time to transformationof approximately 5 years.60,61 These tumors present
clinically as disfiguring, exophytic, cauliflower-likemasses on the penis, vulva, or anus (Fig 2).58,59
Symptoms result from invasive, deeply infiltrativegrowth of these tumors with the subsequent destruc-tion of underlying tissues, and include pain, bleed-ing, itching, and fistulae formation.58,59 Obstructivesymptoms, including ileus and problems with defe-cation, may eventually result in patients minimizingtheir food intake with resulting cachexia.59 Fistulaemay become colonized with bacteria, forming ab-scesses and occasionally resulting in sepsis.59 Suchlocal tissue destruction can have fatal consequences
even before malignant transformation occurs.59,60
Overall, the risk of mortality is estimated to be as highas 21%.60
Histologically, BLTs and ordinary CA are very similar, both showing vacuolization of cells in thesuperficial layer of the epidermis, marked acantho-sis, and parakeratosis, with infrequent mitotic figuresand maintenance of epithelial stratification.58,60 BLTcan be distinguished from common CA by its ten-dency to infiltrate deeper tissue layers,62 with apushing rather than infiltrating pattern of invasion,63
resulting in the compression and displacement
of underlying tissues, sometimes involving the
Fig 2. BuschkeeLowenstein tumor in a young woman.Large verrucous erythematous and hyperpigmented tumorextending from the vulva. Photograph courtesy of JosephMagina.
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musculature of the pelvis.58,60,61 Malignant transfor-mation to SCC is determined by the presence of morefrequent mitotic figures, a loss of intact basementmembrane, 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 beaware of this entity, because BLTs occur most com-monly in patients with immunodeficiency includingHIV infection, posttransplantation, hematologic ma-lignancy, prolonged steroid use, diabetes, duringpregnancy, and in persons with alcohol abuse.59,64-66
Ten cases have been reported in immunosuppressedHIV-positive indi viduals in the English languageliterature.59,65,67-69 It remains unclear as to whetherdecreased cell-mediated immunity plays a role at thetime of initial HPV infection and allows for thedevelopment of more severe, extensive disease, or
whether immune dysfunction allows for worseningof preexisting HPV infection.59 In either case, whenBLT is diagnosed in an HIV-infected or otherwiseimmunosuppressed patient, it is critical that thesepatients be treated early and aggressively for thislocally invasive tumor.59,62
Premalignant and malignant HPV-inducedanogenital 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 formultiple premalignant and malignant lesions of theanogenital region. Anogenital HPV can cause intra-epithelial neoplasias, each named for the affectedsite: AIN, PIN, and VIN, as well as frankly malignantconditions, including invasive anal, penile, or vulvarcarcinoma, all of which have increased prevalence inimmunosuppressed patients.
VIN and vulvar cancer. Vulvar/vaginal neopla-sia is a rare condition, but the incidence of both VINand vulvar carcinoma has been increasing.70 A his-tory of CA, along with a history of genital herpes and
infection with HI V, are particularly common in women with VIN.71,72 Presenting symptoms aregenerally 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 vulvarlesions 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 Anoptimal biopsy specimen should be taken from the
most suspicious part of the lesion, preferably taken
from the edge of the lesion to include a small portion
of normal tissue.72 A punch or small incisionalbiopsy specimen may be used, but in either case, aminimal size of 4 mm is advisable for a reliablediagnosis.72
VIN is categorized according to the updatedInternational Society for the Study of VulvarDisease classification, based on morphologic criteriaas 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, orpapular 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 vulvovaginalcarcinoma,14,75-77 with VIN occurring 29 times morefrequently in HI V-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, andcan even present in childhood.79 Patients takingimmunosuppressant drugs to prevent rejection aftertransplantation or to treat a chronic autoimmunedisease 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 intransplant recipients receiving iatrogenic immunesuppression is even greater than in HIV/AIDS pa-tients, with a standardized incidence ratio of 22.76compared to 6.45.82 The degree of immunosuppres-
sion directly correlates with risk of developing vulvar
Fig 3. Invasive vulvar cancer. Verrucous white plaque with underlying erythema, focal ulceration, and macera-tion arising on nonehair-bearing vulvar skin in a whitepatient. Photograph courtesy of Christopher J. Miller, MD.
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neoplasia. Multiple studies have shown that havingCD4 counts \200 cells/uL is an independent riskfactor for developing VIN.75-77,83
VIN in immunosuppressed patients often presentsas 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 concurrentcervical intraepithelial neoplasia. In some cases, itmay be unclear whether vulvovaginal lesions arearising as an extension of cervical disease or whetherthe 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 andthese women should continue to receive carefulcervical cancer screening and follow-up throughouttheir lives (level IV evidence).
PIN and penile cancer. A history of anogenital warts in men is associated with a five- to six-foldincreased risk of penile SCC.89 The precursor topenile SCC, PIN, can present with a variety of clinicalforms, including bowenoid papulosis, erythroplasiaof Queyrat, and Bowen disease (Fig 4).58 While
Bowen disease and erythroplasia of Queyrat share asimilar histologic appearance and biologic behavior,and premalignant, bowenoid papulosis is probably better considered a separate entity, with a lowerlikelihood of progression to full-thickness in situ orinvasive carcinoma.90,91
Penile cancer (Fig5) appears to developalong twoseparate pathways, only one of which is mediated by HPV infection. PIN is clearly associated with HPV, with the detection of HP V DNA reported in 100% of high-grade PIN lesions.92,93 However, detection ininvasive penile carcinoma is significantly lower, with
only 29% to 81% of all penile cancers containing HPV
DNA (most commonly types -16 and -18; HPV-16[60.23%]; HPV-18 [13.35%]94).90,92,93,95-100 Micalietal91 recently provided an excellent reviewof penilecarcinoma, its risk factors, clinical and histologicpresentations, 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 penilecarcinoma. HIV-positive men have a two- to three-fold increased risk for penile cancer compared totheir HIV-negative counterparts,14,92,101-105 along with higher rates of high-grade PIN than HIV-negative men.105,106 Transplant recipients receivingiatrogenic immune suppression have an even greaterrisk of developing carcinoma of the penis, with astandardized incidence ratio of 15.79, compared to4.42 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 isa rare malignancy that accounts for \1.5% of allgastrointestinal 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 andHIV/AIDS patients, there is a significantly increasedrisk for anal cancer.14,103,108-110
Anal HPV infection, AIN, and anal cancer aresome 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 areextremely 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 analcancer in the HIV-positive population.14,103,109,110
The relative risk for developing anal cancer is 37times greater among HIV -positive MSM than that of the general population.14 Clinicians had initially hoped that the introduction of HAART therapy mightlead to regression of AIN or decreased rates of anal
cancer, because the risk for AIN increases with thedegree of immunosuppression from HIV infection(as measured by CD41 counts).109 However, this hasdisappointingly not been the case, and no regressionof AIN has been observed after the introduction of HAART.113-115 On the contrary, there is concern thatthe incidence of AIN and progression to anal cancermay in fact increase as patients live longer lives withthe initiation of HAART. Sexual health clinicsthroughout the United States have begun to initiatescreening programs to detect AIN in HIV-positivepatients who practice anal intercourse. The authors
of this review urge that this become standard practice
Fig 4. Penile intraepithelial neoplasia. Bowen diseasepresenting as a well-defined, erythematous, nontenderplaque on the shaft of the penis in a white patient.Photograph courtesy of Christopher J. Miller, MD.
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in this population given the high rate of morbidity and mortality caused by HPV-induced AIN and analcancer in the HIV-positive population (level IIIevidence). Palefksy et al11 have proposed an analcancer screening program modeled in part af tersuccessful cervical cancer screening programs.116
Research into anal cancer and precancer inimmunosuppressed groups has mainly concentrated
on the HIV population, with a particular focus onMSM; however, while more moderate in transplantpatients, the risk for AIN and anal cancer is alsosignificantly increased.108 In transplant recipients,the overall prevalence of anal HPV infection is 23%and that of HR types is 15%.117 In renal transplantrecipients specifically, the relative risk for anal can-cer is 10.80,108 While the rates of AIN and anal cancerare clearly increased in iatrogenically immunosup-pressed transplant patients, the case for screening inthis population is less convincing than for HIV/AIDSpatients (level IV evidence).108 Nevertheless, clini-
cians treating transplant patients should be aware of the heightened risk for HPV-induced anal dysplasiaand 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 AINand anal cancer, and that this population warrantscareful surveillance and screening, there are nonational or international practice guidelines forscreening patients for anal dysplasia to date. Norandomized clinical trials have yet been performed
to document the value of screening for AIN; instead,
the rationale for screening has been extrapolatedfrom the success of cervical cytology screeningprograms in the reduction of cervical cancer inci-dence.118 For dermatologists, it is critical to first beaware of the increased risk of AIN and anal cancer inimmunocompromised patients, and second, basedon this awareness, to conduct a simple visual in-spection of the external anal area in order to identify
lesions. Dermatologists should counsel patientsabout their increased risk and recommend an annualdigital rectal examination (DRE).119 While there areno formal studies on the performance of DRE todetect anal cancer, given the ease of performing thisassessment, it is recommended that all at-risk indi- viduals have this procedure annually, in order todetect masses suspicious for anal cancer, with thegoal of identifying these cancers at a treatablestage.119 Patients with worrisome findings on visualexamination or DRE should be referred to clinicianstrained 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 inMSM, the need for increased AIN and anal cancerscreening can logically be extrapolated to otherpopulations at high risk for HR HPV infection,
including men and women with anogenital warts.
Fig 5. Invasive penile squamous cell carcinoma in an uncircumcised patient. A , The patient’sunremarkable physical examination when the foreskin is unretracted highlights the necessity for a thorough examination of the entire anogenital area when screening for dysplasia. B, Twolesions 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.
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While anal Papanicolaou tests may one day prove tobe a preventive strategy with substantial life expec-tancy benefits, additional study is still needed beforedefinitive recommendations for anal cytology screening can be made.122
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