\nA growing body of research shows that human papillomavirus (HPV) is a common and increasing cause of oropharyngeal squamous cell carcinoma (OSCC). Thus, the International Agency for Research against Cancer has acknowledged HPV as a risk factor for OSCC, in addition to smoking and alcohol consumption. Recently, in Finland, the United Kingdom, the Netherlands, the United States, and Sweden, incidence of OSCC has increased, and an increase in the proportion of HPV-positive tumors was noted. On the basis of these data and reports indicating that patients with HPV-positive cancer have their first sexual experience at a young age and have multiple partners, we postulate that increased incidence of OSCC in the United States and some countries in northern Europe is because of a new, primarily sexually transmitted HPV epidemic. We also suggest that individualized treatment modalities and preventive vaccination should be further explored.<\/p>\n
Study<\/strong> Head and neck cancer most commonly is of the squamous cell carcinoma type (HNSCC) and includes cancers of the oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract, and nasopharynx. HNSCC is the sixth most common type of cancer in the world; almost 600,000 cases are reported annually, and of these, \u224810% (or more for some geographic locations) are OSCC (5). Globally, the incidence and localization of HNSCC varies widely. It is the most common form of cancer in India, and incidence is higher in countries in Latin America than in the United States and northern Europe. In addition, men are generally more often affected than women. Smoking, alcohol consumption, and betel chewing are traditional risk factors for HNSCC and OSCC (6). However, during the past decade several reports have documented HPV in OSCC (7\u20139). HPV infection, with dominance of HPV16 infection, has therefore been acknowledged by the International Agency for Research against Cancer as a risk factor for OSCC (10). Moreover, there are accumulating reports from many countries that the incidence of OSCC is increasing. We suggest that this increase is caused by a slow epidemic of HPV infection\u2013induced OSCC.<\/p>\n OSCC<\/strong> HPV<\/strong> During the past few decades, HPV DNA has been detected in \u224825% of HNSCCs overall, but especially in OSCC, for which 45%\u2013100% cases were reported to be HPV positive (7\u20139,11\u201319). The latter variation may depend on OSCC location, the type of specimens available, the techniques used for testing, and the time period and country from which the sample material was obtained (7\u20139,11\u201319).<\/p>\n Analysis of HPV DNA was (and still is) performed primarily by using formalin-fixed, paraffin-embedded tissue, in which the DNA can be partially degraded. It is now widely accepted that it is easier to detect longer HPV DNA fragments in fresh or fresh-frozen material, although newer techniques are more sensitive. Many early studies during the 1980s were based on Southern blot techniques or in situ hybridization for detection of HPV.<\/p>\n Since the 1990s, virology laboratories used PCR for detection of HPV DNA (20\u201323). Screening for HPV was initially performed by using general PCR primers for HPV, which enabled detection of several HPV types (21\u201323). PCR of a control cellular gene was used to assess the DNA quality of samples. These techniques are robust and are still used but need additional methods for HPV typing. There are now many other methods that directly determine the presence of several different HPV types. The Food and Drug Administration\u2013approved Hybrid Capture II (Digene Corporation, Gaithersburg, MD, USA) detects 5 low-risk and 13 high-risk HPV types and uses the fact that HPV DNA hybridizes with synthetic RNA probes complementary to DNA sequences from specific HPV types (20). An assay used in several studies, the Roche (Basel, Switzerland) linear array HPV Genotyping Test, detects 37 HPV types and is based on a method developed by Gravitt et al. (24). In this method, HPV PCR products are hybridized to a linear array of type specific probes. Recently, Schmitt et al developed a sensitive bead-based multiplex method, originally set up for 22 different HPV types but later expanded, in which HPV PCR products are coupled to type-specific probes on beads and analyzed by using Luminex (25).<\/p>\n To assay for biologic activity of HPV in tumors, analysis of E6 and E7 expression by detecting E6 and E7 mRNA by reverse transcription followed by real-time PCR is also often performed (13). In pathology departments, HPV screening is often conducted by in situ hybridization, and in some instances p16 immunohistochemical analysis is used as a substitute to assay for biologically active HPV because there is a correlation between the presence of HPV and overexpression of p16 (26,27). When HPV in OSCC became more obvious, several studies concentrated on characterizing HPV-positive OSCC (4,7\u20139,11\u201319). HPV type 16 was highly prevalent (\u224890%) in OSCC in all studies; other HPV types (e.g., HPV-31, -33, -58, -59, -62, and -72) were less common, and HPV was demonstrated to be episomal or integrated into the cellular genome (14,28).<\/p>\n In several studies, E6 and E7 expression in OSCC were shown, suggesting that HPV was actively involved in the etiology of the tumors (13). In addition, the association of p16 overexpression with HPV was a further indicator of active E7 because of E7-induced cell cycle activation and upregulation of p16 by inactivating the Rb pathway (3,26,27). HPV-positive tumors were also less likely to have mutated p53 (7) and were more frequently aneuploid and less differentiated than HPV-negative tumors (29). Furthermore, comparative genomic hybridization indicated that HPV-positive tonsillar cancer, in contrast to HPV-negative cancer, often showed chromosome 3q amplification similar to that in HPV-positive cervical and vulvar cancer, which further supports the oncogenic role of HPV in OSCC (30).<\/p>\n <\/a> It was also observed that patients with HPV-positive OSCC were younger and lacked the traditional risk factors of smoking and alcohol consumption (7\u20139,13,17). Moreover, a major feature, noted in several studies, was that HPV was a favorable prognostic factor for clinical outcome of OSCC, as demonstrated in Figure 1 (7\u20139,11\u201319). This finding was independent of tumor stage, age, gender, grade of differentiation, p53 immunohistochemical results, or DNA ploidy (7\u20139). However, Lindquist et al. (13) observed that patients with HPV-positive tonsillar cancer who had never smoked had a better prognosis than those who were smokers, and this observation was recently confirmed by Ang et al. (16). The reasons for this finding are most likely complex and should be investigated further. One could speculate, for example, that HPV induces an immune response and that smoking abrogates this response. A different option is that smoking and HPV in combination induce a different category of tumors and that smoking induces additional genetic alterations in these tumors, as was also suggested by Ang et al. (16).<\/p>\n In general, the prognostic value of HPV status is for OSCC and not for HNSCC. In some studies with conflicting findings, the prognostic value of HPV was determined for all HNSCC anatomic sites (9). However, because there are differences in survival rates and presence of HPV at different locations, even for OSCC, studies should be performed per location.<\/p>\n In summary, the accumulated data suggest different entities of OSCC, where some primarily depend on smoking and alcohol and others on HPV infection. It is also likely that there are combined etiologies. Nevertheless, patients with HPV-positive OSCC consistently have a better prognosis (7\u20139,11\u201319). An HPV-induced Epidemic of OSCC<\/strong> Using the Swedish Cancer Registry, which covers basically all cancer cases in Sweden for 1970\u20132002, we disclosed a 2.8-fold increase (2.6-fold for men and 3.5-fold for women) in the incidence of tonsillar cancer in the Stockholm area (12), where 25%\u201330% of all patients in Sweden with tonsillar cancer are treated. In parallel, we examined all 237 available samples from the 515 patients with tonsillar cancer in Stockholm during the same period and found a 2.9-fold increase in the proportion of HPV-positive tonsillar cancer from 23% to 68% (12). We thus suggested HPV infection played a role in the increase of this disease (12).<\/p>\n
\nIn many countries, vaccines against some human papillomavirus (HPV) types are now administered to girls and young women with the goal of protecting them against HPV-induced cervical cancer (1,2). The introduction of HPV vaccines has also drawn more attention to the fact that HPV is associated not only with cervical cancer and genital warts but also with other tumors, such as head neck and anogenital cancers (3). We focus on the role of HPV in the increased incidence of oropharyngeal squamous cell carcinoma (OSCC), the head and neck cancer in which HPV is most commonly found (4).<\/p>\n
\nTonsillar cancer is the most common OSCC, followed by base of tongue cancer. Together, these 2 cancers account for 90% of all OSCCs (6,9). Patients usually do not seek counseling until the tumors are large because small tumors cause little distress and may not be noticed by the patient. Curative treatment implies surgery, radiotherapy, and chemotherapy; the goal is to cause as little functional and cosmetic damage as possible (6,9). If a cure cannot be obtained, palliative therapy is given to treat pain and discomfort. Similar to HNSCC, in general, survival rates for patients with OSCC are poor. Patients with OSCC have an overall 5-year survival rate of \u224825% (6,9). Furthermore, even when standardized treatment is used and tumors are at the same stage and have similar histologic features, it is difficult to predict the outcome. Several reports now describe the incidence of OSCC as increasing and indicate that HPV-positive OSCC has a better clinical outcome than HPV-negative OSCC (7\u20139,11\u201319). Thus, predictive and prognostic markers would be of clinical value for prevention and treatment of OSCC.<\/p>\n
\nThere are >100 HPV types, some found in skin warts and others in mucous tissues, and the association of different HPV types with cervical, some anogenital, and head and neck cancers is well established (3). The 8-kb, double-stranded, circular DNA HPV genome, enclosed in a 52\u201355 nm viral capsid, codes for the L1 and L2 viral capsid proteins and for the E1\u2013E2 and E4\u2013E7 proteins, which play major roles in gene regulation, replication, pathogenesis, and transformation (3). In high-risk HPVs (i.e., those that are more likely to cause lesions that may develop into cancer [www.cancer.gov\/cancertopics\/factsheet\/Risk\/HPV]), E6 and E7 deregulate cell cycle control by E6 binding and degradation of p53, and E7 binds and inhibits the function of the retinoblastoma protein (Rb) (3). The L1 protein can self-assemble into virus-like particles, which form the basis of both currently approved vaccines against HPV infection (1\u20133).
\nHPV and Methods for Detection in OSCC<\/p>\n
\nHPV in OSCC<\/p>\n![\"\"](\"http:\/\/oralcancernews.org\/wp\/wp-content\/uploads\/2010\/11\/fig1a.png\" "\\"fig1a\\"")
<\/a><\/p>\n
\n<\/strong><\/p>\n
\nWe suggest the increased incidence of OSCC depends on HPV infection and results in an increased proportion of HPV-positive OSCCs. During the past decades, studies from the United States, Finland, Sweden, the Netherlands, the United Kingdom, and Scotland showed an increase in the incidence of OSCC, tonsillar cancer, and base of tongue cancer (31\u201336). In addition, during the past 10 years, an increase in the proportion of HPV-positive OSCC has been reported, and we speculate that this is not caused simply by use of more sensitive diagnostic techniques. In many of these studies the same assay was used when studying OSCC over time (12,18,19). Furthermore, the general PCR amplifiability of the DNA from the older tested samples was also validated.<\/p>\n