HPV viruses may affect cutaneous as well as mucosal tissues. Major mucosal surfaces include those of the oral cavity, pharynx, esophagus, bronchus, lung, larynx, anal canal, and genital tract including the uterine cervix and the vulvovaginal areas. Cutaneous involvement results in the development of common warts such as those involving the hands and plantar surfaces of the feet (Viscidi and Shah 2009). HPV infections of the larynx are unique as they may result in the development of recurrent respiratory papillomatosis. This is a rare, chronic, and recurrent disease in which numerous papillomatous lesions of the larynx and tracheobronchial tree may become life threatening on account of their strategic location (Viscidi and Shah 2009). This entity affects young individuals, with about one third to one half of cases occurring in patients under the age of 5 years (Viscidi and Shah 2009). Viral types recovered from these laryngeal papillomatous lesions are HPV 6 and HPV 11, the viral types that are responsible for genital warts (Viscidi and Shah 2009). HPV can be acquired in a variety of ways: through skin abrasions leading to development of cutaneous papillomas (warts), by sexual intercourse (genital warts), during passage through an infected birth canal (juvenile-onset laryngeal papillomatosis), and probably in some other ways (direct inoculation, oral sex) (Viscidi and Shah 2009).

Over the last decade, increases in the number of cases of oropharyngeal cancers associated with HPV type 16 have been recorded in the United States. Reported incidences have ranged from 0.8 cases per 100,000 in 1988 to 2.6 per 100,000 in 2004 (Chaturvedi et al. 2011). It has been hypothesized that these increases may be related to oral sex, particularly among younger men (Herrero et al. 2003; D’Souza et al. 2007; Luc et al. 2010; Marur et al. 2010).

A large body of evidence exists linking HPV infection and cancers of the lung (Klein et al. 2009). These cancers are primarily of the non-small cell type, including squamous cell carcinomas, adenocarcinomas, and large cell carcinomas. There appears to be only rare reports documenting specific pathologic features (such as basaloid, verrucous or condylomatous architecture, or koilocytic change at the cellular level) that may suggest the diagnosis in the absence of molecular testing (Clavel et al. 2000). Considerable effort by Asian and Western investigators have revealed wide variations in the HPV content of lung tumors according to histopathology and geographical location of the various medical centers where the studies have been conducted (Yu et al. 2009; Goto et al. 2011). For example, in a well-designed study from Japan, Baba et al. examined 30 lung adenocarcinomas and 27 lung squamous cell carcinomas. The investigators detected high-risk HPV genome in 9 (30 %) of the adenocarcinomas but only in 2 (7 %) of squamous cell carcinomas (Baba et al. 2010).

The possible presence of HPV in 218 fresh frozen tissue samples from lung tumors was studied by Coissard and collaborators using the Roche line blot assay aiming to detect the expression of mRNAs encoding the E6 HPV oncoprotein. Only four (one squamous and three large cell carcinomas) of the 218 cases were positive for HPV, but the E6 mRNA oncoprotein was undetectable in the four samples. This study from France indicated a very low prevalence of HPV in carcinomas of the lung among patients from Western countries (Coissard et al. 2005). An Italian study examined the prevalence of HPV in lung tumor tissue samples. Koshiol et al. selected 450 lung cancers with adequate tissue material and studied them using real-time polymerase chain reaction (PCR) to test for E6 gene sequences from HPV 16 and E7 gene sequences from HPV 18. The investigators found no evidence of an association between HPV and lung cancer in these Western patients (Koshiol et al. 2011). Another (earlier) Italian study (Ciotti et al. 2006) analyzed 38 patients with non-small cell lung cancers for the presence of E6 and E7 oncogenes of HPV 16, 18, and 31. Eight of the thirty-eight lung cancers were HPV positive (six HPV 16, one HPV 16 and 18, and one HPV 31). The foregoing studies confirm considerable disparity in results but reaffirm the notion that the prevalence of HPV is greater in Asian countries as opposed to Western ones. This notion is further and convincingly supported by the Srinivasan meta-analysis of 2,435 subjects from 27 published studies. In this large study, the overall prevalence of HPV ranged widely from 0.0 % to 78.3 % with marked heterogeneity across geographic regions and histologic tumor tissue types. The study again revealed a higher proportion of Western (European) studies reporting low or no HPV prevalence (0–10 %), as compared to Asian studies (Srinivasan et al. 2009).

None of the studies cited above help to provide evidence of a direct role of HPV infection in the oncogenesis of lung cancer (Zandberg 2013; Syrjänen et al. 2012), but do not entirely discount the possibility that HPV may be a risk factor acting synergistically with tobacco smoke to cause lung cancer (Zandberg 2013).

The morphologic evidence of HPV-related etiology in lung cancers is meager. Earlier reports citing condylomatous changes in bronchial papillomas and squamous carcinomas of the lung aroused considerable interest (Trillo and Guha 1988; Syrjänen 1980; Flieder et al. 1998) and led to the hypothesis postulating an oncogenic role for HPV in pulmonary neoplasia. Overexpression of p16 has been strongly linked to high-risk HPV infection. Studies have shown virtually 100 % sensitivity for p16 in cervical intraepithelial neoplasia. p16 has also been useful in the distinction between in situ and invasive cervical adenocarcinoma and benign endocervical cells (Chivukula and Dabbs 2010). A study examining p16 expression in lung squamous cell cancers showed that about one third of cases were positive for p16. However, the samples were concurrently negative for both high-risk and low-risk HPV subtypes. This finding cast doubt on the efficacy of p16 expression as an indicator of HPV association in squamous cell cancers of the lung (Doxtader and Katzenstein 2012).

Unlike other DNA viruses, conventional culture techniques cannot detect HPV. Likewise, histopathology alone cannot make a diagnosis of HPV-related lung cancer. Consequently, other diagnostic modalities must be considered and relied upon as diagnostic tools. A major objective of these diagnostic tools is detection of HPV DNA within tumor cells. Major diagnostic modalities include tests for viral capsid antigen, HPV identifications by DNA-based assays (PCR-based assays, hybrid capture assays, in situ hybridization), and type-specific serologic assays for HPV that use recombinant capsid protein as antigens (Viscidi and Shah 2009). Currently, approved assays for detecting HPV DNA are used chiefly in the setting of gynecological pre-neoplasia and neoplasia and encompass Hybrid Capture 2 HPV DNA assays, the Cervista HPV HR test, the Cervista HPV 16/18 test, the cobas 4800 HPV test, and the Aptima HPV assay (Zhao and Yang 2012). An in-depth discussion of these diagnostic tools is beyond the scope of this chapter. The design, indications, and validation of the foregoing approved tests are provided in recent publications (Check 2012; Zhao and Yang 2012).