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Rosenblatt C, Lucon AM, Pereyra EAG, Pinnotti JA, Arap S
REVIEW
Human papillomavirus in men – “to screen or not to screen” – A review
Papilomavírus humano em homens – “triar ou não triar” – Uma revisão
Charles Rosenblatt1, Antonio Marmo Lucon2, Elza Ainda Gay Pereyra3, José Aristodemo Pinnotti4, Sami Arap5
ABSTRACT
The objective of this review was to discuss viral infection by
Human papillomavirus because of its elevated incidence among
women and their respective partners, as well as the relation
between the virus groups found in women with cervical
intraepithelial neoplasia or normal women and their respective
partners. The presence of human papillomavirus in male partners
does not necessarily implicate the presence of human
papillomavirus or even cervical epithelial neoplasia in their female
partners. Peniscopy, penile biopsy, and Human papillomavirus
molecular biology tests are discussed in the review. The medical
evaluation of male partners is essential to treat clinical lesions
and to make them aware of the sexually transmitted character of
this infection and the need for peniscopy.
Keywords: Papillomavirus human; Molecular biology; Condylomata
acuminata; Male; Review literature
NATURAL HISTORY
Information obtained from cross-sectional studies
about the prevalence of Human papillomavirus (HPV)
in women, according to age groups, enables us to infer
that HPV infection occurs at the beginning of active
sexual life in adolescence or in the early twenties. The
infection is mostly transient and there might be no
clinical evidence of the disease, due to suppression or
even cure. Some women present minor lesions that heal
spontaneously. Few women develop persistent HPV
infection, probably due to immunological deficiency.
Some of these persistent infections contain virus types
frequently associated with precursors of cervical cancer
and may progress into cancerous lesions. In most cases,
HPV is diagnosed at the age of 25 to 29, whereas cervical
cancer is more frequently diagnosed between 50 and
55 years of age(1).
RESUMO
O objetivo desta revisão é discutir a infecção por papiloma vírus
humano devido à sua alta incidência entre as mulheres e seus
respectivos parceiros, assim como a relação entre os grupos virais
encontrados em mulheres com neoplasia intra-epitelial cervical ou
mulheres normais e seus respectivos parceiros. A presença de
papilomavírus humano nos parceiros não implica necessariamente
a presença de papilomavírus humano ou mesmo neoplasia intraepitelial cervical nas parceiras. Esta revisão discute a peniscopia, a
biópsia peniana e os testes de biologia molecular para papilomavírus
humano. A avaliação médica dos parceiros é essencial para tratar
as lesões clínicas e conscientizá-los sobre a transmissão sexual
desta infecção e a necessidade de fazer uma peniscopia.
Descritores: Papiloma vírus humano; Biologia molecular;
Condiloma acuminado; Masculino; Literatura de revisão
TRANSMISSION
HPV is considered a sexually transmitted infection and
there is a large body of evidence supporting this form of
transmission. Nevertheless, researchers have not come to
a conclusion about what would be the odds of infection
from contact with an infected partner. Some authors
mentioned an incubation period of some weeks, but this
information was only documented for the clinical stage
of infection, that is, condyloma(2). The minimal interval
from contamination to subclinical lesion is still unknown.
This fact has raised some questions that patients and
physicians ask, which translate curiosity to identify the
partner who was the source of contamination. Since the
1
Division of Urology, University Hospital, Medical School of the Universidade de São Paulo (SP) Hospital Israelita Albert Einstein - São Paulo (SP).
2
Division of Urology, University Hospital, Medical School of the Universidade de São Paulo (SP).
3
Department of Obstetrics and Gynecology, Medical School of the Universidade de São Paulo (SP).
4
Division of Urology, University Hospital, Medical School of the Universidade de São Paulo (SP).
Corresponding author: Charles Rosenblatt - Division of Urology, Medical School of the Universidade de São Paulo; Hospital Israelita Albert Einstein - Av. Albert Einstein, 627 - 12º andar - sala 1.204 B
- Morumbi - CEP 05651-901 - São Paulo (SP), Brazil - e-mail: [email protected]
Received on September 16, 2003 - Accepted on July 06, 2004
einstein. 2004; 2(3):212-6
Human papillomavirus in men – “to screen or not to screen” – A review
incubation period is unknown, and it is possible that
the virus remain in a latent state for a long period with
no manifestation, it has been virtually impossible on
clinical routine to set a likely time for contamination.
The answer could be sought with other data, such as
the presence of a single partner or a suspected sexual
contact. Some authors suggested that not every contact
with HPV is able to determine an infection(3-4). Since
the infection begins on the epithelial basal layer, these
authors argued it is likely to occur in sites where this
layer is exposed, such as in the squamocolumnar
junction (SCJ), or after microinjuries, possibly during
intercourse. Extragenital lesions, such as in the oral
cavity and nipple, are rare. This theory could explain
why generally there are no resulting lesions in other
non-intercourse-related forms of transmission. Several
authors demonstrated the presence of HPV in amniotic
fluid, skin, and throat of newborns achieving a rate as
high as 73%. And other authors reported HPV particles
present in vaginal discharge, on contaminated surfaces,
on surgical instruments, and in fumes resulting from
electrosurgical or laser procedures. The unanswered
question is whether or not those virus particles would
be contaminants(4).
CLINICAL FEATURES AND EPIDEMIOLOGY
Clinical disease
Condyloma acuminatum presents as warty granular
multiple lesions. They are skin-colored, red or
hyperpigmented; larger lesions look like a “cauliflower”,
while the smaller ones could be a papule, a patch or even
be filiform. The preferential sites in men are the glans,
frenulum, corona, and foreskin, which are areas more
susceptible to microinjury during intercourse. Lesions may
be observed in the urethral meatus and perianal area. In
cases of urethral lesions patients complain of itching,
burning, bleeding, and obstruction.
Subclinical disease
Subclinical lesions are much more frequent than
clinically evident lesions and may be well visualized on
peniscopy after application of a 5% acetic acid solution
on suspected areas. They are elevated acetowhite
lesions with irregular edges, and their surface may be
rough, punctiform or have a mosaic pattern, and called
condyloma latum. In this form of infection, HPV
produces diffuse areas of non-papilliferous epithelial
hyperplasia rather than a classic condyloma. Despite
the gross differences between condyloma and the latter
form of infection, both are characterized by basal
germinal layer proliferation, epithelial denaturation
and characteristic cytological changes. The most marked
213
histological difference is that condyloma has an evident
papillary appearance, whereas subclinical disease is flat
or micropapillary. In men, this form of infection may
be present as acetowhite epithelium, acetowhite macula
and acetowhite papule on peniscopy.
HPV infection is suspected when a warty lesion is
seen or acetowhite lesions are observed after application
of a 5% acetic acid solution and magnification. Acetic
acid coagulates and produces deposits of intracellular
proteins, revealing white lesions or elevated lesions.
Through this procedure, it is possible to standardize
the location of suspected sites and collect a specimen
to be analyzed. Troffatter observed that most lesions
are subclinical and, even in experienced hands, this
method has low specificity(5).
Latent disease
Latent infection represents the stage during the virus
incubation period, which may extend indefinitely, up to
lesion healing. Infected keratin cells are morphologically
normal, showing virus DNA in the nucleus of infected
basal cells. In this kind of infection, HPV DNA is
diagnosed in the female genital tract by molecular
technology; there is no clinical, cytological, colposcopic
or histological evidence of the infection(6). In this kind of
infection, virus DNA is believed to have an episomal
appearance, apparently non-functional, being replicated
only once in each cell cycle, which means that the number
of virus copies for molecular diagnosis by older methods,
such as in situ hybridization, may be less than needed.
Since the virus is not functional in this kind of infection,
there are no cytological changes due to its presence(7).
The immunological factors are probably determinants of
this condition(7). The biological meaning of viruses and
the period they may stay in this state are unknown.
Moreover it is not clear how many cases progress from
this kind of infection to others. According to Ferenczy
and Winkler, the presence of HPV in normal tissue would
explain recurrent lesions regardless of treatment(8).
Diagnostic methods
Several changes establish cytological diagnosis features
for HPV infection. Koylocitosis is the presence of large
perinuclear vacuoles(9); dyskeratosis means defective
keratinization of isolated epidermal cells. (9); and
dyskaryosis is a nuclear abnormality, like
hyperchromatism, with shape irregularities and
increased number of nuclei per cell, with no sizable
enlargement of cytoplasm or cell contour (9). Some
authors considered koylocytes a pathognomonic sign
of HPV infection(10), though, in 1994, Jacyntho et al.
defined other criteria to diagnose HPV, like wide
superficial and intermediary cells, irregular cytoplasm
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Rosenblatt C, Lucon AM, Pereyra EAG, Pinnotti JA, Arap S
borders, clear cytoplasm perinuclear zone, dyskeratosis
and dyskaryosis, giant nuclei in binucleated ou
multinucleated cells, nucleus and cytoplasm changes(11).
Frequently koylocytes are not found in cases of
latent infection. The presence of cytological and
histological findings depend on the stage of infection(5).
Several Brazilian studies found similar outcomes in
assessing partners of women with HPV lesions. Nicolau
obtained 1,279 biopsies in 433 men and reported 23.53%
of koilocytic atypias and 0.94% of penile intraepithelial
neoplasm (12). Guidi evaluated 562 men and found
33.2% of koilocytic atypias and 0.7% of penile
intraepithelial neoplasm in the pathological
examination (13) . These authors pointed out that
peniscopy demonstrated many non-specific findings
therefore, this method cannot confirm who is not
infected. In 1989, Dores concluded that colposcopic,
cytological, and histological examinations fail in
approximately 13%, 24%, and 20% of cases,
respectively(14). In 1995, the same author presented a
study of 526 women and showed that out of 275 positive
cytological examinations for HPV, only 95 had virus
DNA confirmed by hybrid capture moreover, in 286
positive specimens for HPV by histological
examinations, hybrid capture confirmed virus DNA in
only 68 cases. The author concluded these methods
provide an overdiagnosis rate of 47%, and the
diagnosis of HPV infection must be confirmed by an
accurate method(15). On the other hand, Gil stated in
his thesis that the presence of koylocytosis in cells
adjacent to penile tumors has a strong correlation with
HPV DNA detection(16).
Electronic microscopy demonstrated the presence
of virus particles that are spherical, with an approximate
diameter of 55 nm in crystal arrangement or scattered
around the nucleus. Likewise, they may be found in
the cytoplasm when the nuclear membrane is
disrupted(9). It is the only method to directly diagnose
the virus; however high costs makes its use unfeasible(17).
Employing molecular biology methods to identify
infective agents allows for the use of DNA and RNA
detection techniques, as well as quantification of
bacteria, fungi, and viruses with high sensitivity and
specificity(18). When DNA or RNA is analyzed, the
methods can be divided into two large groups: one
group has nucleus material amplification – mostly
polymerase chain reaction and its variants – and the
other group uses signal amplification, including
hybridization, such as hybrid capture. This distinction
is relevant because material amplification methods have
higher sensitivity, though they might be contaminated
by specimens to be tested with amplified material from
other samples(19).
einstein. 2004; 2(3):212-6
Polymerase chain reaction (PCR) was developed by
Mullins(20), in 1983. It is a technique that shows great
sensitivity and allows amplification from very scanty
DNA or RNA specimens. This feature makes it the
test more susceptible to exogenous nucleus material
contamination or to other specimen contamination(5).
Molecular hybridization tests are based on the
following phenomenon: under appropriate conditions,
a single strand nucleic acid has specific complement.
Known nucleic acid molecules labeled with P32, S35,
and H3 (known as hot probes) or non-radioactively
labeled with biotin (known as cold probes) enable
specific detection of their unknown complement, the
so-called targets. They also build complete hybrid
molecules. In 1987, Lorincz(21) reviewed hybridization
methods and made the following comments: 1.
Southern blot – the technique is slow to perform, but
it is sensitive and specific for virus DNA detection,
using biopsy fragment ou cell exfoliate; 2. Reverse
Southern blot – less sensitive than the last technique;
3. Northern Blot – this technique is analog to Southern
Blot, but it is used to detect virus RNA; 4. Dot Blot –
this technique is used either for virus RNA or DNA
detection; biopsy fragments or cell exfoliate may be
used, but results can be false-positive if virus subtypes
cannot be distinguished; 5. In situ hybridization on
filter – this technique is different from Dot blot and
uses tissue fragments in paraffin or cell smears fixed
on a slide(21).
Hybrid capture (DIGENE Diagnostics Inc.) is a
sensitive test able to detect several infectious disease
etiologic agents, such as HPV, hepatitis B virus,
cytomegalovirus (CMV), herpes simplex virus,
Chlamydia trachomatis, HIV, Treponema pallidum, and
Neisseria gonorrhoeae. Concerning HPV, hybrid capture
detects the 18 most common types of human
papillomavirus infecting the anogenital tract, and
accurately determines the presence or absence of virus
DNA in low-risk groups (6, 11, 42, 43, and 44) or in
intermediate-risk groups (16, 18, 31, 33, 35, 39, 45, 52,
56, 58, 59, 68)(22).
Role of male partners
The influence of male sexual behavior in the risk of
women developing the disease has been poorly studied.
The importance of the male factor was suggested by
Stocks (23), in 1955, when he reviewed mortality by
cervical cancer in 48 sites in England and Wales, and
found great mortality rates in harbor places. He raised
the hypothesis that social status characteristics in this
kind of place and/or male merchant activity could
increase the risk of the disease in the female
population. The high mortality from cervical cancer in
Human papillomavirus in men – “to screen or not to screen” – A review
women whose husbands’ occupation involved long trips
and long stays away from home also suggested the
important role played by men, given the well known
association between these occupations and sexually
transmitted diseases(24).
Two recent case-control studies about cervical cancer
examined HPV infection using PCR in exfoliated cells
obtained from patient husbands’ penis and urethra(25,26).
While an investigation conducted in Spain(25) showed
high risk of cervical neoplasm related to HPV DNA
detection in husbands, no associated risk was found in
Colombia(26). Another interesting result in these studies
was the fact that the female disease was associated to
the husband’s sexual behavior only in Spain, that is,
multiple sexual partners and a history of contact with
prostitutes. Contradicting results observed in these
studies indicate the importance of investigating the
role of the male factor in countries with high incidence
of cervical cancer(25,26).
Up to some years ago, the partner role increased in
value as to frequent relapses or persistent infection,
but this factor has been less and less important. Ferenczy
stated that the treatment of subclinical lesions in male
partner does not reduce recurrence rates of anal and
vulvar condylomata, as well as of cervical intraepithelial
neoplasm. Some observations suggested recurrence after
effective treatment in a monogamic relationship is likely
to be caused by latent infection activation rather than
reinfection by the partner(1). In these cases, there is limited
indication for peniscopy, which aims to identify and treat
subclinical lesions, thus preventing reinfection(12).
Reid et al.(27) supported the idea that male partners
would benefit more from screening HPV-related lesions
in the partner than women. Thus, the relevant lesions
are identified and treated in men.
When only one of the partners is observed and has
lesions detected on peniscopy, one could argue about
the real need for examining both partners.
Furthermore, its influence on relapse of lesions or on
prevention of female genital cancer is discussed(28-31).
REFERENCES
1. Ferenczy A. Epidemiology and clinical pathohysiology of condylomata
acuminata. Am J Obstet Gynecol. 1995; 172:1331-9.
2. Kaye JN, Cason J, Pakarian FB, Jewers RJ, Kell B, Bible J, Raju KS, Best JM.
Viral load as a determinant for transmission of human papillomavirus type 16
from mother to child. J Med Virol. 1994;44 (4):415-21.
215
5. Trofatter KF Jr. Diagnosis of human papillomavirus genital tract infection. Am
J Med. 1997; 102(5A):21-7.
6. Richart RM, Wright TC Jr. Pathology of the cervix. Curr Opinion Obstet
Gynecol. 1991; 3(4):561-7.
7. Wright TC, Richart RM, Ferenczy A. Electrosurgery for HPV. Related diseases
of the lower genital tract. A practical handbook for diagnosis and reatment by
loop electrosurgical excision and fulguration procedures. New York: Arthur
Vision; 1992.
8. Ferenczy A, Winkler B. Cervical intraephitelial neoplasia and condyloma. In:
Kurman RJ. Blaustein’s pathology of the female genital tract. 3rd ed. New
York: Springer; 1993. p.179-82.
9. Casas-Cordero M, Morin C, Roy M, Fortier M, Meisels A. Origin of the
Koilocyte in condylomata of the human cervix: ultrastructural study. Acta
Cytol. 1981; 25:(4): 383-92.
10. Meisels A, Fortin R, Roy M. Condylomatous lesions of the cervix II: Cytologic,
colposcopic and histopathologic study. Acta Cytol. 1977; 21(3): 379-90.
11. Jacyntho C, Souza MCB, Fonseca NM, & Canella P. Nota previa. A importância
do teste azul de Toluidina no diagnóstico das lesões genitais pelo papilomavirus
humano (HPV). Rev Bras Ginecol Obstet. 1987;9(8):151.
12. Nicolau SM. Diagnóstico da infecção por pailomavírus humano: relação
entre a peniscopia e a histopatologia das lesões acetobrancas na genitália
masculina [tese]. São Paulo:Escola Paulista de Medicina;1997.
13. Guidi HGC. Estudo do parceiro masculino de casais infectados pelo vírus do
papiloma humano: aspectos epidemiológicos e clínicos, [tese]. Campinas:
Unicamp; 1997.
14. Dores GB.Diagnóstico da infecção cervicovaginal por papilomavírus humano.
Valor da colposcopia, citologia e da histopatologia como métodos diagnósticos,
[tese]. São Paulo:Escola Paulista de Medicina;1989.
15. Dores GB das, Ribalta JCL, Martins NV, Focchi JN, Ferreira N, Kosmiskas JB,
Lima GR. Tratamento da infecção do colo uterino por papilomavírus humano
com interferon gel. Rev Paul Med. 1991; 109(4):179-83.
16. Gil AO. Análise crítica da associação do papilomavírus humano (HPV) e da
proteína p53 no câncer de pênis [tese]. São Paulo: Faculdade de Medicina da
Universidade de São Paulo; 1998.
17. Della Torre G, Pilotti S, De Palo G, Rilke F. Viral particles in cervical
condylomatous lesions. Tumori. 1978; 64(5):549-53.
18. Zur Hausen H, De Villiers EM. Human papillomaviruses. Annu Rev Microbiol.
1994; 48: 427-47.
19. Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W, Kurman RJ.
Human papillomavirus infection of the cervix: relative risk associations of 15
common anogenital types. Obstet Gynecol. 1992; 79(3):328-37.
20. Mullins K. Bioinforme 96. Lab.Sergio Franco: o passado, o presente, o futuro.
Rio de Janeiro, Faulheber MHW, & Cruz MCP; 1996.
21. Lorincz AT. Detection of human papillomavirus infection by nucleic acid
hybridization. Obst Gynecol Clin North Am. 1987; 14(2):451-69.
22. Shiffman MH, Kiviat NB, Burk RD, Shah KV, Daniel RW, Lewis R, Kuypers J,
Manos MM, Scott DR, Sherman ME. Accuracy and interlaboratory reliability
of human papillomavirus DNA testing by hybrid capture. J Clin Microbiol.
1995; 33 (3):545-50.
23. Stocks P. Cancer of the uterine cervix and social conditions. Br J Cancer.
1955; 9(4):487-94.
24. Beral V. Cancer of the cervix: a sexually transmited infection? Lancet. 1974;
1 (7865):1037-40.
3. Kaye JN, Starkey WG, Kell B, Biswas C, Raju KS, Best JM, Cason J. Human
papillomavirus type 16 in infants: use of DNA sequence analyses to determine
the source of infection. J Gen Virol. 1996; 77(pt6) : 1139-43.
25. Bosch FX, Castellsague X, Munoz N, de Sanjose S, Ghaffari AM, Gonzalez LC,
et al. Male sexual behavior and human papillomavirus DNA: key risk factors
for cervical cancer in Spain. J Natl Cancer Inst. 1996; 88(15):1060-7.
4. Tseng CJ, Liang CC, Soong YK, Pao CC. Perinatal transmission of human
papillomavirus in infants: relationship between infection rate and mode of
delivery. Obstet Gynecol. 1998; 91(1):92-6.
26. Munoz, N, Castellsague X, Bosch FX, Tafur L, de Sanjose S, Aristizabal N, et
al. Difficulty in elucidating the male role in cervical cancer in Colombia, a
righ-risk area for the disease. J Natl Cancer Inst. 1996; 88(15):1068-75.
einstein. 2004; 2(3):212-6
216
Rosenblatt C, Lucon AM, Pereyra EAG, Pinnotti JA, Arap S
27. Reid R, Stanhope CR, Herschman BR, Crum CP, Agronow SJ. Genital warts
and cervical cancer. IV. Colposcopic index for differentiating subclinical
papillomaviral infection from cervical intraepithelial neoplasia. Am J Obstet
Gynecol. 1984; 149(8):815-23.
28. Syrjanen KJ, Syrjanen SM. Papillomavirus infections in human pathology.
Chichester: John Wiley & Sons; 1999.
29. Teixeira JC, Santos CC, Derchain SFM, Zeferino LC. Lesões induzidas por
papilomavírus humano em parceiros de mulheres com neoplasia intra-epitelial
einstein. 2004; 2(3):212-6
do trato genital inferior. Rev Bras Ginecol Obstet. 1999; 21:431-7.
30. Barrasso R. HPV-related genital lesions in men. In: Munoz N, Bosch FX, Shah
KV, Meheus A. The epidemiology of cervical cancer and human papillomavirus.
Lyon: Intenational Agency for Research on Cancer; 1992. p. 85-92.
31. Frega A, Stentella P, Villani C, Di Ruzza D, Marcomin GL, Rota F, Boninfante
M, Pachi A. Correlation between cervical intraepithelial neoplasia and human
papillomavirus male infections: a longitudinal study. Eur J Gynaecol Oncol.
1999; 20(3):228-30.