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 Chapter 7

Clinical Manifestations of the Human Papillomavirus

Miguel ngel Arrabal-Polo,

Mara Sierra Girn-Prieto, Jacinto Orgaz-Molina,
Sergio Merino-Salas,
Fernando Lopez-Carmona Pintado,
Miguel Arrabal-Martin and Salvador Arias-Santiago

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55623

1. Introduction

1.1. Skin injuries

1.1.1. Benign skin lesions

The global prevalence of papillomavirus in the 4- to 18-year-old population has been estimated
to be 24% (12% for those aged 4 to 6 years and 24% for those aged 16 to 18 years) [1]. The
prevalence is significantly reduced in adults (3.5%) [2]. There are no significant differences
related to gender. There is, however, a higher prevalence in rural versus urban schools. While
plantar and common warts generally number 1 or 2, flat warts frequently appear as multiple
lesions [1].
HPV transmission requires the inoculation of the virus into the basal epithelia cells, which
occurs on sites that are particularly predisposed to microtraumas. Therefore, it is not surprising
to frequently find common warts on the hands and fingers (Figure 1). Lesion regression is
frequently spontaneous, and the immune system plays an important role, as is reflected in
practice by the increased HPV susceptibility of immunosuppressed patients. In these cases,
the lesions are clinically more exuberant and recalcitrant to treatment [3]. It is important to
highlight a particular collective group composed of butchers and slaughterhouse workers
who, without immunosuppression, have a higher risk compared to the general population [4,
5]. This group has an increased incidence of the HPV7 subtype, and it is thought that some
component of meat favors the replication of this viral subtype [6, 7].

2013 Arrabal-Polo et al.; licensee InTech. This is an open access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
188 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

1.1.1.1. Common warts

This infection is fundamentally produced by HPV subtypes 1, 2, 4, and 7 [8]. The lesions are
usually asymptomatic, although they can be painful when located in pressure zones. Clinically,
they are easily diagnosable; thus, the patient frequently brings up the presence of lesions
during a consultation. Common warts can manifest as a single lesion; however, because of the
viruss infectious nature, multiple lesions can be found in the same patient [1]. The lesions
present progressive growth such that they are initially about the size of the head of a pin, and
they are smooth and shiny. Over the course of weeks, they acquire their typical characteristics.
On inspection, they present as papules with well-defined borders and with the same color as
the skin. The surface is flattened; it may be whiter than the surrounding skin as an expression
of hyperkeratosis of the lesion itself, and it may have a multilobulated aspect (Figures 1 and
2). The hyperkeratosis and multilobulate aspect confer a rough surface upon palpation.
Occasionally, the exuberant development of hyperkeratosis can produce the formation of a
cutaneous horn. Depending on the characteristics of the host and the anatomical location of
the cutaneous horn, a histological study of the lesion may be necessary for a differential
diagnosis with malignant lesions, such as epidermoid carcinoma. When the lesions are
multiple, they can present as distinct isolated lesions, as close-by lesions and even as confluent
lesions (mosaic). Lesions can be numerous in immunosuppressed patients (i.e., those who
are transplanted or HIV-positive or have Hodgkins lymphoma or leukemia) [3, 8-11].
Characteristically, lesions may be located on the nail fold. This location is particularly associ
ated with the habit of nail biting [12]. Thus, breaking this habit can prevent new lesions in
adjacent nails that have not yet been affected.

Figure 1. Erythematous hyperkeratotic papule on the arm: common wart.

Although the clinic is generally sufficient for diagnosis, dermatoscopy is a useful tool that
provides complementary information for cases involving clinical doubts. Dermatoscopically,
common warts are characterized by the presence of dense papillae, each centered around a
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Figure 2. Papule with well-defined borders and with the same color as the skin on the finger compatible with com
mon wart.

central red dot or a loop surrounded by a whitish halo. This combination of characteristics
creates a frog spawn appearance [13].

Because of their frequency and similarity from a clinical point of view, the main differential
diagnoses are nonpigmented seborrheic keratosis, fibrous papule of the nose (angiofibroma),
intradermic nevus and warty epidermal nevus.

The histology is characterized by marked hyperkeratosis, acanthosis and papillomatosis.

Nevertheless, these features are not specific to this type of lesion. As a characteristic sign of
HPVs cytopathic effect, koilocytes (cells with a pyknotic nucleus surrounded by a clear halo)
are observed [14].

1.1.1.2. Filiform warts

These are considered a special variant of common warts. They are predominantly localized in
the palpebral and perioral regions and in the neck. Their distinctive characteristic is the special
filiform or elongated morphology, with a narrow pedicle and pronounced digital projections
on the surface (because of this, they are also called digitiform papilloma) (Figure 3). The main
differential diagnosis is with acrochordons, which can have a similar morphology but are
differentiated by their smooth surface (they lack digital projections). The histological peculiari
ty of filiform warts is that the papillae are more elongated than those of common warts.

1.1.1.3. Plantar warts

HPV 1 frequently causes these lesions, and it occasionally causes Type 4 lesions [14]. They can
manifest as single or multiple (mosaic) lesions (Figure 4). Trauma plays an important role
in the inoculation of the warts, as the most commonly affected sites are the heel and the heads
of the metatarsi.
190 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

Figure 3. Filiform papule on the upper lip with pronounced digital projections on the surface compatible with filiform
wart.

The main differential diagnosis between plantar warts and plantar callus is important
because the two disorders are frequently confused in clinical practice. Although the most
frequent locations for the emergence of warts are pressure zones, warts can also appear in
areas that experience less pressure, such as the arch of the foot. This location, however, is
not common for calluses, which are produced as a consequence of pressure on the skin. A
clinical maneuver for distinguishing warts from calluses is tangential scraping: in callus
es, the detachment of multiple hyperkeratosic layers with a clean central fundus is
observed, whereas warts present a multilobulated aspect above the superficial hyperkera
tosic layer, accompanied by multiple black dots that correspond to thrombosed capilla
ries. In contrast, warts are indicated by certain dermatoscopic signs, such as black to red
dots, globules corresponding to dilated and thrombosed capillaries of the papillae and
interrupted dermatoglyphics in the lesion. Calluses present a translucent central corn or a
homogeneous opacity [15].

The use of the dermatoscope has been described as useful for monitoring the need for new
treatment sessions for warts because dermatoscopes are more sensitive than the naked eye [15].

1.1.1.4. Flat warts

HPV 3 and 10 commonly produce this lesion. [14] This type of wart is typical in childhood. It
is very rare in male adults and has been described in the context of HIV infection [16]. The
most commonly affected area is the face, followed by the back of the hands and the shins. [14]
The aspect is that of a papule or slightly elevated flat plaques (2-3 mm) and low desquamation
(smooth surface). Coloration ranges from light brown to the color of the individuals skin, thus
making flat warts hard to detect with simple inspection. Histologically, flat warts are charac
terized by less acanthosis than common or plantar warts, and papillomatosis is minimal or
absent.
 Clinical Manifestations of the Human Papillomavirus 191
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Figure 4. Plantar wart: Multiple hyperkeratotic lesion on the sole of the foot with thrombosed capillaries (black dots).

For differential diagnosis in the face, the syringomas, seborrheic keratosis, and papulosis nigra
standout. Warty epidermal nevus, present from early childhood and following the Blaschko
lines, is another diagnosis to consider.

1.1.1.5. Pigmented warts

Subtypes 65, 4 and 60 are the main causes of pigmented warts [17]. Egawa was the first to
describe these subtypes in 1988 [18]. Although common warts and molluscum contagiosum
can transform to a black color [19, 20] in their involutionary phases, pigmented warts are
pigmented from the initial phases. They are fundamentally located on the hands and feet. The
lesions are morphologically similar to common warts when they are located in the lateral side
of the hands and feet and on the fingers and toes (Figure 5); when they are located on the sole,
they can have the aspect of flat, pigmented warts with light hyperkeratosis on the surface [17],
but with the particularity of their brown-black coloration. Although the clinical diagnosis is
not difficult, lesions on the sole can be proposed for a differential diagnosis with acral
melanoma. Surface hyperkeratosis usually guides diagnosis. However, when in doubt,
histological analysis can be used for diagnosis.

One histological peculiarity of pigmented warts is the presence of intracytoplasmic inclusion

bodies consisting of a homogeneous eosinophilic substance together with swollen nuclei, very
similar to cases associated with Types 65 and 4. In the case of HPV 60, the inclusion bodies are
similar but have a much rounder shape and no edema in the nucleus [17]. In contrast, not all
of the other HPV subtypes are associated with inclusion bodies; when present, inclusion bodies
are characterized by eosinophilic bodies and not by a homogeneous substance [21].
192 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

Figure 5. Pigmented hyperkeratotic papule on the finger: pigmented wart

1.1.1.6. Epidermodysplasia verruciformis

This is a rare genodermatosis that is generally autosomal recessive hereditary, although X-
associated heritage has also been described. It has been classified as a primary immunodefi
ciency [22] in which there is a curious and particular susceptibility to infection by HPV-
subtypes [23]. The types most frequently implicated are HPV 5 and 8, although many others
have also been associated. Most of the cases are associated with mutations in one of the genes
located in the long arm of chromosome 17 (EVER1 or TMC6, and EVER2 or TMC8) [24]. These
genes code for transmembrane proteins that are fundamentally found in the endoplasmic
reticulum and interact with the zinc transporter (ZT1) [23]. It is believed that a selective
inhibition of T lymphocyte immune responses against HPV exists, most likely because of
defective viral antigen presentation on keratinocyte surfaces [25].
Clinically, this infection is characterized by the appearance at an early age of multiple flat
warts, pityriasis versicolor-type lesions, and other lesions similar to seborrheic keratosis
(Figure 6) [14]. However, the major interest is in the high risk of developing squamous cell
carcinoma, especially in photoexposed zones (30 to 50% of patients) between the third and
fourth decades of life [14, 23]. Based on the risk of developing malignant lesions, two pheno
types have been distinguished. One phenotype is indicated by more benign lesions that are
flat, desquamous and hypo- or hyperpigmented in a manner similar to that of tinea versicolor;
these lesions are distributed on the neck, torso and extremities. The other phenotype is
characterized by seborrheic keratosis-type warty lesions that have a higher malignant poten
tial. These lesions are distributed primarily on photoexposed zones, such as the face and hands,
and on the feet. The development of these malignant lesions is usually associated with Types
5 and 8. However, unlike the pathogenesis of other oncogenic HPV, these types do not seem
to require integration into the host genome [23].
Recently, epidermodysplasia verruciformis (EV)-like clinical appearances have been described
in immunosuppressed patients, such as HIV and transplantation patients [26, 27] This
phenomenon has been called acquired EV form [26]. It has been hypothesized that these
 Clinical Manifestations of the Human Papillomavirus 193
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forms can create minor defects in patients with predisposing genes, and these defects manifest
clinically upon immunosuppression [24].
From a histology perspective, EV is characterized by the presentation of hyperkeratosis,
hypergranulosis, and acanthosis. However, the characteristic feature is the presence of large
keratinocytes with a blue-grey granular cytoplasm in the superior portions of the squamous
stratum and in the granulose. As has been noted, the lesions can present a progressive atypia
until the development of invasive squamous cell carcinoma [14].

Figure 6. Multiple flat warts and pityriasis versicolor-type lesions in a patient with epidermodysplasia verruciformis

1.2. Malignant skin lesions

1.2.1. Squamous cell carcinoma of the skin

Squamous cell carcinoma (SCC) is the second commonest malignant skin tumor (the first one
is basal cell carcinoma). Ultraviolet (UV) radiation is the main risk factor for skin cancer and
this tumor usually appears in sun-exposed areas specially the face, neck, arms and hands.
Changes in lifestyle over recent decades have led to greater exposure to ultraviolet radiation;
this phenomenon increases the risk of developing skin cancer. In the last 25 years there have
been an increased in the incidence of this tumor due to sun exposure and increased life
expectancy [28]. SCC can complicate other lesions as burn scar, lichen planus, discoid lupus,
epidermoid cyst or venous ulcers. Other risk factors include older age, fair skin and immuno
supression. Emerging evidence suggests that cutaneous human papillomavirus (HPV)
infection may also be a risk factor for SCC.
Despite the role of HPV in sunlight induced malignancies is uncertain as in squamous cell
carcinoma there have been some evidence of the association between some subtypes of HPV
and squamous cell carcinoma of the genital area. HPV 16 has been detected in squamous cell
carcinoma of the vulva, penis and perianal region. [29] The inactivation of tumor suppressor
genes by HPV has been implicated in the development of SCC. In HPV infection, the onco
194 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

protein E7 inactivates the tumor suppressor Rb, leading to p16 upregulation. Recently new
studies have shown that Genus-beta HPV (seropositivity) infections were associated with SCC
in any locations [30]. Patients with HPV related squamous cell carcinoma are characterized by
a higher rate of recurrences but not more metastases compared to ordinary SCC and also many
patients present genital lesions containing the same HPV type [31]. Moreover patients with
SCC of penis, scrotum an anus are associated with higher risk of metastases. Also immuno
suppressed patients for renal transplantation or with epidermodysplasia verruciformis (HPV
5) develop SCC associated with VPH. UV radiation and HPV may play a synergic role in the
development of squamous cell carcinoma and a recent study has shown that seropositivity for
HPV types in genera alpha or beta increased the risk of SCC associated with poor tanning
ability [32].

Clinically SCC presents as shallow ulcers, papules or plaques often with keratinous crust and
elevated surrounds commonly in photo-exposed areas (Figure 7). It is not uncommon to find
an in situ SCC under a cutaneous horn. Patients rarely complain about pain or pruritus. SCC
usually bleeds with minor trauma. The adjacent skin usually shows features of actinic damage
(actinic keratosis). Pigmented variants are rare. SCC should be suspected in patients with
permanent or bleeding recurrent ulcer. Prognosis depends on the risk of recurrence and
metastasis. The overall recurrence rate varies from 3 to 11% and the overall metastatasis rate
is around 5%. Tumor thickness and desmoplasia are multivariate factors associated with local
recurrence and tumor thickness, immunosuppression, ear location and tumor diameter with
the risk of metastasis.

Figure 7. Infiltrated and erosive tumor of the helix compatible with squamous cell carcinoma of the skin

Actinic keratosis is a well-established precancerous skin lesion that has the potential to
progress to squamous cell carcinoma. Clinically it is presented as a circumscribed scaly
erythematous lesions, usually less than 1cm in diameter on the sun-exposed (face, ears, scalp,
hands) skin of older individuals. They may remit or remain unchanged for a long time but
between 8-20% gradually transform into a SCC. Several clinical variant of actinic keratosis has
 Clinical Manifestations of the Human Papillomavirus 195
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been described: hypertrophic, acantholytic, pigmented and lichenoid. Intermittent sun

exposure and sunburns during the childhood are strongly associated with the prevalence of
actinic keratosis. Recently HPV infection has been associated also with the risk of developing
these lesions [33].
A clinical well-differentiated variant of SCC is verrucous SCC which is named different
according to the localization, in oral mucosa florid oral papillomatosis, in the genital area
giant condyloma of Buschke-Lowenstein and in the soles caniculatum carcinoma. Differen
tial diagnosis includes verrucous hyperplasia, pseudoepitheliomatous hyperplasia and
giant condylomas. These tumors present a low rate of metastases but tend to infiltrate
easily. Radiotherapy is not indicated as usually recur in a more aggressive manner. The
role of human papillomavirus infections in the development of verrucous carcinoma is
controversial in the literature, and although some clinical cases have shown and HPV
positivity (type 6, 11, 16, 18) a recent study do not support a causal role of HPV in the
development of verrucous carcinoma. [34]
SCC of the oral or anogenital mucosa tends to metastasize and be more aggressive than the
one originated in sun-exposed skin. Oral carcinoma usually affects lower lips but also in the
tongue and inside the oral cavity (palate). Special risk factors for this location are smoking and
alcoholism. SCC in oral mucosa begins as an eritroplasia plaque that evolves into a nodular
and granulomatous plaque. A recent study which included 172 patients with advanced oral
cavity squamous cell carcinoma detected a prevalence of HPV infection in 22% of the tumors
[HPV-16 (9%) and HPV-18 (7%)]. A comparison with the group of patients with HPV-16
negative infection revealed that those with a single HPV-16 infection are at higher risk of
distant metastases and poor survival despite undergoing radiation-based adjuvant therapy
and require a more aggressive adjuvant treatment and a more thorough follow-up whereas
HPV-18 infection had no impact on 5-year prognosis [35].
Keratoacanthoma is a rapidly growing skin tumor arising predominantly on the exposed
surfaces of the body that should be considered as a variant of SCC rather than a benign or
pseudomalignant neoplasm. Clinically they present as a smooth, hemispherical papule that
rapidly enlarges over the course of a few weeks with a central keratin-filled crater. Usually
involution occurs with tumor resorption and loss of the keratin plug. The role of HPV in
keratoacanthoma remains thus elusive but a study showed that 51% of keratoacanthoma
presented DNA of HPV. [36]

1.2.2. BowenS disease

Bowens disease (BD) is considered a squamous cell carcinoma in situ that predominantly
affects sun-exposed areas in middle-aged or elderly patients. It presents as an asymptomatic
well-defined erythematous scaly plaque which grows centrifugally resembling psoriasis or
dermatitis (Figure 8). It is not uncommon the presentation of Bowens disease as non-steroid-
responsive dermatitis. The clinical differential diagnosis of Bowens disease includes psoriasis,
eczema, superficial basal cell carcinoma or cutaneous Pagets disease. It may affect any part
of the integument, mucous membranes or nail bed, but it commonly presents on the trunk,
head, extremities or genitalia. Some clinical variants of Bowens disease include a verrucous,
196 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

nodular, eroded or pigmented variant that may be confused with melanoma. Invasive
carcinoma develops in nearly 5-10% of untreated cases with a metastatic potential of 13-30%
of cases. This complication should be suspected when a rapidly growing tumor is present in
a previous scaly lesion. Complete or partial regression has been described in Bowens disease
[37] but this is not a common phenomenon. Some authors proposed that Bowens disease was
considered a marker of an internal malignancy; however a later meta-analysis showed that
this association was inconsistent [38].

Figure 8. Well-defined erythematous scaly plaque on the limb clinically and histopathologically compatible with Bo
wens disease.

Bowens disease of the penis is regarded as erythroplasia of Queyrat and this disease is
characterized by slightly, erythematous, velvety, bleeding macules or plaques. Perianal lesions
present the same clinical characteristics, but they are more common in females than males.

The etiology of Bowens disease is mainly multifactorial and different factors have been
associated as UV light or arsenic. Also HPV have been associated with Bowens disease,
initially periungueal and anogenital lesions, but later studies have shown an association in
other locations. Many types of HPV have been associated with BD: HPV
2,16,18,27,31,33,34,39,52,56,58,59,67,76,82 and the implication in the prognosis of the disease
remains elusive.[39]

1.2.3. Basal cell carcinoma of the skin

Basal cell carcinoma (BCC) is the most common malignant cutaneous neoplasm and the
incidence is rising in the last decades [28]. They usually arise from the lowermost layer of the
epidermis, although a small percentage may originate from the outer root sheath of the
pilosebaceous unit. It is slightly more common in men than in women and although these
tumors metastasize exceptionally rarely they have a tissue destruction potential particularly
lesions on the face. This tumor is mainly found on areas of skin exposed to the sun. Up to 70%
of all lesions are found on the head and neck and 30% on the shoulders, back, chest and lower
 Clinical Manifestations of the Human Papillomavirus 197
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extremities. This tumor has been described in nearly every location of the body, but lesions on
the scrotum are of particular importance because of a high rate of metastasis associated. The
most common sites of metastasis (less than 0.5% of the cases) include lymph nodes, lung, bone
and skin. In sunny climates the clinical presentation is in much younger patients but in less
sunny climates it usually happens during the sixth decade [40].

Basal cell carcinoma may develop in some benign lesion as organoid nevi, pore of Winer,
rhinophyma, epidermal nevi, port wine stain, epidermal cysts, multiple trichoepiteliomas,
solar lentigos The presence of multiples BCC in young people is associated with different
syndromes as Gorlin syndrome, Bazex syndrome, cartilage hair hypoplasia syndrome or
ROMBO syndrome that should be discarded.

BCC is characterized by a papulonodular lesion with pearly translucent edge and it is usually
ulcerated (Figure 9). The lesion is usually indurated and telangiectasias on the surface of the
lesion are easily visible. Five main clinical variants have been described: nodular/ulcerative,
superficial, pigmented, infiltrative or morpheaform and fibroepithelioma of Pinkus. Nodular
variant resembles a cutaneous cyst with telangiectasias on the surface, the sizes varies from 1
to various centimeters. The ulcerative variant usually starts as a small translucent papule with
a pearly appearance with a central erosion or ulceration with a rolled margin (ulcus rodens).
The superficial variant is usually located on the trunk as a slowly enlarging, scaly red patch
for a long time. Lesions may be confused with psoriasis, dermatits or eczema.. These lesions
are usually treated with topical corticosteroids but a careful examination of the edges of the
lesions shows a rolled translucent border and dermatoscopy may be useful for the diagnosis
of these tumors. Infiltrative or morpheaform BCC presents a poorly demarcated and cicatricial
lesion which enlarges over several years. BCC may contain pigment on it and in some cases it
is necessary to differentiate from melanocytic lesions. BCC tends to enlarge progressively and
to be destructive, also atypical forms simulating cervical adenopathies have been described
[41-42]. Fibroepithelioma of Pinkus is an uncommon erythematous tumor usually located on
the trunk or extremities with typical histopathologic features.

Figure 9. Basal cell carcinoma: papulonodular lesion with pearly translucent edge on the upper back.
198 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

UV radiation and sunburns correlates properly with BCC of the head and neck. The history of
sunburns during the childhood and recreational exposure during the first two decades of live
are associated with higher risk of this tumor. Low phototype is also a risk factor (fair skin and
red hair). Primary prevention is very important and recently a study has demonstrated that a
programme entirely conducted via Internet significantly reduces by half self-reported sunburn
risk (main risk factor of melanoma and BCC) in an adolescent population achieving very high
satisfaction rates [43]. BCC can be a complication of PUVA therapy, irradiation, burns,
immunosuppression, renal transplant recipients, HIV infection, or leukemia. Mutation in
PTCH1 has been found in sporadic and syndromes associated wih BCC. The pathogenic role
of beta-HPVs in non melanoma skin cancer (NMSC), is not still completely understood, and
literature data indicate that they might be at least cofactors in the development of certain
cutaneous squamous cell carcinomas. However, only few reports contain data on basal cell
carcinoma (BCC). Some studies have shown an overexpression of some protein associated with
beta-HPV species [44] but other authors conclude that HPV does not seem to play a funda
mental role in the aetiopathogenesis of either nodular or superficial BCC. The presence of HPV
appears to be more related to actinic damage and possibly to an alteration of the barrier
function associated with ageing [45].

2. Mucosal lesions

2.1. Benign mucosal lesions

Human papillomavirus (HPV) produces a wide variety of lesions in all the mucosae that
are in contact with the environment outside the organism. In addition to genitourinary
lesions, benign lesions associated with HPV have been described in the oral cavity, nasal
mucosa, and ocular conjunctiva [46]. Some serotypes are frequently associated with specific
lesions: focal epithelial hyperplasia (13, 32), buccal papilloma (2, 6, 11, 57), condyloma
acuminata (6, 11), laryngeal papilloma (11), squamous conjunctival papilloma (6, 11, 16)
and nasosinal papilloma (6, 11).

The diagnosis can be made clinically, but some cases require the use of DNA techniques or
microscopy techniques to establish the presence of koilocytes (elongated cells with eccentric
and pyknotic nuclei that are frequently surrounded by a perinuclear halo).

2.1.1. Focal epithelial hyperplasia or Hecks disease

Although several etiopathogenic factors have been considered, this disease is associated with
HPV, particularly Types 13 and 32. However, other factors play a role, as the zones where the
disease is most frequently observed (the oral mucosa) are contact areas with dental prostheses
[47]. There are also family and ethnic associations (the disease was first described in Inuits and
is not common in Caucasians), thus supporting a possible genetic component associated with
HLA-DR4 [48]. Sexual transmission is not considered common, as the disease is most common
in patients before the second decade of life.
 Clinical Manifestations of the Human Papillomavirus 199
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The basic lesion consists of a rounded or oval papule with a soft consistency that is usually
multiple (figure 10). Its surface is smooth, not keratinized, and the same color as the mucosa
or slightly lighter. Its maximum diameter is usually 5 mm, although it can be confluent;
therefore, the sizes reported in the literature vary between 1 and 10 mm, and the lesion may
even have a cobbled aspect. It is asymptomatic [47, 48]

Hecks disease lesions have been described almost exclusively in the oral mucosa. The most
common location is the lower lip, followed by the jugal mucosa, the upper lip and the tongue.
Lesions are also associated with contact zones. Much more rarely, lesions occur on the palate,
the floor of the mouth, or the oropharynx.

Histologically, epithelial hyperplasia is observed with elongation and horizontal anastamosis

between the interpapillary crests. Also described are hyperkeratosis, parakeratosis, focal
acanthosis, koilocytosis and mitosoid figures (cells that present degenerative nuclear changes
that simulate mitosis) in superficial keratinocytes [3,4]. When HPV DNA is detected, either by
PCR or in situ hybridization, Genotypes 12 and 32 are appreciated in more than 90% of cases
and in Types 1 and 11. To date, no malignant potential has been demonstrated [49].

Differential diagnosis is made against other benign lesions produced by HPV, such as the
common wart, squamous papilloma and condyloma acuminata, all of which are associated
with sexual transmission and with possible abuse, in the case of a minor. It is necessary to
differentiate against fibroma and bite papilloma, as lesions occur in a friction zone. Mucosal
neuroma, white sponge nevus, florid oral papillomatosis and diffuse epithelial hyperplasia in
tobacco chewers are considered in the differential diagnosis. Neurofibromas on the mucosal
affectation of the neurofibromatosis and the papule or labial papillomas of Cowdens syn
drome are usually located in similar zones, thus indicating these systemic diseases [47, 48].

Figure 10. Hecks disease: rounded papule with a soft consistency on the upper lip.

Treatment deserves a brief mention. Because the lesions usually remit spontaneously in
months or years, no specific treatment is suggested. However, if treatment is needed in the
200 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

absence of remission or because of aesthetics or friction-related nuisance, surgery (cryosurgery,

electrosurgery, CO2 laser) or pharmacological therapy similar to any other HPV lesion can be
considered (imiquimod, salicylic acid, podophyllin or trichloroacetic acid)

2.1.2. Condyloma acuminata

The prevalence of this entity, which is associated with human papillomavirus, has progres
sively increased in the developed world, affecting an estimated 6% of the population with an
incidence close to 2% [50]. The most common viral types are 6 and 11. These types have a low
carcinogenic potential, although others types with a higher carcinogenic potential are also
associated with these lesions.

The most frequent mode of transmission is sexual contact, although it is not exclusive. The
disease can also be transmitted vertically in the birth canal or by direct contact via the hands.
Consequently, its presence in children does not necessarily imply sexual abuse.

In addition to infection by papilloma viruses Types 6 and 11 (HR of 12.42), the risk factors
associated with condyloma age (HR of 0.43; if we compare 45-70 years against 18-30 years),
high number of female sexual partners (HR of 5.69) and number of male partners (HR 4.53)
[51]. Classically, it has been considered that there is an inverse association between circumci
sion and HPV prevalence in men, although meta-analyses are inconclusive [52].

The incubation period is variable, lasting from 3 weeks to 8 months (2 to 3 months on average)
[50]. In addition, the infection can be present and contagious in the absence of lesions (sub
clinical infection). Consequently establishing the source of infection is practically impossible,
and it should be assumed that both members of a couple are infected at the time of diagnosis.

In the beginning, the lesion is asymptomatic because it initially affects the basal epidermal
cells. With time, a papule lesion appears, and new lesions develop from there. The evolution
of the disease depends on viral (type, virulence), host (e.g., age, sex, promiscuity, immune
system, toxic abuse) and other factors (location, friction). After infection, evident lesions may
appear, or the lesions may be difficult to appreciate, even with the help of 3 to 5% acetic acid
(inapparent subclinical forms). In other cases, it is impossible to diagnose the lesion even after
histopathological study, and only in situ hybridization (latent forms) can provide a diagnosis.
The evolution of the disease allows the coexistence of the three types of lesions.

Clinically, several forms have been described:

Classical form: These lesions are defined as a fleshy mass, exophytic and vegetating,
pedunculated, with digitations, classically described as having the shape of a cauliflower
(Figure 11). They are keratinized, and the color is variable but generally clear. They are
located in humid areas exposed to friction, such as the balanopreputial sulcus, the frenulum
and the introitus or meatus of the genitals. When they are located in the oral cavity, the
nodules and digitations are frequently softer, but the cauliflower shape is more pronounced
[53]. Their most frequent location is on the superior lip, the lingual frenulum, the back of
the tongue, the inferior lip and the corner of the mouth. The size is also variable, from 1-2
cm to 15 or 20 cm.
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Spicule form: These lesions are more hyperkeratosic, rough and digitiform than the
classical form. They are usually isolated on the preputial mucosa or plate-clustered in
the perianal zone.
Papule form: These lesions are 1-mm papules that are well delimited, non-confluent,
cupuliform and disseminated. When located in the penis, they require differential diagnosis
from hypertrophic sebaceous glands; heterotypic, pearly papules or hirsutoid papillomas;
and Tysons glands.
Flat condyloma or leukoplakia: These lesions present a confluence of viral papules. They
react poorly to acetic acid and do not respond to treatment.
Macular form: These lesions take the form of erythematous spots with a vascular or
granulomatous aspect, with or without a hypopigmented halo. They have a moist surface
with a velvety aspect. They must be differentiated from bacterial or candida chronic
balanoposthitis in immunosuppressed patients and from with Queyrats erythroplasia.
Micropapillar form: These lesions are small fibroepithelial projection with central capillaries.
Inverse punctuated form: These lesions present as erythematous spots.

Figure 11. Multiple condyloma acuminata in penis in an HIV patient

All of these forms are usually asymptomatic, although they can produce pruritus, stinging or
discrete hemorrhages from trauma. If they are large, they can produce a bad odor or pain.
Dysuria, pollakiuria or hematuria can appear if the location is intraurethral, and a ureteroscopy
will be necessary. If the lesions are located in the anus, they can produce constipation and
dyschezia. An anuscopy with exfolliative cytology is recommended, particularly in passive
homosexuals with lesions, as the risk of affecting the rectum is near 50%.
Other forms are much more striking and have benign tumor characteristics but are locally
aggressive. These forms are the giant penile condyloma (Buschke-Lowenstein tumor) and the
florid oral papillomatosis.
202 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

The diagnosis of acuminate condylomas is clinical, requiring a biopsy for confirmation because
of atypical lesions, a malignant aspect, no improvement with therapy or immunological
problems.

In addition to typical koilocytes, the histopathological study of the epidermis will show strong
acanthosis with diverse degrees of papillomatosis, hyperkeratosis and parakeratosis and a
total obliteration of the granule cell layer. The crests tend to be elongated and point towards
the center of the lesion, and the dermis presents increased vascularization with the presence
of capillary thrombosis. In unclear lesions, immunohistochemical staining with peroxidase-
antiperoxidase or MIB1 antibody (against the protein Ki-67) allows the direct visualization of
a viral presence [50].

Treatment will depend on the size and location of the lesion, and surgery is preferable when
lesions are large or are located in the urethral meatus.

2.1.3. Bowenoid papulosis

This disease is fundamentally associated with HPV Type 16, although it is also related to Types
18 and 33 (along with Type 16, these are the most oncogenic types), 32 (in oral mucosa lesions) and,
in a small percentage of cases, to Types 31, 34, 35, 39, 42, 48, 51 and 54 [54]. Bowenoid papulosis is
most frequent in the second and third decades of life (earlier than for Bowens disease). It is located
in the prepuce and less frequently in the glans. In women, it appears in the labia majora and minora,
the clitoris, the groin and around the anus. It is less common in the oral area and is generally
associated with HIV, thus possibly posing a differential diagnosis problem [55].

The lesions are defined as macular lesions (less frequent), papular or multiple verruciform.
They are less than 1 cm in size and are usually confluent. They are usually hyperpigmented,
pink to red-violet or brown (Figure 12). The surface is regular with scales or velvety with a soft
consistency. The disease is asymptomatic, and the lesions rarely ulcerate or bleed (unlike in
Bowens disease).

Figure 12. Violaceous papular lesions on the back of foreskin support Bowenoid papulosis
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The pathological anatomy has similar characteristics to Bowens disease and few differences
from in situ squamous cell carcinoma. At times, Bowenoid papulosis is considered a low-
degree in situ carcinoma [54, 56]. We find hyperkeratosis with parakeratosis foci and hyper
granulosis, irregular acanthosis, occasional papillomatosis and vacuolated keratinocytes with
mitosis in the same phase. Such findings distinguish these lesions from those of Bowens
disease, in which maturation is disorderly and appears as dysplasia. The basement membrane
is intact [9]. However, nuclear alterations can also appear, along with dyskeratosis, atypical
mitosis and multinucleated keratinocytes [11]. In fact, some authors propose that there is a risk
of neoplastic transformation in 2.6% of the cases, and the frequency is higher if there is some
type of immunodeficiency [57].

The main differential diagnosis is made with Bowens disease but may also involve condyloma
acuminata, Queyrats erythroplasia, lichen planus, psoriasis, seborrheic keratosis, anular
granuloma and molluscum contagiousum [54, 57].

Treatment should be conservative because of the high percentage of spontaneous regression,

although the terms are variable and the lesions can persist for 2-3 weeks to 2-3 years or longer.
Simple partial or total excision has been used, as have ablative treatments and local or systemic
pharmacological approaches [54, 56]. A wait-and-see approach with clinical management and/
or repeated biopsies is also a good option [54].

2.2. Malignant mucosal lesions

2.2.1. Queyrats erythroplasia

Queyrats erythroplasia is an in situ squamous carcinoma (intraepidermic) that can evolve into
invasive squamous carcinoma in 3 to 5% of cases. Aside from human papillomavirus (princi
pally Serotypes 16 and 18), the risk factors that influence the development of erythroplasia
include sun exposure, light skin, radiation, PUVA therapy, immunosuppression, smegma and
poor hygiene [58].

Clinically, Queyrats erythroplasia presents as an erythematous-squamous plate of slow

growth and irregular borders (Figure 13), with a smooth surface, hyperkeratosic or warty
appearance and pigmentation in less than 2% of the cases. It is usually present in the multiple
form, although it can also appear as a single lesion. It is frequently located in the penis, although
it can also be found in the urethra, vulva, oral mucosa, tongue and conjunctiva. The diagnosis
must be made by a biopsy or the exeresis of the lesion, and cellular atypia with an intact basal
membrane is typically observed. Differential diagnosis is required against psoriasis, seborrheic
dermatosis, actinic keratosis, invasive squamous cell carcinoma, surface basocellular carcino
ma and Pagets disease [59].

2.2.2. Vulvar cancer

The vulva is the only visible and external part of the female genital system, and its pathology
should be well-known and quickly diagnosed. However, vulvar pathology has been under
valued because it is not very symptomatic or very frequent. Vulvar cancer has a biological and
204 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

Figure 13. Slightly raised erythematous lesion occupying the glans. Queyrats erythroplasia

social impact and requires early diagnosis. It represents 3 to 4% of gynecologic cancers;

epidermoid carcinoma is the most frequent, representing 90% of malignant vulvar tumors.

Vulvar exploration must be meticulous and exhaustive, especially in women with referred
symptomatology. Subclinical lesions frequently require special detection techniques. The
study must be performed via simple vulvoscopy and expanded with a complete biopsy of the
suspicious lesion. An adequate anamnesis, in which personal background is documented
(sexually transmitted diseases, toxic habits, hygienic habits and immunosuppression status)
is important. In addition, visual inspection and inspection with panoramic light must be
performed to observe coloration, trophism and macroscopic lesions, and the other female
genitalia must be examined [60]. The vulvoscopic exam should be undertaken with frequent
applications of 5% acetic acid to corroborate the white color reaction. Another applicable study
is the Collins test, which involves the application of 1% toluidine blue, followed by washing
with 3% acetic acid. However, the most definitive test for diagnosis is a vulvar biopsy with a
rongeur, punch, scalpel or scissors.

It has been observed that one of the etiological agents implicated in the development of vulvar
cancer is the human papillomavirus, specifically Serotype 16, although other serotypes that
influence molecular mechanisms associated with cancer development, such as inactivation of
the p53 gene, have also been implicated.

Although epidermoid vulvar cancer is the most common type, other types include warty
carcinoma, Pagets disease of the vulva, adenocarcinoma, basocellular carcinoma, Bartholin
gland carcinoma and vulvar sarcoma.

Our primary focus will be the clinical description of squamous or epidermoid vulvar carcino
ma, which is the type most directly related to human papillomavirus. Squamous or epidermoid
carcinoma is characterized by the presence of long-evolution pruritus (between 40 and 50%);
flux or vulvar exudate, sometimes with bad odor; bleeding outside menstruation; vulvar pain;
dysuria; and tumor formation (in almost 50% of patients). In the initial stages, this carcinoma
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is observed as an indurated, overelevated lesion; sometimes it can be hyperkeratosic, with

variable coloration ranging from erythematous to white. In the initial phases, it can coincide
with other lesions, such as lichen sclerosus, vulvar intraepithelial neoplasia (VIN), genital
atrophy, squamous cell hyperplasia and overinfection with lichenification from scratching
[61]. In more advanced phases, the squamous carcinoma presents as reddish, ulcerated lesions
(Figure 14), either polypoid or nodular, or with white coloration, even when associated with
palpable inguinal lesions.
Different stages can be differentiated by tumor size, ganglionar affectation and metastatic
affectation. Stages IA, IB and II are usually the initial stages of the localized disease, and the
most frequently affected zones are the anterior part of the vulva, followed by the labia majora
and minora, the clitoris and the vulvar fourchette. In more advanced stages, it frequently
propagates to neighboring organs, such as the anus, urethra and vagina. Dissemination to
other organs such as bone, liver, lungs and brain is rare [62].

Figure 14. Irregular and ulcerated lesion on the vulva histopathologically compatible with vulval cancer

2.2.3. Penile carcinoma

Penile carcinoma is a rare malignant tumor, but it has a major medical and psychological
impact. Amongst the risk factors that influence and contribute to its development are phimosis,
balanoposthitis, ultraviolet radiation, smoking, cervical cancer in the partner, sexually
transmitted diseases, poor hygiene and human papillomavirus, fundamentally Types 16 and
18, which are highly metastatic.
There are different precursor lesions that carry the risk of developing penile spinocellular
cancer or penile squamous-cell invasive carcinoma, such as bowenoid papulosis, balanitis
xerotica obliterans, cutaneous horn and Queyrats erythroplasia that affect the mucous
membrane; or Bowens disease that affects the rest of the genital area.
Penile spinocellular cancer or penile squamous-cell invasive carcinoma is the histological type
present in more than 95% of malignant penile invasive neoplasias. Approximately half are well
differentiated. They usually metastasize via the lymphatic system, first at the inguinal-femoral
206 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

level, then at the pelvis; finally, they migrate to distant areas. The hematogenous spread can
affect the lungs, liver, brain, pleura, bone, skin and other organs [63].

Clinically, penile carcinoma initially manifests as an elevated papular-type or pustulous lesion

that does not resolve with topical treatment and can evolve into an exophytic, polypous or
infiltrating lesion (Figure 15). Erythematous and superficial lesions can also appear. They are
usually located in the glans and less frequently in the balanopreputial sulcus. If the patient
presents phimosis or if the lesion is under the prepuce or is evolved, it protrudes outside the
prepuce. These patients can present initially with an inguinal-level adenopathic lesion
resulting from an inflammatory or metastatic reaction. The lesions can be single or multiple,
fixed or free and can become overinfected.

Figure 15. Excrescent lesion on the penis, that after surgery, histological study confirmed penile cancer

The natural clinical evolution of the disease normally progresses through several stages.
Initially a papillar lesion appears, gradually ulcerates and overinfects, affecting Bucks fascia
and potentially invading the cavernous bodies [64]. In a second stage, the lesion disseminates
via the lymphatic pathway, especially at the inguinal level. Finally, the disease produces
distant metastases that are uncommon upon initial diagnosis.

2.2.4. Anal carcinoma

Anal carcinoma is not very frequent, representing 1 to 2% of digestive system cancers. Among
the risk factors that influence the development and genesis of this cancer, in addition to human
papillomavirus (fundamentally, Types 16, 18 and 31), are poor hygiene, chronic anal irritation,
smoking, seropositivity for herpes virus, seropositivity for human immunodeficiency virus,
sexual promiscuity, passive anal sex, anal fistulas and other less-relevant factors.

Generally, the most frequent type of anal carcinoma associated with papilloma virus is
squamous or spinocellular carcinoma. There are also other types, such as basaloid, cloacogenic,
basal-squamous, epithelioid, trasitional and mucoepidermoid cancer. As observed with cancer
in other locations, there may be premalignant lesions with the potential for developing into
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anal carcinoma, as in Bowens disease, Pagets disease, Bowenoid papulosis, leukoplakia and
condyloma acuminata [65].
Clinically, anal cancer presents with hemorrhages and constant pain associated with other
symptoms, such as changes in defecation, secretion that can be purulent if there is overinfection
and pruritus. In more advanced stages, the patient has the sensation of a palpable mass, and
the tumor can become ulcerated. In the first stages, during which bleeding, pruritus and pain
occur, anal cancer can be easily confused with hemorrhoidal processes, perianal fistulas or
anal fissures; thus, it is necessary to carefully explore the area [65, 66].
Exploration of the anal channel must be directed toward identifying the lesion or possible
lesions; establishing their size, anatomical limits and relationship with the dentated line; and
looking for any other concomitant lesion with different characteristics. Small lesions must be
totally resected for study, while bigger lesions require a biopsy.

2.2.5. Cervical cancer

Cancer in the neck of the uterus is the second most common cancer in women (the first is breast
cancer). Among the multiple causes related to the development of this neoplasia are smoking,
immunosuppression, chlamydia infection, poverty, poor hygienic/dietary conditions, differ
ent dietary habits, diethylstilbestrol, promiscuity, early-age pregnancy and infection with
human papillomavirus. Different types of human papillomavirus have been implicated in the
development of cervical cancer. The most important types are 16, 18, 31, 33 and 45, and the
first two are responsible for approximately 2/3 of all cancers in the neck of the uterus.
Cervical cancer can be prevented with cytologic techniques and by applying the Papanicolaou
method. The objective is to establish an early diagnosis so that therapy can begin quickly;
because the initial stages of this cancer are asymptomatic, frequent and exhaustive reviews are
important [67].
As we have previously mentioned, the initial stages of cervical cancer do not produce symp
toms; however, when the tumor increases (Figure 16), women present abnormal vaginal
bleeding that can occur between menstrual cycles, following sexual relations and after
menopause, or the bleeding can prolong menstrual-bleeding periods [68]. Cervical cancer can
also be associated with other symptoms, such as pelvic pain and dyspareunia, and it can
increase flux and vaginal secretions.

3. Other types of tumors

Next, we will describe other tumoral clinical processes that have been associated with HPV
infection. It is important to highlight that the majority of people infected with HPV do not
present symptomatology or health-problems related to the infection. In 90% of the cases, the
immune system naturally eliminates the virus within two years. However, sometimes HPV
infections become chronic, and they can be associated with other lesions or tumors aside from
the previously described pathology. These lesions and tumors include warty lesions in the oral
208 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

Figure 16. Excrescent ulcerated lesions in cervix clinically compatible with carcinoma

cavity and pharynx (recurrent respiratory papillomatosis [RRP]) and rare but serious cancers
such as those of the bladder, lung and oropharynx (the posterior area of the throat, including
the base of the tongue and the tonsils).

3.1. Oral and cervical cancer

Eighty-five percent of oral cavity cancers are epidermoid (we will be referring primarily to this
type), and their incidence increases progressively with age. HPV 16/18 are the types most
frequently associated with oral and cervical cancer, especially in the oropharynx and tonsils
[69, 70]. The principal lesions associated with HPV infection in the oral cavity are oral papil
lomatosis (associated with HPV 6 and 11), focal epithelial hyperplasia (HPV 13 and 32) and
erythroplasia (HPV 16).

Causal factors strongly associated with oral and cervical cancer are tobacco and alcoholic
beverage consumption. Therefore, investigations to determine the possible etiological role of
HPV will need to consider these factors. Several studies that controlled for age, gender,
smoking, tobacco chewing and drinking have not observed significant differences among these
factors for HPV detection in tumoral tissue, with the exception of smoking. That is, HPV DNA
was less likely to be found in the biopsy samples of ex-smokers and smokers than those of
people who had never smoked. In comparison, patients with more than a single sexual partner
had a higher possibility of HPV DNA detection than those who had a single lifetime sexual
partner. Similar observations were obtained when comparing oral sex practitioners versus
nonpractitioners. These associations were similar for oral cavity and oropharynx cancer [71].

The clinical manifestations of patients with epidermoid carcinoma are very diverse and
depend on the location and size of the lesions. Leukoplakia and erythroplasia are premalignant
lesions over which neoplastic lesions can develop. The most common initial presentation is a
painful ulcer. Pain appears precociously in lesions that affect the base of the mouth or the gums;
however, it is delayed in other locations, such as the base of the tongue. Dysphagia occurs with
lesions that affect the oropharynx or that alter the mobility of the tongue. Hemorrhage usually
occurs in ulcerated lesions. Other associated symptoms include dysphonia, tooth mobility or
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loss, anesthesia or trismus. Clinically, the tumor manifests in exophytic, ulcerative or warty
forms (Figure 17). It is important to completely explore the entire oral cavity and to obtain a
biopsy of the lesion when it is accessible, or a puncture-aspiration with a fine needle when
biopsy is difficult. The neck must be carefully explored to detect adenopathies, and a radiologic
or endoscopic study should be performed to establish tumoral extension.

The importance of HPV in oropharyngeal carcinoma patients is increasing. It is important to

determine the presence or absence of this virus in patients who present epidermoid carcinoma
in the oropharynx or who have cervical adenopathy of uncertain origin to obtain information
on the patients therapeutic attitude, prognosis and survival [72].

Figure 17. Squamous cell carcinoma of the lip: exophytic, ulcerative, warty tumor of the lower lip.

3.2. Recurrent respiratory papillomatosis and lung cancer

Recurrent respiratory papillomatosis (RRP) is characterized by warty lesions produced by

HPV infection of the airways. These lesions can obstruct the airways or cause dysphonia,
among other symptoms. Two clinical variants are recognized depending on the patients age
at onset: the juvenile (before 5 years) and the adult form (after 40 years). The juvenile variant
is more frequent and severe than the adult form. HPV 6 and 11 are the types most frequently
involved in this clinical picture [73]. HPV 11 produces a more severe clinical picture than the
other viral variants do, and HPV 11 infection more frequently requires tracheostomy. The
transmission mechanisms of the infection are not always clear, but sexual transmission should
be considered in adults, and mother-to-child transmission should be considered in the juvenile
RRP variant. In this regard, some risk factors associated with this variant have been confirmed.
These risk factors include a mother younger than 20 years, vaginal delivery and being firstborn.
Sexual abuse should also be suspected in diseased children older than 5 years.
210 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

The symptomatology of this disease is varied, and diagnosis is generally delayed because of
the diseases rareness. The predominant symptoms are related to upper airway obstruction
caused by the frequent involvement of the larynx. These symptoms can occasionally threaten
the patients life. Dyspnea, snoring, dysphonia, the sensation of a foreign body in the throat,
coughing or wheezing are common clinical symptoms. The diagnosis should be suspected
with these clinical data, and appropriate complementary tests should be requested for
diagnosis. Such diagnostic tests include bronchoscopy or laryngoscopy, which will show
typical warty images on the airway. HPV serotyping is necessary and has prognostic value.

Lung cancer is one of the most common cancers. It has one of the highest mortality rates among
cancers and is particularly associated with smoking. The majority of cancerous lung tumors
originate from the bronchial epithelia (bronchogenic carcinomas); the rest derive from other
cells and constitute a more heterogeneous group. The maximal incidence is from 40 to 70 years,
and the disease is more frequent among men. The diagnosis is usually made late, and only
15% of the patients present a localized disease. Usually there is ganglionar or metastatic disease
upon diagnosis. Several histological subtypes have been distinguished and have important
prognostic implications. These subtypes are squamous cell carcinoma, adenocarcinoma, large
cell carcinoma and microcytic carcinoma.

The most important etiological factors are the substances inhaled when smoking cigarettes;,
thus, the risk increases 60- to 70-fold in an individual who smokes two packs per day. The risk
diminishes if the habit is abandoned, but it does not become equal to that of nonsmokers. In
addition, genetic alterations in lung cancer patients have been widely studied and corroborate
the oncogene activation (Ras, Myc, among others) and inactivation of tumor-suppressing
genes (p53). The relationship between lung cancer and HPV infection was initially established
in 1975 [74]. More recent studies have suggested a 25% HPV infection prevalence associated
with lung cancer, with an important variation between countries [75]. High-risk subtypes that
have been detected are 16, 18, 31, and 33; the lower-risk subtypes are 6 and 11. Therefore, it
has been suggested that HPV infection is the second-most-important risk factor after smoking.
The transmission mechanism is not properly known, but it appears that multiple sex partners
and oral and anal sex may be among the transmission factors. A higher-than-expected
incidence of lung cancer was detected in cervical and anal cancer patients in whom HPV was
implicated [76], suggesting a possible hematogenous dissemination of the virus. The action
mechanisms that explain the role of HPV in tumor promotion and development are complex.
In addition, it has recently been demonstrated that HPV and smoking can have a synergistic
effect on tumor promotion [77].

The symptomatology that the disease produces is associated with growth and obstruction of
the lung and neighboring structures. Although in some cases the tumors are diagnosed in their
asymptomatic phase using radiography, most of the tumors debut with coughing, hemoptysis,
wheezing, stridor or dyspnea. If there is eccentric growth, the tumor can irritate the pleura,
leading to pain, coughing and restrictive-origin dyspnea. If the tumor grows towards the
thorax, it can produce tracheal obstruction, esophageal compression, snoring (by paralyzing
the recurrent laryngeal nerve), hemidiaphragm elevation (phrenic nerve paralysis) or Horners
syndrome, Pancoast syndrome or superior vena cava syndrome. Paraneoplastic syndromes
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can also be detected and are associated with the ectopic production of such hormones as PTH
and ACTH by microcytic carcinomas. Eaton-Lambert myasthenic syndrome and Trousseaus
migratory thrombophlebitis may also be associated with this clinical presentation, although
in very low percentages.

Metastasis is observed in 50% of epidermoid carcinoma patients, 80% of those with adenocar
cinoma and up to 95% in microcytic carcinoma patients. The metastases can appear in the brain,
bones, bone marrow and liver.

3.3. Bladder cancer

Bladder cancer is the malignant tumor that most frequently affects the urinary tract. Its
prognosis is highly variable. It is one of the most common cancers among men. The majority
of the tumors are transitional cell carcinomas (90%), which have a high tendency to recur after
treatment or become invasive and overwhelm subjacent muscular structures. AS a conse
quence, it is necessary to periodically control the urothelium. Pure epidermoid carcinoma
constitutes 3% of cases, and adenocarcinoma constitutes 2%.

Tobacco consumption also plays an important role in the development of this tumor; it is
thought to contribute to up to 50% of urothelial carcinomas. Other risk factors implicated in
the development of this tumor are certain drugs, such as cyclophosphamide and phenacetin;
infection with Schistosoma haematobium; and external radiotherapy. Genetic alterations have
also been detected, including deletions of the RB gene or p53 overexpression. The association
between bladder cancer and HPV infection is still controversial, considering that one of the
viruss natural reservoirs is the urethra and that it could easily migrate to the bladder. Some
authors have strongly implicated the virus in tumors that affect younger patients. A recent
meta-analysis of all the published studies on the relationship between HPV and bladder cancer
concludes that there is a moderate and clear association amongst both processes and estab
lishes an odds ratio of 2.13 [78]. However, more studies are needed that evaluate the pathogenic
relationship between the processes.

The clinical manifestations of this tumor are varied. Hematuria is related to exophytic-growth
tumors, whereas irritation symptoms (dysuria, pollakiuria and micturition urgency) are more
frequent in patients with localized disease (in situ carcinoma), even though they can also be
observed in patients who present tumoral invasion towards the muscle layer of the bladder.
However, other important causes of macroscopic and microscopic hematuria must be consid
ered, such as cystitis and prostate problems. When hematuria is found, a complete evaluation
should be performed. This evaluation should include urinary cytology, ultrasound (Figure
18) or intravenous pyelogram and cystoscopy. Less common clinical manifestations are pain
or nuisance in the renal fossa related to urethral obstruction or pelvic pain and lower extremity
edema produced by the obstruction of the iliac vessels. With less frequency, metastatic disease
is the first manifestation of these tumors. Once bladder cancer is diagnosed, it is very important
to establish whether the muscle layer has been affected. To determine this, ultrasound, CT and
nuclear magnetic resonance are of great help.
212 Human Papillomavirus and Related Diseases From Bench to Bedside A Diagnostic and Preventive Perspective

Figure 18. Bladder ultrasound, in which, it can be observed the presence of a lesion that histologically was urothelial
cancer.

3.4. Other tumors

Other tumors, including cancers of the larynx, sinonasal tract, nasopharynx, salivary gland,
vulva, esophagus and breast, have also been associated with HPV infection [79].

Author details

Miguel ngel Arrabal-Polo1, Mara Sierra Girn-Prieto2, Jacinto Orgaz-Molina1,

Sergio Merino-Salas1, Fernando Lopez-Carmona Pintado1, Miguel Arrabal-Martin1 and
Salvador Arias-Santiago3

1 San Cecilio University Hospital, Spain

2 Granada District, Spain

3 Baza Hospital. Granada School of Medicine, Spain

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