**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. © 2013 The Author(s). Licensee InTech. This chapter is 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.

#### *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 virus's 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 Hodgkin's 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.

central red dot or a loop surrounded by a whitish halo. This combination of characteristics

**Figure 2.** Papule with well-defined borders and with the same color as the skin on the finger compatible with com‐

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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),

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 HPV's cytopathic effect, koilocytes (cells with a pyknotic nucleus surrounded by a clear halo)

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.

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

creates a "frog spawn" appearance [13].

are observed [14].

mon wart.

*1.1.1.2. Filiform warts*

*1.1.1.3. Plantar warts*

of the metatarsi.

intradermic nevus and warty epidermal nevus.

**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

**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 HPV's cytopathic effect, koilocytes (cells with a pyknotic nucleus surrounded by a clear halo) are observed [14].

### *1.1.1.2. Filiform warts*

*1.1.1.1. Common warts*

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

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 virus's 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 Hodgkin's 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

188 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

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.

**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].

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

**Figure 4.** Plantar wart: Multiple hyperkeratotic lesion on the sole of the foot with thrombosed capillaries (black dots).

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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,

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].

lines, is another diagnosis to consider.

histological analysis can be used for diagnosis.

*1.1.1.5. Pigmented warts*

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 individual's 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.

**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*

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

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

190 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

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].

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 individual's 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

homogeneous opacity [15].

*1.1.1.4. Flat warts*

wart.

absent.

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].

forms can create minor defects in patients with predisposing genes, and these defects manifest

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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

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

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)

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‐

clinically upon immunosuppression [24].

**1.2. Malignant skin lesions**

*1.2.1. Squamous cell carcinoma of the skin*

infection may also be a risk factor for SCC.

until the development of invasive squamous cell carcinoma [14].

#### *1.1.1.6. Epidermodysplasia verruciformis*

This is a rare genodermatosis that is generally autosomal recessive hereditary, although Xassociated 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-β 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 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**

*1.1.1.6. Epidermodysplasia verruciformis*

This is a rare genodermatosis that is generally autosomal recessive hereditary, although Xassociated 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-β 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

192 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

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

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

defective viral antigen presentation on keratinocyte surfaces [25].

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

to require integration into the host genome [23].

### *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‐ 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].

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

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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

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

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

Bowen´s 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 Bowen´s disease as non-steroidresponsive dermatitis. The clinical differential diagnosis of Bowen´s disease includes psoriasis, eczema, superficial basal cell carcinoma or cutaneous Paget´s 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 Bowen´s disease include a verrucous,

these lesions [33].

development of verrucous carcinoma. [34]

presented DNA of HPV. [36]

*1.2.2. Bowen´S disease*

HPV-18 infection had no impact on 5-year prognosis [35].

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 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. Bowen´S disease*

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

194 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

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

**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

ability [32].

the risk of metastasis.

Bowen´s 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 Bowen´s disease as non-steroidresponsive dermatitis. The clinical differential diagnosis of Bowen´s disease includes psoriasis, eczema, superficial basal cell carcinoma or cutaneous Paget´s 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 Bowen´s disease include a verrucous, 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 Bowen´s disease [37] but this is not a common phenomenon. Some authors proposed that Bowen´s disease was considered a marker of an internal malignancy; however a later meta-analysis showed that this association was inconsistent [38].

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

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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

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

sunny climates it usually happens during the sixth decade [40].

the trunk or extremities with typical histopathologic features.

**Figure 9.** Basal cell carcinoma: papulonodular lesion with pearly translucent edge on the upper back.

ROMBO syndrome that should be discarded.

**Figure 8.** Well-defined erythematous scaly plaque on the limb clinically and histopathologically compatible with Bo‐ wen´s disease.

Bowen´s 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 Bowen´s disease is mainly multifactorial and different factors have been associated as UV light or arsenic. Also HPV have been associated with Bowen´s 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 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].

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 Bowen´s disease [37] but this is not a common phenomenon. Some authors proposed that Bowen´s disease was considered a marker of an internal malignancy; however a later meta-analysis showed that

196 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

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

Bowen´s 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 Bowen´s disease is mainly multifactorial and different factors have been associated as UV light or arsenic. Also HPV have been associated with Bowen´s 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

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

this association was inconsistent [38].

wen´s disease.

remains elusive.[39]

*1.2.3. Basal cell carcinoma of the skin*

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.

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].

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

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Heck's 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,

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

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 Cowden's syn‐ drome are usually located in similar zones, thus indicating these systemic diseases [47, 48].

and in Types 1 and 11. To date, no malignant potential has been demonstrated [49].

**Figure 10.** Heck´s 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

even have a cobbled aspect. It is asymptomatic [47, 48]

the floor of the mouth, or the oropharynx.
