**3.2. Recurrent respiratory papillomatosis and lung cancer**

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

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

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

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

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

The clinical manifestations of patients with epidermoid carcinoma are very diverse and depend on the location and size of the lesions. Leukoplakia and erythroplasia are premalignant lesions over which neoplastic lesions can develop. The most common initial presentation is a painful ulcer. Pain appears precociously in lesions that affect the base of the mouth or the gums; however, it is delayed in other locations, such as the base of the tongue. Dysphagia occurs with lesions that affect the oropharynx or that alter the mobility of the tongue. Hemorrhage usually occurs in ulcerated lesions. Other associated symptoms include dysphonia, tooth mobility or

the base of the tongue and the tonsils).

**3.1. Oral and cervical cancer**

erythroplasia (HPV 16).

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

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

can also be detected and are associated with the ectopic production of such hormones as PTH and ACTH by microcytic carcinomas. Eaton-Lambert myasthenic syndrome and Trousseau's migratory thrombophlebitis may also be associated with this clinical presentation, although

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

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

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

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

constitutes 3% of cases, and adenocarcinoma constitutes 2%.

in very low percentages.

**3.3. Bladder cancer**

bones, bone marrow and liver.

relationship between the processes.

nuclear magnetic resonance are of great help.

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

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

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

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

### **3.3. Bladder cancer**

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

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

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

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

The symptomatology that the disease produces is associated with growth and obstruction of the lung and neighboring structures. Although in some cases the tumors are diagnosed in their asymptomatic phase using radiography, most of the tumors debut with coughing, hemoptysis, wheezing, stridor or dyspnea. If there is eccentric growth, the tumor can irritate the pleura, leading to pain, coughing and restrictive-origin dyspnea. If the tumor grows towards the thorax, it can produce tracheal obstruction, esophageal compression, snoring (by paralyzing the recurrent laryngeal nerve), hemidiaphragm elevation (phrenic nerve paralysis) or Horner's syndrome, Pancoast syndrome or superior vena cava syndrome. Paraneoplastic syndromes

cell carcinoma and microcytic carcinoma.

effect on tumor promotion [77].

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

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

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

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

#### **3.4. Other tumors**

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