The Open Dermatology Journal, 2009, 3, 103-110 103

Open Access
Common Clinical Manifestations of Human Papilloma Virus (HPV) Infection

A. Guerra-Tapia*,1, E. González-Guerra2 and C. Rodríguez-Cerdeira3

1
Dermatology Department, Hospital Doce de Octubre, Madrid, Spain
2
Infanta Cristina Hospital, Madrid, Spain
3
Dermatology Department, CHUVI & University of Vigo, Vigo, Spain

Abstract: The Papillomaviruses are DNA viruses which belong to the Papova family, having a great affinity for epithelial
tissue. They can produce proliferative lesions either in the skin or mucosa, either in man or other animals. Various kinds
of lesions, mainly benign, are caused by numerous types of human papillomavirus (HPV) involving the well-known
verruca vulgaris, respiratory laryngeal papillomatosis, condylomata acuminata and focal epithelial hyperplasia, as well as
a possible association with other alterations and lesions.
We present in this paper an update on common clinical manifestations and treatment of HPV infection.
Keywords: Verruca vulgaris, respiratory laryngeal papillomatosis, condiloma acuminatum, treatment.

INTRODUCTION
The most common clinical manifestation is the verruca,
with its different morphological forms: verruca vulgaris,
verruca plana, anogenital warts or condylomata acuminata
(CA), and Levandowsky-Lutz. Frequently the HPV 1, 2, 3,
4, 5 and 8 subtypes are detected.
The histological study results are similar in all of them;
they show alcanthosis, elongation of the dermal papillae,
presence of vacuolated cells with dense and wrinkled nuclei
and with basophilic inclusion, composed of viral particles,
and eosinophilic inclusions of abnormal keratin in the
superficial layers of the epidermis (coilocytes).

VERRUCA VULGARIS
Verruca vulgaris are the most common warts and are
produced by serotypes 2 and 4. They are papules with rough
surfaces, firm consistency, colour similar to the surrounding
skin, brown or greyish, but always uniform, and generally
less than 1cm in diameter. They may form large masses by
coalescence. They are asymptomatic. Although they may be
found in any part of the skin, they are preferably found on
the fingers and back of the hand and, in children, on the
knees. The periungeal form is generally painful and,
frequently, produces dystrophy, which is seen as deformity
of the nail. On the face, neck and periorificial areas they Fig. (1). Periungeal warts.
generally have an elongated shape with a small fixation base grey or yellowish, rounded or polygonal, and are less than 5
(filiform warts) (Figs. 1-3) [1]. mm in diameter. They are found in the peripheral areas of
the face, back of the hands and pretibial areas in children and
VERRUCA PLANA youths. Lineal grouping is typical following scratch lines
These are associated with types 3 and 10 HPV. They are (isomorphism) (Fig. 4) [1].
small papules which are hardly raised, flat, skin coloured,
PLANTAR WARTS

*Address correspondence to this author at the Dermatology Department,

These are associated with types 1, 2 and 4 HPV. They are
Hospital Doce de Octubre, Madrid, Spain; observed in two forms: endophytic and exophytic or in a
Tel: 606626124; Fax: 914608377; mosaic. Endophytic plantar warts are generally unique, deep,
E-mails: auroraguerratapia@gmail.com, aurora@auroraguerra.com

1874-3722/09 2009 Bentham Open

104 The Open Dermatology Journal, 2009, Volume 3 Guerra-Tapia et al.

painful and are manifested by a circumscript keratinous Therefore, the objective of the treatment is to eliminate
plaque, with a black pointed central area (thrombosed the cutaneous lesions with minimum damage to the normal
capillaries) and with the periphery of the whole lesion tissues. The treatment will depend on the type of warts, their
covered by a thick whitish keratinous ring. They are found in number, size and location, the experience of the doctor and
weight bearing areas of the foot, particularly on the front the wishes of the patient. A conservative treatment is always
plantar arch (Fig. 5). recommended due to the tendency for warts to spontaneously
remit. If the warts do not disappear on their own accord they
may be treated with irritant liquids to stimulate the body's
defences against virus and keratolytics to reduce their size.
In the case that these fail to be effective, methods such as
cryotherapy, electric scalpel or laser may be used (Tables 1
and 2) (Fig. 4) [1, 2].

Fig. (2). Filiform warts in the neck. Fig. (4). Verruca plana on the face of a child.

Fig. (3). Warts in the beard.

The exophytic plantar verruca or mosaic plantar verruca
are generally multiple, superficial, painless or only slightly
painful, and are manifested by a slightly raised plaque
formed from circumscript keratinous lesions grouped
together into a mosaic. They are most frequently found on
the heels.
At present no specific antiviral treatment exists for HPV
infection, so the various treatments available try to destroy
all the cells infected by the virus or attempt to get the Fig. (5). Plantar warts.
individuals own immune system to destroy them. In immunodepressed patients good results have been
achieved with the antigen of the Candida genus [4].
Common Clinical Manifestations of Human Papilloma Virus (HPV) Infection The Open Dermatology Journal, 2009, Volume 3 105

Table 1. Different Types of Treatments observed on the trunk. In a third of the cases, starting from
the second or third decade of life, there is a malign
Electrodessication and/or curettage transformation of the lesions, above all in areas exposed to
Surgical Treatment
the sun, which are mainly related to HPV 5 and 8, but also
Excision
with 3, and to a lesser extent, with 9, 12, 14, 15, 17, 19-25,
Laser (extremely effective) 36-38, 46, 47, 49, 50 etcetera [1].
Cryotherapy With ethyl chloride or liquid nitrogen.
BUTCHER'S WARTS
At present not used due to high rate of undesirable
Radiotherapy
effects. They owe their name as they are observed in
0.15% solution of 8-methoxypsoralen, followed by professionals who process meats. They are extensive
Photochemotherapy verrucous papules or in the shape of a cauliflower on the
sessions of UVA.
back, palm or periungeal borders of the hands and fingers
The most used is salicylic acid. The healthy skin
Keratolytics
should be protected.
and are associated to HPV 7 [1].

Tretinoin The treatment choice for verruca plana. CONDYLOMATA ACUMINATA

Interferon
2a,
2b, , above all in very widespread CA also known as genital warts, venereal papillomas or
Interferon
and resistant cases.
venereal warts are characterised by the presence of fleshy
Psychotherapy Has its main application in young children. excretions found generally in the mucous membranes of the
Formaldehyde, bleomycin, 5-flourouracil, anogenital area. CA will appear in the area of the mucous
cantharidin, podophyillin, 20% ammoniated membrane or skin where an infection has been found.
Others
mercury, glutaraldehyde, immunotherapy, zinc
sulphate and cimetidine*. CA are generally of exophytic appearance, are generally
*Zinc sulphate at a dose of 10 mg/Kg/day seems to be more effective than cimetidine
pediculed and papular, with a sessile base, and even
in children and adults for hand warts [3]. occasionally flattened. In the mucous membranes the CA are
observed with the aspect of a hyperplastic lesion, fleshy and
humid, with a pink or white colour, due to the maceration
EPIDERMODYSPLASIA VERRUCIFORM (LEVAND- that is generally associated with them, by the neighbouring
OWSKY-LUTZ) secretions or a secondary concomitant infection. These
clinical signs vary when the condylomas are found in
This is a rare hereditary disease, transmitted with surrounding skin, with an aspect of dry and hyperkeratinous
autosomal recessive character, which determines an lesions being possible or even as pigmented papules. During
abnormal immunological response to HPV infection. Family their development, CA can remain indefinitely with the
consanguinity is often observed. It is more frequent in aforementioned characteristics, evolve or progressively
women. There is mental retardation observed in 10% of the extend. In the latter case they may form wide infiltrated
cases. plaques of a tumoural and mamelonated aspect, which may
The clinical picture begins in infancy and is characterised even mask the anatomical signs of the area where they are
by the presence of lesions which appear similar to verruca found (giant condylomas).
vulgaris and verruca plana, which tend to be located in areas The second clinical aspect of CA is their appearance as
exposed to the sun: back of the hands, forearms, sides of the small, multiple papules which vary between 1 and 6 mm in
neck and face. Hypochromic maculose lesions are also

Table 2. Most Frequent Treatments Used Daily in the Consultancy

Hands Feet Face Rest of Body

Verruca vulgaris Local application of Local application of Local application of salicylic acid, Cryotherapy, curettage and
salicylic acid or lactic acid, salicylic acid on a dressing cryotherapy, Imiquimod curettage electrodessication
glutaraldehyde, with 40% glutaraldehyde, and electrodessication
cryotherapy, curettage and cryotherapy, curettage and Imiquimod
electrodessication electrodessication,
Imiquimod Imiquimod
Filiform warts Cryotherapy, electrodessication and /or curettage
Verruca plana Tretinoin
Local application of salicylic acid
Cryotherapy and electrodessication
Imiquimod
Tretinoin
Plantar warts Glutaraldehyde, cryotherapy, electrodessication, laser
Imiquimod
106 The Open Dermatology Journal, 2009, Volume 3 Guerra-Tapia et al.

diameter. They are generally indurated to the touch and are

generally found on the edges of the mucous membrane with
the skin (papular condylomas) [1, 5].

a) Localization of Condylomata Acuminata in Men

In the genitals of men the most frequent affected areas
are the frenulum, balanopreputial fold and the mucous
membrane of the penis and foreskin, presumably as these are
areas which are exposed to the greatest trauma during coitus.
The urethra may also be affected, but in the anterior part,
generally in its first segment, and rarely in more distant
segments. CA may also be found in the scrotum and
perigenital areas, albeit in generally sub-clinical forms. The
location of CA in the anal region is generally related to anal
coitus in 90% of the cases. In 50% of the cases it may affect
the rectal mucous membrane. It is necessary to examine the
area using anuscopy. The clinical aspect is generally
papillomatose (Figs. 6-8) [6].

Fig. (8). Condyloma acuminata on the tongue.

b) Location of Condylomata Acuminata in Women

Exophytic CA appears in women, generally, first found
in the fouchette and greater and lesser lips of the pudendum,
but due to the humid conditions of the female genital
apparatus and possible associated infections it generally
rapidly propagates to all the vulva, and even the perineum
and perianal area.
In the vulva and perineum they can be observed as
exophytic condylomas or as lesions of the papular,
micropapillar or macular types. Colposcopic exploration of
this area would be totally necessary and more accentuated in
the introitus and interlabial folds.
CA located in the anus, both in men and women are
generally exophytic and may be related with anal coitus, but
also with the possible propagation of vulvar secretions. It is
totally necessary to perform both genital and anal
examinations together (Fig. 9) [5].
Fig. (6). Condylomas acuminatas on the gland and preputial-balanic Sub-Clinical Manifestations
fold in a HIV+ patient.
These are extremely important, above all
epidemiologically, as they are invisible to the human eye. As
a general rule, sub-clinical lesions are flattened and multiple.
Their clinical insignificance facilitates their spread, and their
persistence is possibly related to genital cancer, above all in
women. They may be observed by application of a solution
of acetic acid followed by viewing using a magnifying glass
or colposcope.
Manifestations of Genital Infection by HPV in Women
Once HPV has infected any region of the epithelium of
the inferior genital tract, in approximately 80% of the cases
the organism will totally eliminate the infection, whilst in the
rest of the cases the virus may remain latent, even for
decades, in which case, it is only possible to diagnose
through molecular biological methods, which detect the
Fig. (7). Scrotal condylomas. presence of viral DNA, or rather enter into a stage of active
expression with morphological manifestations depending on
Common Clinical Manifestations of Human Papilloma Virus (HPV) Infection The Open Dermatology Journal, 2009, Volume 3 107

the induced histology in the epithelium, which present as The sub-clinical lesions are found on the majority of the
clinical or sub-clinical manifestations. mucous membranes and are seen as white coloured stains,
which appear after the application of acetic acid and should
be interpreted by a specialist. In the cervix, infection by HPV
may affect the squamous epithelium or the joining area
between the glandular and squamous epithelium in the same
way. Outside these, the acetowhite epitheliums express
either a sub-clinical HPV infection or abnormal epithelium
with defects in maturity and benign character, whilst within
these, apart from the changes referred to, they may indicate
HPV-associated preneoplastic lesions with various grades of
severity, and as such should undergo biopsy for histological
confirmation and be evaluated by a specialist, who,
depending on the morphological form, will decide on the
most convenient places for taking the biopsy (Fig. 10) [7-
10].

Fig. (9). Condylomatous masses in the fouchette and perineum.

The clinical forms are generally benign, whilst the sub-
clinical may be expressed as benign lesions or precursory
lesions with the potential to develop malignant lesions.
Although the clinical lesions are evident with direct
ocular examination, broadened examination via colposcopic
allows a more real evaluation of the extension of the disease
and better evidence of its clinical aspects, on which a correct
therapeutic plan will depend. On the other hand, sub-clinical
lesions are only evident on colposcopic examination after
applying 5% acetic acid. These lesions may affect any area
of the inferior genital tract and the simultaneous existence of
mixed forms of clinical and sub-clinical manifestation is
frequent.
Clinical lesions are seen as CA or genital warts, which
macroscopically appear to be made of a series of papilla of
fleshy appearance, which sprout from a common root, more
frequently, extensive and keratinised on the cutaneous
surface than on the mucous membranes, with a characteristic
cockscomb or cauliflower appearance and with a highly Fig. (10). Vegetative tumourations made up from irregular
variable size and extension. A very infrequent form is the acanthosis and accentuated papillomatosis.
giant condyloma, in general benign, although it is sometimes
Treatment and Follow-Up of Condylomata Acuminata
seen with malignant histology of the verruciform carcinoma,
known as the Buschke-Lowenstein tumour. Rounded, The treatment of CA should be established in the context
slightly raised, papular forms may also be seen in the vulva, of the fact that they are going to have therapeutic failures,
which whiten with acetic acid and are sometimes pigmented and a moderate to high rate of relapses (8-33%), so the
(bowenoid papulosis), in which case a possible serious therapeutic objective will be to achieve periods without
preneoplastic lesion (in situ carcinoma), or macular lesions, condylomas and not apply highly aggressive methods.
reddish or grey-white, which generally affect the mucous Nonetheless, the treatments we have available still have
membranes should be suspected. Condylomas are nearly secondary effects (stinging, pain, ulceration, etcetera), which
always benign, although 5% may contain oncogenic virus, the patient must be informed about. Moreover, we do not
whilst the papules and macules may have from HPV's have a specific treatment for CA and the disappearance of
without important histological repercussions to serious the condylomatous lesion does not imply the elimination of
precursory lesions, and should, thus, always have a biopsy HPV.
performed on them.
108 The Open Dermatology Journal, 2009, Volume 3 Guerra-Tapia et al.

The previous treatment method consisted of ruling out reached a rate of complete elimination of the external genital
other possible associated sexually transmitted diseases and and perianal warts in 56% of the group treated with 5%
included exploration of the sexual partner(s) and their imiquimod cream. The effectiveness observed was higher in
treatment. The treatment plan in each case would be women (77%) than in men (40%), although these
determined by a series of factors, which could condition the percentages considerably increased (81% of all patients, 91%
therapeutic choice, such as: of women and 74% of men) when the variable measured was
elimination equal to or greater than 50% of the area of the
1. Number, size and anatomical distribution of the
verrucas. The therapeutic effects of Imiquimod were seen in
lesions. Their extension, grade of keratinisation, time
the first 2-4 weeks, with the mean time for complete
of development and resistance to other treatments.
disappearance of the lesions being 8 weeks in women and 12
2. The immunological state of the patient. weeks in men [11].
3. The effectiveness, availability and ease of application One of the most interesting findings in this study was the
of the therapeutic method. low remission rate of 13% at 12 weeks, which could be in
4. Toxicity. relation to the potential immunological response given by
imiquimod. The treatment was well tolerated by the patients,
5. Cost. with erythema appearing in a third of the patients and
6. Age. erosion or ulceration with lower frequency. Only 6% of the
patients experienced pain. In the majority of cases the
7. Preference and previous experience of the patient. reactions were slight or moderate, leading to a rate of
8. Experience of the health professional with respect to abandonment of the therapy below 2%.
the method used. Therapeutic Methods Administered by Health
Although the possibility of spontaneous regression may Professionals
exist, the generalised tendency is to treat the clinical lesions The therapeutic methods recommended by the CDC to be
in order to control the disease, relieve the anxiety of the administered by health professionals, such as cryotherapy
patient and improve their self-esteem. The possibility that with liquid nitrogen, 10-25% podofilin resin or surgical
they contain oncogenic virus, albeit infrequently, is yet extirpation with cold scalpel or electrocoagulation, should be
another reason that leads to treatment. chosen according to the experience of the specialist, and the
The chosen methods used at present, following the latest basic equipment available for application, which are
recommendations of the CDC-1998 in the USA, which are generally found in specialist centres or hospitals.
also used in Spain, are of two types: methods applied by the Other alternative treatments, such as C02 laser or
patient themselves, such as 0.5% podophyllotoxin in solution treatments in uncommon places, such as the CA of the
or gel or 5% imiquimod cream, and methods administered by urethral meatus or anal CA, which occasionally require
a specialist consultant, such as cryotherapy with liquid general anaesthesia, should always be referred to a hospital,
nitrogen, surgical extirpation or 10-25% podophyllin resin. as they sometimes require a multidisciplinary approach.
Therapeutic Methods Administered by the Patients Of the topical treatments applied by the doctor, 10-25%
Themselves podofilin resin is now unused, due to its side effects, toxicity
0.5% podophyllotoxin is locally applied twice a day for and unpredictable dosage. Bi- and tricholoroacetic acids are
three consecutive days, followed by four days without also infrequently used in our environment, being used on
treatment, with this regime being repeated for up to four mucous membranes, non-extensive lesions and during
cycles (four weeks). It is effective for condylomas of the pregnancy [1, 5].
penis and vulvar cutaneous lesions. The risk of systemic Among surgical treatments we may include surgical
toxicity is low although it may produced slight local excision using scissors or cold scalpel and also
irritation. It is contraindicated for mucous membrane lesions electrocoagulation, which, although it is difficult to control
and during pregnancy. 0.15% podophyllotoxin cream is the depth of destruction, may be advisable when there are a
effective for anal CA. They are, in general, recurrent. small number of lesions. Cryotherapy with liquid nitrogen is
Topical 5-flourouracil is infrequently used and is highly greatly used at present as it controls the depth of destruction
irritant, although it may be of use in mucous membrane better and is highly effective. The use of C02 laser allows for
lesions, including those associated with intraepithelial greater control of the depth of destruction and attains good
lesions, with treatment being done under strict medical results.
control due to the risks of long-term ulcerations. In general, in the case of initial lesions, which are small
Imiquimod is the first of a family of molecules and localised, topical therapies are recommended which are
(imidazoline heterocyclic amines) which, as opposed to the applied by either the patients themselves or the doctor, whilst
treatments available to date, does not work by destroying the in old, more extensive and relapsed lesions surgical
lesions but rather by inducing the local synthesis of treatment should be used. In very extensive and relapsed
cytokines, mainly interferon alpha, thus modifying the lesions the possibility of a mixed treatment of medical and
immunological response of the organism infected by HPV. surgical should be considered.
This way of working leads to the elimination of the lesions, New treatments introduce substances derived from green
as was demonstrated in the double blind placebo controlled tea (Polyphenon E) in 15% cream, which contain
study in which 311 patients were included and which
Common Clinical Manifestations of Human Papilloma Virus (HPV) Infection The Open Dermatology Journal, 2009, Volume 3 109

polyphenols and catechin . The authors obtained variable may reduce, but not eliminate, the risk of transmission to
results [12]. uninfected partners [19, 20].
Another innovative technique is using ultrasound Special Situations in Genital Infection by HPV
technology for anal and perianal CA. The authors obtained
good results using this technique [13]. Fluoracil combined Pregnancy
with lidocaine is used with excellent results in urethral Due to the existing immunological depression and the
lesions [14] (Table 3). higher concentration of steroid hormones during pregnancy
Table 3. Special Situations
there is a higher risk of HPV infection and spread of the
disease, to such an extent that we can accept that 2.5% of all
pregnant women have CA, of which a large proportion
A confirmatory biopsy should be carried out.
diminish or regress after delivery, while sub-clinical lesions
Children Surgical exeresis with local anaesthetic and or laser. are hardly modified by pregnancy [21].
Evaluate the existence of sexual abuse. The transmission of infection to the newborn is generally
Conventional surgery and cryotherapy may be used produced during its passage through the delivery canal,
even before full-term TCA 1 although there are some studies which detect viral DNA in
podophyllotoxin is contraindicated.
amniotic liquid with intact membranes. The most important
consequence of the viral infection in the newborn is juvenile
Imiquimod has not been approved. laryngeal papillomatosis, whose risk is thought to oscillate
Pregnancy
The majority disappear spontaneously after delivery. between 1 in every 400 to 1500 newborns of mothers
infected by the virus. They may also develop anogenital CA,
Vaginal delivery should be used except in cases of
obstruction of the delivery canal or important risk of especially in newborns born by breech delivery, and very
haemorrhage. occasionally conjunctive lesions.
No data exist that supports different treatment of these Treatment may be carried out with tri- or bichloroacetic
HIV+ patients patients. Nonetheless topical or intralesional Cidofovir acids, cryotherapy, vaporization with CO2 laser or excision
has been proven to work well. with a diathermic knife. The other treatment regimes are
1
Recommended by various authors for recurrent cases. contraindicated, except Imiquimod, although this is not
recommended by the manufacturer (Table 3) [22].
Anogenital CA are awaiting more conclusive results with HPV Infection in Paediatrics
immunotherapy using Mycobacterium w (Mw vaccine).
Initially 0.1 ml is intradermally injected in the deltoids, There are three possible transmission routes:
followed by an intralesional injection at two weeks and is 1. At the Time of Delivery from an Infected Mother
repeated weekly for a maximum of 10 weeks [15].
Photodynamic therapy is successfully being used albeit Although it is infrequent, this possibility must be
pending more conclusive results [16]. considered, above all in children below two years of age.
The verruca are found, fundamentally, in the anogenital area
Another antiviral drug is Cidofovir which is in breech births and in the conjunctiva or the larynx in
intravenously used in AIDS patients. At present it may be cephalic deliveries (Table 3).
used topically or intralesionally [17] (Table 3).
2. Autoinoculation in Other Areas or Accidental
A group of HIV+ patients satisfactorily evolved with Heterinoculation
IFN-PEG. They were administered subcutaneously at a dose
of 80 micrograms once a week for 24 weeks [18]. This route is more easily observed in children of over
two years old, either from verruca on the child's hands, or
Follow-Up of the Patients Treated and their Partner(s) verruca from the caretaker's hands. The most prevalent
Once the CA are treated and eliminated, the patient genotype is HPV-2 [23].
should be periodically examined, above all in the first three 3. Sexual Abuse
months, which is when most relapses exist. Nonetheless,
their control should be longer term, recommending the This circumstance is found in 50% of all anogenital
patient to perform their own examinations, educating and verruca, with the incidence increasing with the age of the
advising them on any doubts with respect to the child. It is more frequent in girls. The habitual location is the
contagiousness and later relapses and sometimes helping vulva (40%), followed by the perianal region (34%). The
them in physiological matters. most common genotypes are generally HPV-6, 11, 16 and
18.
The sexual partner of the individual diagnosed of HPV
infection, should be examined by a specialist, both The clinical differential diagnosis is simple and the same
physically (external genitalia, anus) and cytologically as for adults. Nonetheless, the problem exists at the time of
(vagina, cervix), not only for the detection of CA but also evaluating the transmission route. In no case should the
any other associated STD, as well as forewarning cervical or doctor act in an indolent or passive way, but should
genital cancer in another location. understand that it is his moral obligation to try to clarify if a
situation of child abuse exists. On the other hand he should
After treatment of both of them and the disappearance of tread very carefully since the desire of the doctor to protect
the visible lesions, they should be informed that the HPV has the child should not lead to falsely accusing an innocent
probably not been eliminated and that the use of condoms adult.
110 The Open Dermatology Journal, 2009, Volume 3 Guerra-Tapia et al.

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Received: April 20, 2009 Revised: April 30, 2009 Accepted: May 11, 2009

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