HPV related oropharyngeal cancers is a non cervical cancer second to cervical in US, and with evidence of increasing prevalence worldwidely
The development of most cancers is known to be induced by multiple factors. One of these, such as cancers induced by infectious agents, has received much attention in recent years. The most common cancer-associated infectious agent worldwide is Helicobacter pylori, constituting 5.5% of all cancers; and the second most prevalent one was human papillomaviruses (HPV) related, which accounted for 5.2% of all cancers, as indicated in the global health study by Parkin (200). 
The majority of HPV infections is asymptomatic and usually resolves without any treatment, like the common warts which grow on hands and feet. However, a minority of HPVs may lead to the development of cancers, which are usually found in throat and genital area. [2,3]
Given the well established causal link between HPV infection and cancers, HPV vaccines are currently administered to young females with the goal of protecting them against HPV virus-associated cervical cancers. The advent of such vaccines has also heightened our awareness to the fact that HPV is associated not only with cervical cancer and genital warts, but also with other non-cervical tumors, such as those of the head and neck and anogenital regions. [1,4, a15]
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HPV infection, in particular, with HPV16 is now acknowledged by the International Agency for Research against Cancer as a risk factor for oropharyngeal squamous cell carcinomas [a4, a7,A10]
HPV is a DNA virus. They are named 'papillomavirus' as the initial serotypes were found to cause warts, or papillomas. HPV is a ubiquitous virus which can infect skin and mucous membranes, in particular, stratified squamous epithelium of the anogenital region as well as upper aerodigestive tract. [2,3] There are now more than 150 serotypes found [ 2], and they are identified by numbers, in order of their discovery. Some serotypes such as 16, 18, 31 and 45, are considered by some, but not all, to be 'sexually transmitted', and are known to associated with the development of cervical, vulvovaginal, anal and penile cancers. [ 1,a15 ] These serotypes are also referred to as "high-risk" types HPV. By contrast, those "low-risk" HPVs, do not cause carcinogenesis, like those common warts caused by HPV types 2 and 7.
Among the carcinogenesis HPVs, the most dominant one is cervical cancer, while the second most is oropharyngeal cancer, which is a non-cervical cancer [1,a15 ]. These may be due to the morphological similarity between oral and cervical squamous cell, both are strongly associated with HPV type 16.
HPV E6/ E7 ONCOPROTEINS
The HPV-16 genome, is a double strand circular DNA of about 8 kb, and is enclosed in a 52-55 nm viral capsid. The DNA sequence codes for the L1 and L2 viral capsid proteins, and the E1-E2 and E4-E7 proteins. [6,a10] These proteins are known to play a crucial role in gene regulation, replication, pathogenesis, and transformation  The E6 and E7 oncoproteins are key factors that lead to HPV-induced carcinogenesis. [a13, a18, a19]
Under normal circumstances, should cells be infected by the HPV virus, our body's immune system will clear the virus rapidly and will not progress to cancer development. However, in those with persistent infection, the virus interacts with the host DNA and may lead to development of cancers. This process of viral transformation is so slow that in many people who are infected, it takes many years before any symptoms would appear.
HPV E6 and E7 oncoproteins cause an impairment in our body's immune system, which is a complex interaction between these oncoproteins to our body's normal cell cycle including the p53, Rb, cylin-CDK complex, p21 and p27.  These factors are believed to be the key behind the development of neoplasia. With persistent infection, the viral load becomes high and the viral DNA becomes integrated into the cellular DNA, which led to the upregulation of the HPV E6 and E7 oncoproteins. The E6 oncoprotein mainly cause the degradation of the tumor suppressor gene p53 and lead to the delay in cell apoptosis. While the E7 oncoprotein mainly inhibit the function of retinoblastoma protein (Rb), and stimulate the cellular DNA synthesis and pathological cell growth. [6, c1 ]
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THE ETIOLOGIC ROLE OF HPV IN CANCER
As noted earlier, the cause of cancer is multifactorial, and it is logical to assume that HPV viral agent on its own is not sufficient to cause cancer, like those in cervix; there should be some co-factors that lead to the development of cancer. [c2,a11, a12 ] These additional factors include tobacco use, alcohol consumption, malnutrition, immunocompromised states, which are often implicated in most cancer studies. [4,7 ]
METHODS FOR HPV DETECTION
With advances in molecular genetics, HPV DNA can be more accurately detected and analyzed from patient samples using paraffin or frozen materials. Polymerase Chain Reaction (PCR), Southern blot and in-situ hybridization are the major powerful techniques employed in all recent studies. Apparently, this may be one of the reasons why more HPV positive cases were reported in past decade. [ 6 ]
With the use of generic mixture of HPV primers or HPV type specific primers in PCR, identification of HPV type can be achieved and the results can be confirmed by the Southern blot hybridization. Besides the detection of E6 and E7 expression using PCR or real-time PCR, L1 region primer was also used for detecting HPV viral genome. [a13, a14, a19 ] In laboratories where molecular techniques are not available, p16 immunohistochemical analysis may also be used as a surrogate marker for HPV infection.[6, a17 ]
EVIDENCE OF ASSOCIATION BETWEEN HPV AND OROPHARYNGEAL CANCERS
More focus is now on the etiologic role of HPV in the increase incidence of oropharyngeal squamous cell carcinomas (OSCC), which is a subset of head and neck squamous cell carcinoma (HNSCC). HNSCC is regarded as the sixth most common type of cancer, and within the HNSCC, about 10% are OSCC. [1,6]
In the study of Gillison et al. (2000), by using the combination of the L1 and E7 region primers for PCR amplification and sequencing with Southern blot hybridization, has revealed that 25% of the overall HNSCC samples had HPV genomic DNA, in which HPV-16 accounted for 90% of the cases. 
Similar finding was reported by D'Souza et al. (2007), revealed that 72% of the oropharyngeal cancer specimens were HPV 16 positive, whereas, in the study of Nasman et al. (2009), 78% of the samples were found to be HPV 16 positive. [b51]
In the same study of Gillison et al. (2000), on the HPV positivity at different anatomic sites of HNSCC revealed that HPV DNA was predominantly found in oropharynx samples, which account for 57%, as compared to 19% found in larynx, 12% in oral cavity. Furthermore, within the HPV positive oropharyngeal tumors, it was revealed that 94% were palatine or lingual tonsils tumor and 62% were tonsil or base of tongue tumor. These become the important subsites of HNSCC that recently studies on HPV related HNSCC are focus on, and account for the overall high prevalence of HPV related HNSCC or OSCC. [a9, a12, a13, a14, a19]
Beside HPV 16 was found in significantly high percentage in head and neck or oropharyngeal tumors, HPV 18 was the second most frequent type of HPV found in OSCC. In the case-control study conducted by Anaya-Saavedra (2008), revealed that
a 55.6% of HPV 16 and 18.5% of HPV 18 were detected in the OSCC samples, suggesting that HPV 16 and HPV 18 are risk factors for oral squamous cell carcinoma. [a37, b55, 7 ] In additions, HPV 33 and HPV 31 were also reported in some studies, but in minor percentage as found in HPV positive HNSCC or OSCC . For example, in the study of Attner (2010) a 10% of HPV 33 was detected [a19], whereas in the study of Mellin (200), one HPV 33 was detected in the samples.[a14]
Obviously, with more HPV serotypes found in HPV related tumors over time, it is likely that one day the majority of the HNSCC or OSCC are found to be HPV positive.
GLOBAL PREVALENCE AND CONSEQUENCES OF HPV RELATED OSCC
During the past decades, studies from various part of the world showed a significant increase in HPV related OSCC, tonsillar cancers and base of tongue cancers. 
In Sweden, a study from Hammarstedt et al. (2006) discovered a 2.8 fold increased in HPV positive tonsillar cancers in Stockholm during the period 1970-2002.[a12 ] This result was concurred with a similar study for that period conducted by Nasman et al. (2009). Nasman further reported on the growth rate for 2000-2007 (68% between 2000-2002, 77% between 2003-2005 and 93% between 2006-2007), and revealed that the HPV positive tonsillar cancers in Stockholm almost double for each decade between 1970-2007, suggesting an epidemic of HPV induced carcinoma the country. [B#51] And in contrast, there revealed a parallel decrease in HPV negative cases.
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In Finland, the study of Syrjanen S. (2005) revealed a overall increase in HPV positive oral cancer increase from 22% to 51% in the year 2002, and also pointed out that tonsillar cancers seem to be the highest prevalence ones among all non-genital cancers. [A#4] While in Australia, a study by Hong et al. (2010) reported that there was increase from 19% to 47% during the year 1987 to 2005 for HPV related oropharynx cancer. [B#55]
Another study performed in Czech Republic, also agreed that the association of HPV to the risk oropharyngeal tumor was strong, and revealed a 51.5% of HPV DNA detected in the samples; and 80% of them was HPV 16 positive.[B#54] Interestingly, this study also found out that HPV cancer is higher in non-smoker (100%) and non-drinker (68%), which were believed to be the traditional etiologic factors of cancer [a6]. This finding was also supported by other studies, like the one by D'Souza et al (2007), revealed that smoking or dinking had no effect on HPV positivity [4 ] This also imply that HPV infection is the key causative agents of the oropharyngeal tumor. [B#54, a11 b46 ]
While in United States, HPV related OSCC was found significantly increase from 1973 to 2004 by Chaturvedi et al. (2008), mainly in white men and at younger ages. [b46, a35]
Besides the world wide increase incidence in HPV related oropharyngeal cancers, with a parallel declined in HPV unrelated OSCC [A35], and also reported to be found in younger age, these should initiate the governments and health organizations to aware of it. Further studies in early clinical diagnosis, better treatment and prevention should be focus by the research communities. [a7,a8,a9]
CLINICAL DIAGNOSIS, TREATMENT AND PREVENTION of OSCC
CANCER OF OROPHARYNX
Oropharynx is a tube like structure from behind the nose down to the neck, and is the middle part of the throat (also call pharynx), and form part of the esophagus. It includes the soft palate, the base of the tongue, and the tonsils.
The symptom of oropharyngeal cancer include sore throat, odynophagia, and ear-ache. If patient is suspected of oropharyngeal cancer, the clinician will take a biopsy for confirmative diagnosis. When patient has diagnosed oropharyngeal cancer, clinician needs to know the cancer stage (staging) for planning the treatment. [A#6]
TREATMENTS AND PROGNOSIS
Treatments of oropharyngeal cancer basically have three kinds, including surgery, radiation therapy and chemotherapy. For stage I and II, standard treatment usually involve the surgery and radiation therapy; whereas for stage III and IV are more complicated as tumors have begin to spread, usually it will be a mixing of surgery, radiation therapy and chemotherapy. [A#6]
In the study of prognostic significance in oropharyngeal tumors with the presence of HPV, Gillison et al. (2000) found that there was a significant reduction of 60% in the risk of death from cancer, in patient with HPV-positive tumors. While in the study of Nguyen et al. (2010) suggested that the HPV positive oropharyngeal cancers have better prognosis was due to its responsive radio and chemo therapy. [b46]. However, some studies revealed that it was due to the active anti-viral immune response, as revealed in the experiment by Spanos et al. (2009) by comparing the in vitro cell line to in vivo HPV positive tumors. This also concur with the study of Dahlstrand and Dalianis (2008) which found that HPV positive patient were more frequently to have impaired immune system. [A#9]
Furthermore, Mellin et al. (2000) found that survival rate of HPV positive tonsillar patients were significantly better, regardless of the treatment received. The 3-year survival rate in HPV positive and negative patients were found to be 65.3% and 31.5% respectively, while the 5-year survival rate in HPV positive and negative patients were found to be 53.3% and 31.5% respectively. Similarly, Ang et al. (2010) revealed that patients with HPV positive oropharyngeal tumors had a better 3-year overall survival rate and a 58% reduction in risk of death after adjustment, regardless of the type of radiotherapy received [a16]. However, Ang also found out that the risk of death will increase with the number of pack-year of smoking in HPV positive tumor patients, suggesting a smoking induced genetic alteration in the HPV tumors. [a16]
As these studies revealed that there was a better prognosis and survival rate on HPV positive OSCC patient, there should be better treatment and therapy profile optimized for them in future. This also rely on the development in predictive markers and clinical diagnosis to located these HPV positive OSCC patients. [6, a8 ]
POSSIBLE CAUSES AND PREVENTIONS
Smoking and drinking are the traditional etiologic factors of oropharyngeal cancers as already described in previous studies [a6], some studies agreed with it [a37], whereas others did not [#4]. But the trend of increasing of oropharyngeal cancers among both non-smoker and non-drinkers were observed worldwide [b46]
Moreover, HPV infection of oropharynx, was found to be associated with high-risk sexual behavior, just like those in cervical cancer. [b46, a38, a35] As suggested in the study of Chaturvedi et al.(2008) that the increased in HPV related OSCC in U.S. from 1973 to 2004 was due to the changing of sexual behavior. [a35]
Further studies reveal that increase in lifetime sex partners, practice oral sex and even open mouth kissing were associated with the development of HPV related OSCC. [ a37,a38] Also, start sex at young age as may be a etiological role for the development of HPV related OSCC as indicated by Anaya-Saavedra et al. (2008) [a37] This may be the reason why the patients are found tend to be younger in studies [a35,b46]
PREVENTION AND VACCINATION
Prevention can be achieve by education to the public on the harmful of smoking and have cigarette control, as suggest in the study of Sturgis (2007) which may help to reduce the prevalence of head and neck cancer. [a11]
In additions, safe-sex education to young people and reduce the lifetime sex partners should also reduce the incidence of oropharyngeal cancers as it was found to be associated with sexual behavior. But the more important and to greater extent is the vaccination program in protection public against HPV induced cancers.
The Gardasil and Cervarix are two FDA approved vaccines against HPV types 6, 11, 16 and 18 (also known as quadrivalent HPV vaccine). They are not just for protection women against cervical cancer, but can also be used to protect the public against HPV related non-cervical cancer. HPV 16 is the one that found strongly associated with oropharyngeal cancers and basically these four HPV types in the vaccines already covered most of the cervical and non-cervical cancer etiologic HPV types [a15, a40].
The effectiveness of the prophylactic vaccines on cervical cancer already show great promise as observed in many studies [a1,a2,a15]. In the study of Munoz et al. (2010) found that vaccination was up to 100% effective in HPV negative population in reducing high grade cervical, vulva, vaginal lesion and genital warts. [a2] But currently has few measures on the effectiveness on non-cervical cancers.
It was also suggested the HPV vaccination program should be highly encourage to men and adolescent, not just covering the young women, as those non-cervical HPV cancer, anal, oropharyngeal and penile cancer, are more likely found on men [a15, a11]. And should be started at younger age.
The widespread HPV vaccination program should eventually reduce the burden of HPV associated non-cervical cancer, in addition to the cervical cancers [A15], and resulting in reduction of cytological abnormalities, diagnostic and therapeutic procedures. [a2]
Further suggestion to the vaccination program as made by Gilison et al. (2008) is to establish more effective and widely used screening programs in non-cervical cancers [a15] And the cost-effectiveness of HPV vaccination should be review as the benefit of preventing non-cervical HPV cancer are already included in the vaccination. [a40]
Despite there is evidence of increasing HPV associated oropharyngeal cancers, it seem to be optimistic that HPV positive oropharyngeal tumors have better prognosis and survival rate, and hopefully can be impeded by the high coverage HPV vaccination if the effectiveness is the same as in cervical cancer.