**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 Heck's 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.

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]

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

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

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)

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

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

and pyknotic nuclei that are frequently surrounded by a perinuclear halo).

function associated with ageing [45].

**2. Mucosal lesions**

**2.1. Benign mucosal lesions**

and nasosinal papilloma (6, 11).

*2.1.1. Focal epithelial hyperplasia or Heck's disease*

in patients before the second decade of life.

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

**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 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)

**•** 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

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**•** 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;

**•** Flat condyloma or leukoplakia: These lesions present a confluence of viral papules. They

**•** 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 Queyrat's erythroplasia. **•** Micropapillarform:These lesions are smallfibroepithelialprojection with central capillaries.

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

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

homosexuals with lesions, as the risk of affecting the rectum is near 50%.

react poorly to acetic acid and do not respond to treatment.

**•** Inverse punctuated form: These lesions present as erythematous spots.

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

florid oral papillomatosis.

the perianal zone.

and Tyson's glands.

#### *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.


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

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

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

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.

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‐

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.

**•** 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

Consequently, its presence in children does not necessarily imply sexual abuse.

sion and HPV prevalence in men, although meta-analyses are inconclusive [52].

The evolution of the disease allows the coexistence of the three types of lesions.

Clinically, several forms have been described:

cm to 15 or 20 cm.

considered (imiquimod, salicylic acid, podophyllin or trichloroacetic acid)

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

*2.1.2. Condyloma acuminata*

associated with these lesions.

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.

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.

The pathological anatomy has similar characteristics to Bowen's disease and few differences from in situ squamous cell carcinoma. At times, Bowenoid papulosis is considered a lowdegree 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 Bowen's 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

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The main differential diagnosis is made with Bowen's disease but may also involve condyloma acuminata, Queyrat's erythroplasia, lichen planus, psoriasis, seborrheic keratosis, anular

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/

Queyrat's 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

Clinically, Queyrat's 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‐

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

type of immunodeficiency [57].

**2.2. Malignant mucosal lesions**

*2.2.1. Queyrat's erythroplasia*

ma and Paget's disease [59].

*2.2.2. Vulvar cancer*

poor hygiene [58].

granuloma and molluscum contagiousum [54, 57].

or repeated biopsies is also a good option [54].

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 peroxidaseantiperoxidase 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 18and33(alongwithType16,thesearethemostoncogenictypes),32(inoralmucosalesions)and, in a small percentage of cases, to Types 31, 34, 35, 39, 42, 48, 51 and 54 [54]. Bowenoid papulosis is mostfrequentinthesecondandthirddecadesoflife(earlierthanforBowen'sdisease).Itislocated intheprepuceandlessfrequentlyintheglans.Inwomen,itappearsinthelabiamajoraandminora, 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 Bowen's disease).

**Figure 12.** Violaceous papular lesions on the back of foreskin support Bowenoid papulosis

The pathological anatomy has similar characteristics to Bowen's disease and few differences from in situ squamous cell carcinoma. At times, Bowenoid papulosis is considered a lowdegree 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 Bowen's 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 Bowen's disease but may also involve condyloma acuminata, Queyrat's 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. Queyrat's erythroplasia*

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

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

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 peroxidaseantiperoxidase or MIB1 antibody (against the protein Ki-67) allows the direct visualization of

Treatment will depend on the size and location of the lesion, and surgery is preferable when

This disease is fundamentally associated with HPV Type 16, although it is also related to Types 18and33(alongwithType16,thesearethemostoncogenictypes),32(inoralmucosalesions)and, in a small percentage of cases, to Types 31, 34, 35, 39, 42, 48, 51 and 54 [54]. Bowenoid papulosis is mostfrequentinthesecondandthirddecadesoflife(earlierthanforBowen'sdisease).Itislocated intheprepuceandlessfrequentlyintheglans.Inwomen,itappearsinthelabiamajoraandminora, the clitoris, the groin and around the anus. It is less common in the oral area and is generally

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

associated with HIV, thus possibly posing a differential diagnosis problem [55].

**Figure 12.** Violaceous papular lesions on the back of foreskin support Bowenoid papulosis

problems.

a viral presence [50].

*2.1.3. Bowenoid papulosis*

Bowen's disease).

lesions are large or are located in the urethral meatus.

Queyrat's 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, Queyrat's 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 Paget's 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

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

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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

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

membrane; or Bowen's disease that affects the rest of the genital area.

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

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 Queyrat's erythroplasia that affect the mucous

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

other organs such as bone, liver, lungs and brain is rare [62].

palpable inguinal lesions.

*2.2.3. Penile carcinoma*

18, which are highly metastatic.

**Figure 13.** Slightly raised erythematous lesion occupying the glans. Queyrat's 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, Paget's 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 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].

#### *2.2.3. Penile carcinoma*

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.

**Figure 13.** Slightly raised erythematous lesion occupying the glans. Queyrat's erythroplasia

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

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

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

Although epidermoid vulvar cancer is the most common type, other types include warty carcinoma, Paget's disease of the vulva, adenocarcinoma, basocellular carcinoma, Bartholin

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

rongeur, punch, scalpel or scissors.

the p53 gene, have also been implicated.

gland carcinoma and vulvar sarcoma.

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 Queyrat's erythroplasia that affect the mucous membrane; or Bowen's 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 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].

anal carcinoma, as in Bowen's disease, Paget's disease, Bowenoid papulosis, leukoplakia and

Clinical Manifestations of the Human Papillomavirus

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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

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

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

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

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

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

first two are responsible for approximately 2/3 of all cancers in the neck of the uterus.

anal fissures; thus, it is necessary to carefully explore the area [65, 66].

totally resected for study, while bigger lesions require a biopsy.

condyloma acuminata [65].

*2.2.5. Cervical cancer*

important [67].

increase flux and vaginal secretions.

**3. Other types of tumors**

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 Buck's 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 anal carcinoma, as in Bowen's disease, Paget's 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.
