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Acta Cytologica
Genital Human Papillomavirus Infection and
Associated Penile Intraepithelial Neoplasia in
Males Infected with the Human
Immunodeficiency Virus
Mary Gomousa-Michael, M.D., Efthimia Gialama, M.D., Nikos Gomousas, M.D., and
Georgia Gialama, C.T.
OBJECTIVE: To investigate the association between
(50%) than among their HIV-seronegative counterparts
human
papillomavirus
(30%). There was immuno(HPV) infections and penile
cytochemical evidence of
intraepithelial
neoplasia
HPV in HIV-infected men in
Infection with HIV enhances
(PIN) in genital lesions from
a greater proportion (50%)
human immunodeficiency the expression of HPV, especially
than in HIV noninfected
virus (HIV)+ men. For commen (37.5%). By in situ hyhigh-risk HPV related to
parison, we also investigated
bridization it was found that
immunosuppression.
the same association using
there was a higher prevalence
specimens from HIV− men.
of potentially oncogenic
STUDY DESIGN: Imprint
HPV (16/18, 31/33/35):
smears from penile lesions were obtained from 70 men
75% in moderate or severe dysplasia (PIN 2 and 3) and
(mean age, 30 years) who visited a dermatologist. Thirty
66.6% in HIV+ men as compared with HIV− men
of them were known to be HIV seropositive. Two study
(10–16.6%).
groups were formed: one of 40 HIV− and another of 30
CONCLUSION: HIV-seropositive males showed an
HIV+ males. The smears were examined cytologically for
unbalanced distribution of HPV, with a predominance
HPV identification or PIN, immunocytochemically for
of “high-risk” HPV types. This suggests that imHPV detection and by in situ hybridization for HPV
munodepression encourages infection by this oncogenic
typing.
virus, thereby contributing to the frequency of precanRESULTS: The rates of detecting HPV infection cytocerous lesions in HIV+ men. (Acta Cytol 2000;44:
logically were higher among men with HIV infection
305–309)
From the Department of Cytology, Thriassio General Hospital, Elefsina, Athens, Greece.
Dr. Gomousa-Michael is Director.
Dr. Gialama is Cytologist.
Dr. Gomousas is Dermatologist.
Ms. Gialama is Cytotechnologist.
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.
Received for publication December 2, 1998.
Accepted for publication September 14, 1999.
0001-5547/00/4403-0305/$19.00/0 © The International Academy of Cytology
Acta Cytologica
305
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Address reprint requests to: Mary Gomousa-Michael, M.D., 29 Zossimadon Street, Piraeus 185 31, Greece.
306
Gomousa-Michael et al
Acta Cytologica
Keywords: papillomavirus, human; human immunodeficiency virus; penile neoplasms; immunocytochemistry; hybridization, in situ.
Human papillomaviruses (HPV) have been reported to be one of the major causes of verrucae, condylomata acuminata and other epithelial proliferative
It is likely that immunosuppressed
men with a high prevalence of
HPV and genital intraepithelial
neoplasia are at greater risk of
developing cancer than are
nonimmunosuppressed men.
lesions. Several studies indicated that precancerous
and invasive neoplastic lesions of the female genital
tract contain HPV DNA at high rates.8,17
In men some types of HPV have been implicated
as possible causative agents in the induction of anal
dysplasia and carcinoma.26 The penile area is also a
site of dysplasia. Most of the benign condylomata
acuminata of the male anogenital tract have been
proven to contain HPV 6–11, whereas higher grade
precancers and invasive tumors frequently contain
HPV 16–18.17 Penile precancerous lesions, classified as Bowenoid papulosis, invariably yield HPV
type 16.20
A relationship has also been shown between the
presence of anal HPV infection, anal intraepithelial
neoplasia and immune abnormalities.3 As reported,
penile and anal warts are twice as common in HIVseropositive men as in seronegative men.22
The objective of this study was to investigate the
presence of HPV penile intraepithelial neoplasia
(PIN) in genital lesions from HIV+ men by means of
cytology, immunocytochemistry and in situ hybridization.
Materials and Methods
The study included 70 men (mean age, 30 years)
who visited the dermatologist because of penile lesions. Thirty of them were known to be HIV
seropositive. Two study groups were formed: one
of 40 HIV-seronegative and another of 30 HIVseropositive males. Six imprint smears from penile
lesions in each man were taken. Two of them were
processed as for routine Papanicolaou smears. One
specimen was stained immunocytochemically by
the polyclonal antibody method (Immune Omnitags, alkaline phosphatase, Shandon, Lipshaw
Immunon, Pittsburgh, Pennsylvania, U.S.A.), and
the other three smears were processed for in situ
hybridization using the Pathogene DNA Probe
Assay (Enzo Diagnostics, Farmingdale, New York,
U.S.A.) with 3-amino-9-ethyl-carbazole as the colored substrate and Mayer’s hematoxylin as the
counterstain.
Results
Criteria for HPV identification were koilocytosis
and dyskeratosis and for PIN were those established for cervical cells.
Immunocytochemically, the presence of HPV
was indicated by red staining of the nucleus of affected cells, whereas by in situ hybridization HPV
typing was made by the presence of brown-red
grains in the nucleus, also.
Table I shows the findings in the HIV-seronegative
group (40 men). In 12 subjects (30%), HPV and PIN
were diagnosed morphologically (cytologically).
Ten (83.3%), had low grade lesions (HPV-PIN 1),
and two (16.6%), high grade lesions (PIN 2). Immunocytochemically, HPV was present in 15 of 40
males (37.5%). By in situ hybridization, HPV subtypes were detected in 20 smears (50%). HPV lowrisk types (6/11) were found in 18 of 20 samples
(90%), whereas high-risk types (16/18, 31/33/35)
were found in 2 cases (10%).
Table II shows the findings in the HIV-seropositive
group (30 men). Cytologic findings of HPV-PIN
Table I HIV-Negative Group
Result
n
N=40.
Cytologic diagnosis
(HPV-PIN): 12 (30%)
Low grade
(HPV-PIN 1)
10 (83.3%)
High grade
(PIN 2–3)
2 (16.6%)
Immunocytochemical
diagnosis: 15 (37.5%)
—
—
In situ hybridization
diagnosis: 20 (50%)
Low-risk types,
6/11
18 (90%)
High-risk types,
16/18, 31/33/35
2 (10%)
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Parameter
Genital HPV and PIN
Volume 44, Number 3/May–June 2000
307
Table II HIV-Positive Group
Parameter
Result
n
Cytologic diagnosis
(HPV-PIN): 15 (50%)
Low grade
(HPV-PIN 1)
5 (33.3%)
High grade
(PIN 2–3)
10 (66.6%)
Immunocytochemical
diagnosis: 15 (50%)
—
—
In situ hybridization
diagnosis: 20 (66.6%)
Low-risk types,
6/11
5 (25%)
High-risk types,
16/18, 31/33/35
15 (75%)
were present in 15 cases (50%). Ten of them (66.6%)
presented high grade lesions (PIN 2–3), whereas 5
(33.3%) had low grade lesions (HPV-PIN 1). The immunocytochemical method detected HPV in 15
cases (50%). In situ hybridization detected HPV
DNA in 20 samples (66.6%). In 15 of them (75%),
high-risk types (16/18, 31/33/35) were identified,
and 5 cases (25%) were positive for low-risk types
(6/11).
Discussion
That infection with HPV is associated with cancer of
the cervix, vulva, vagina, anus and penis is now
well established.10,13 Numerous studies have
shown that cervical cancer is preceded by increasing degrees of intraepithelial neoplasia and that
both these disorders are associated with HPV infection.14,31
Exogenous immunosuppression is known to influence the acceleration of the development of squamous neoplasia of the female genital tract,21,31,32
and some reports14,23,24,29 clearly document a significant association between HPV infection and cervical intraepithelial neoplasia with HIV seropositivity.
The findings of several studies indicate that homosexual men with HIV have a high prevalence of
anal HPV infection and anal intraepithelial neoplasia, and that immunosuppression may play an important role in the pathogenesis of disease in association with HPV infection.4,6,7,12,15,16,18,19
In this study the findings from penile lesions indicate that rates of detecting HPV infection cytologically are higher among men with HIV infection
(50%) than among their HIV-seronegative counterparts (30%), as also reported by Vernon.31 Also, immunocytochemically there was evidence of HPV in
HIV-infected men in a greater proportion (50%)
than in HIV-noninfected men (37.5%).
We have observed a higher prevalence of potentially oncogenic HPV (75%) and moderate or severe
dysplasia (66.6%) in HIV-seropositive men as com-
pared with HIV-seronegative men (10–16.6%), as
found in other studies.1,28 This finding is not in
agreement with reports demonstrating that the potentially oncogenic HPV types were no more common in men with antibodies to HIV than in those
who were HIV seronegative.26
High-risk HPV types were detected in both
groups, mainly in smears with high grade lesions
(PIN 2–3), and low-risk types (6/11) were associated essentially with HPV-PIN 1, as found by previous studies.2,26 However, Bernard et al1 observed
that lesions showing no or minor signs of HPV infection were positive for HPV 16/18 or 31/33/35.
HIV infection might promote the persistence or
reactivation of HPV in the genital tract and the progression of neoplasia,1,28,31 as previously reported
by dot-blot and polymerase chain reaction in anal
swabs from HIV-seropositive homosexual men,3
and it might facilitate the primary HPV infection.24
Iatrogenic immunosuppression in renal transplant recipients,9 in patients with chemotherapy for
malignancy and in pregnant women2 has been associated with more-severe dysplasia due to HPV infection. The mechanism through which immunosuppression may activate and accelerate the
pathogenic course of HPV infection is not clear. It
has been suggested that immunosuppression allows the establishment of chronic, active HPV infection, favoring the likelihood of oncogenic progression3 or allows HPV to replicate to higher levels
with more clinically aggressive lesions. Disruption
of cellular and/or humoral immunity, however,
could be a causative factor in infection with highrisk HPV.1
As seen in women, HIV disease may affect local
epithelial immunity by decreasing the quantity or
function of Langerhans’ cells.5 Some reports also
noted the presence of natural killer cells in cervical
warts, showing the major role of cell-mediated immunity in such lesions.1
The strong association between HIV and HPV
without measurable immunosuppression may be
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N=30.
Gomousa-Michael et al
explained by direct interactions between the two
viruses.27,30 Such interactions may also contribute
to the pathogenesis of neoplasia. However, the association between HIV and HPV can be accounted
for in part simply by common behavior risk factors.
The opposite mechanism has been ascribed to cervical lesions; HPV infection may disrupt the normal
mucosal integrity or alter the immune status of patients, representing the first step in HIV contamination.25,29
Analysis of the association between HIV, HPV
and HPV-related disease is complicated by the similarity in risk factors for the acquisition and transmission of the two viruses. Both HPV and HIV are
sexually transmitted, and both are associated with
such risk factors as sexual behavior, infection with
other sexually transmitted pathogens and socialcontext variables (e.g., poverty). Any of these factors may contribute to the development of HPVassociated genital dysplasia.31
In conclusion, our results clearly show that infection with HIV enhances the expression of HPV, especially high-risk HPV related to immunosuppression. It is likely that immunosuppressed men with a
high prevalence of HPV and genital intraepithelial
neoplasia are at greater risk of developing cancer
than are nonimmunosuppressed men. In addition,
HIV-seropositive, sexually active men could act as
foci for spreading HPV (and its associated diseases)
in the general population. Since the mechanisms of
HPV transmission are poorly understood,11 we cannot assume that practices that control HIV transmission will also control HPV.
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