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HPV related oropharyngeal malignant neoplastic diseases is a non cervical malignant neoplastic disease second to cervical in US, and with grounds of increasing prevalence worldwidely

Introduction

The development of most malignant neoplastic diseases is known to be induced by multiple factors. One of these, such as malignant neoplastic diseases induced by infective agents, has received much attending in recent old ages. The most common cancer-associated infective agent worldwide is Helicobacter pylori, representing 5.5 % of all malignant neoplastic diseases ; and the 2nd most prevailing one was human papillomaviruses ( HPV ) related, which accounted for 5.2 % of all malignant neoplastic diseases, as indicated in the planetary wellness survey by Parkin ( 200 ) . [ 1 ]

The bulk of HPV infections is symptomless and normally resolutenesss without any intervention, like the common warts which grow on custodies and pess. However, a minority of HPVs may take to the development of malignant neoplastic diseases, which are normally found in pharynx and venereal country. [ 2,3 ]

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Given the good established causal nexus between HPV infection and malignant neoplastic diseases, HPV vaccinums are presently administered to immature females with the end of protecting them against HPV virus-associated cervical malignant neoplastic diseases. The coming of such vaccinums has besides heightened our consciousness to the fact that HPV is associated non merely with cervical malignant neoplastic disease and venereal warts, but besides with other non-cervical tumours, such as those of the caput and cervix and anogenital parts. [ 1,4, a15 ]

HPV infection, in peculiar, with HPV16 is now acknowledged by the International Agency for Research against Cancer as a hazard factor for oropharyngeal squamous cell carcinomas [ a4, a7, A10 ]

HUMAN PAPILLOMAVIRUS

HPV is a Deoxyribonucleic acid virus. They are named ‘papillomavirus ‘ as the initial serotypes were found to do warts, or villoma. HPV is a omnipresent virus which can infect tegument and mucose membranes, in peculiar, stratified squamous epithelial tissue of the anogenital part every bit good as upper aerodigestive piece of land. [ 2,3 ] There are now more than 150 serotypes found [ 2 ] , and they are identified by Numberss, in order of their find. Some serotypes such as 16, 18, 31 and 45, are considered by some, but non all, to be ‘sexually transmitted ‘ , and are known to associated with the development of cervical, vulvovaginal, anal and penial malignant neoplastic diseases. [ 1, a15 ] These serotypes are besides referred to as “ bad ” types HPV. By contrast, those “ low-risk ” HPVs, do non do carcinogenesis, like those common warts caused by HPV types 2 and 7.

Among the carcinogenesis HPVs, the most dominant one is cervical malignant neoplastic disease, while the 2nd most is oropharyngeal malignant neoplastic disease, which is a non-cervical malignant neoplastic disease [ 1, a15 ] . These may be due to the morphological similarity between unwritten and cervical squamous cell, both are strongly associated with HPV type 16.

HPV E6/ E7 ONCOPROTEINS

The HPV-16 genome, is a dual strand round Deoxyribonucleic acid of about 8 kilobits, and is enclosed in a 52-55 nm viral mirid bug. The Deoxyribonucleic acid sequence codifications for the L1 and L2 viral mirid bug proteins, and the E1-E2 and E4-E7 proteins. [ 6, a10 ] These proteins are known to play a important function in cistron ordinance, reproduction, pathogenesis, and transmutation [ 6 ] The E6 and E7 oncoproteins are cardinal factors that lead to HPV-induced carcinogenesis. [ a13, a18, a19 ]

Under normal fortunes, should cells be infected by the HPV virus, our organic structure ‘s immune system will unclutter the virus quickly and will non come on to malignant neoplastic disease development. However, in those with relentless infection, the virus interacts with the host DNA and may take to development of malignant neoplastic diseases. This procedure of viral transmutation is so slow that in many people who are infected, it takes many old ages before any symptoms would look.

HPV E6 and E7 oncoproteins do an damage in our organic structure ‘s immune system, which is a complex interaction between these oncoproteins to our organic structure ‘s normal cell rhythm including the p53, Rb, cylin-CDK composite, p21 and p27. [ 7 ] These factors are believed to be the key behind the development of neoplasia. With relentless infection, the viral burden 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 chiefly do the debasement of the tumour suppresser cistron p53 and lead to the hold in cell programmed cell death. While the E7 oncoprotein chiefly suppress the map of retinoblastoma protein ( Rb ) , and excite the cellular DNA synthesis and pathological cell growing. [ 6, c1 ]

THE ETIOLOGIC ROLE OF HPV IN CANCER

As noted earlier, the cause of malignant neoplastic disease is multifactorial, and it is logical to presume that HPV viral agent on its ain is non sufficient to do malignant neoplastic disease, like those in neck ; there should be some co-factors that lead to the development of malignant neoplastic disease. [ c2, a11, a12 ] These extra factors include baccy usage, intoxicant ingestion, malnutrition, immunocompromised provinces, which are frequently implicated in most malignant neoplastic disease surveies. [ 4,7 ]

METHODS FOR HPV DETECTION

With progresss in molecular genetic sciences, HPV DNA can be more accurately detected and analyzed from patient samples utilizing paraffin or frozen stuffs. Polymerase Chain Reaction ( PCR ) , Southern smudge and unmoved hybridisation are the major powerful techniques employed in all recent surveies. Apparently, this may be one of the grounds why more HPV positive instances were reported in past decennary. [ 6 ]

With the usage of generic mixture of HPV primers or HPV type particular primers in PCR, designation of HPV type can be achieved and the consequences can be confirmed by the Southern smudge hybridisation. Besides the sensing of E6 and E7 look utilizing PCR or real-time PCR, L1 part primer was besides used for observing HPV viral genome. [ a13, a14, a19 ] In research labs where molecular techniques are non available, p16 immunohistochemical analysis may besides be used as a alternate marker for HPV infection. [ 6, a17 ]

EVIDENCE OF ASSOCIATION BETWEEN HPV AND OROPHARYNGEAL CANCERS

More focal point is now on the etiologic function of HPV in the addition incidence of oropharyngeal squamous cell carcinomas ( OSCC ) , which is a subset of caput and cervix squamous cell carcinoma ( HNSCC ) . HNSCC is regarded as the 6th most common type of malignant neoplastic disease, and within the HNSCC, approximately 10 % are OSCC. [ 1,6 ]

In the survey of Gillison et Al. ( 2000 ) , by utilizing the combination of the L1 and E7 part primers for PCR elaboration and sequencing with Southern smudge hybridisation, has revealed that 25 % of the overall HNSCC samples had HPV genomic DNA, in which HPV-16 accounted for 90 % of the instances. [ 7 ]

Similar determination was reported by D’Souza et Al. ( 2007 ) , revealed that 72 % of the oropharyngeal malignant neoplastic disease specimens were HPV 16 positive, whereas, in the survey of Nasman et Al. ( 2009 ) , 78 % of the samples were found to be HPV 16 positive. [ b51 ]

In the same survey of Gillison et Al. ( 2000 ) , on the HPV positiveness at different anatomic sites of HNSCC revealed that HPV DNA was preponderantly found in oropharynx samples, which account for 57 % , as compared to 19 % found in voice box, 12 % in unwritten pit. Furthermore, within the HPV positive oropharyngeal tumours, it was revealed that 94 % were palatal or linguistic tonsils tumour and 62 % were tonsil or base of tongue tumour. These become the of import subsites of HNSCC that late surveies on HPV related HNSCC are focus on, and history for the overall high prevalence of HPV related HNSCC or OSCC. [ a9, a12, a13, a14, a19 ]

Beside HPV 16 was found in significantly high per centum in caput and cervix or oropharyngeal tumours, HPV 18 was the 2nd most frequent type of HPV found in OSCC. In the case-control survey 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, proposing that HPV 16 and HPV 18 are risk factors for unwritten squamous cell carcinoma. [ a37, b55, 7 ] In add-ons, HPV 33 and HPV 31 were besides reported in some surveies, but in minor per centum as found in HPV positive HNSCC or OSCC [ 7 ] . For illustration, in the survey of Attner ( 2010 ) a 10 % of HPV 33 was detected [ a19 ] , whereas in the survey of Mellin ( 200 ) , one HPV 33 was detected in the samples. [ a14 ]

Obviously, with more HPV serotypes found in HPV related tumours over clip, it is likely that one twenty-four hours the bulk of the HNSCC or OSCC are found to be HPV positive.

GLOBAL PREVALENCE AND CONSEQUENCES OF HPV RELATED OSCC

During the past decennaries, surveies from assorted portion of the universe showed a important addition in HPV related OSCC, tonsillar malignant neoplastic diseases and base of lingua malignant neoplastic diseases. [ 6 ]

In Sweden, a survey from Hammarstedt et Al. ( 2006 ) discovered a 2.8 crease increased in HPV positive tonsillar malignant neoplastic diseases in Stockholm during the period 1970-2002. [ a12 ] This consequence was concurred with a similar survey for that period conducted by Nasman et Al. ( 2009 ) . Nasman farther reported on the growing rate for 2000-2007 ( 68 % between 2000-2002, 77 % between 2003-2005 and 93 % between 2006-2007 ) , and revealed that the HPV positive tonsillar malignant neoplastic diseases in Stockholm about double for each decennary between 1970-2007, proposing an epidemic of HPV induced carcinoma the state. [ B # 51 ] And in contrast, there revealed a parallel lessening in HPV negative instances.

In Finland, the survey of Syrjanen S. ( 2005 ) revealed a overall addition in HPV positive unwritten malignant neoplastic disease addition from 22 % to 51 % in the twelvemonth 2002, and besides pointed out that tonsillar malignant neoplastic diseases seem to be the highest prevalence 1s among all non-genital malignant neoplastic diseases. [ A # 4 ] While in Australia, a survey by Hong et Al. ( 2010 ) reported that there was addition from 19 % to 47 % during the twelvemonth 1987 to 2005 for HPV related oropharynx malignant neoplastic disease. [ B # 55 ]

Another survey performed in Czech Republic, besides agreed that the association of HPV to the hazard oropharyngeal tumour 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 survey besides found out that HPV malignant neoplastic disease is higher in non-smoker ( 100 % ) and non-drinker ( 68 % ) , which were believed to be the traditional etiologic factors of malignant neoplastic disease [ a6 ] . This determination was besides supported by other surveies, like the one by D’Souza et Al ( 2007 ) , revealed that smoke or dinking had no consequence on HPV positiveness [ 4 ] This besides imply that HPV infection is the cardinal causative agents of the oropharyngeal tumour. [ B # 54, a11 b46 ]

While in United States, HPV related OSCC was found significantly increase from 1973 to 2004 by Chaturvedi et Al. ( 2008 ) , chiefly in white work forces and at younger ages. [ b46, a35 ]

Besides the universe broad addition incidence in HPV related oropharyngeal malignant neoplastic diseases, with a analogue declined in HPV unrelated OSCC [ A35 ] , and besides reported to be found in younger age, these should originate the authoritiess and wellness organisations to aware of it. Further surveies in early clinical diagnosing, better intervention and bar should be focus by the research communities. [ a7, a8, a9 ]

Clinical DIAGNOSIS, TREATMENT AND PREVENTION of OSCC

CANCER OF OROPHARYNX

Oropharynx is a tubing like construction from behind the nose down to the cervix, and is the in-between portion of the pharynx ( besides call throat ) , and organize portion of the gorge. It includes the soft roof of the mouth, the base of the lingua, and the tonsils.

The symptom of oropharyngeal malignant neoplastic disease include sore pharynx, odynophagia, and ear-ache. If patient is suspected of oropharyngeal malignant neoplastic disease, the clinician will take a biopsy for collateral diagnosing. When patient has diagnosed oropharyngeal malignant neoplastic disease, clinician needs to cognize the malignant neoplastic disease phase ( presenting ) for be aftering the intervention. [ A # 6 ]

Treatments AND PROGNOSIS

Treatments of oropharyngeal malignant neoplastic disease fundamentally have three sorts, including surgery, radiation therapy and chemotherapy. For phase I and II, standard intervention normally involve the surgery and radiation therapy ; whereas for phase III and IV are more complicated as tumours have begin to distribute, normally it will be a commixture of surgery, radiation therapy and chemotherapy. [ A # 6 ]

In the survey of predictive significance in oropharyngeal tumours with the presence of HPV, Gillison et Al. ( 2000 ) found that there was a important decrease of 60 % in the hazard of decease from malignant neoplastic disease, in patient with HPV-positive tumours. While in the survey of Nguyen et Al. ( 2010 ) suggested that the HPV positive oropharyngeal malignant neoplastic diseases have better forecast was due to its antiphonal wireless and chemo therapy. [ b46 ] . However, some surveies 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 tumours. This besides concur with the survey of Dahlstrand and Dalianis ( 2008 ) which found that HPV positive patient were more often to hold impaired immune system. [ A # 9 ]

Furthermore, Mellin et Al. ( 2000 ) found that survival rate of HPV positive tonsillar patients were significantly better, irrespective of the intervention received. The 3-year endurance rate in HPV positive and negative patients were found to be 65.3 % and 31.5 % severally, while the 5-year endurance rate in HPV positive and negative patients were found to be 53.3 % and 31.5 % severally. Similarly, Ang et Al. ( 2010 ) revealed that patients with HPV positive oropharyngeal tumours had a better 3-year overall endurance rate and a 58 % decrease in hazard of decease after accommodation, irrespective of the type of radiation therapy received [ a16 ] . However, Ang besides found out that the hazard of decease will increase with the figure of pack-year of smoking in HPV positive tumour patients, proposing a smoke induced familial change in the HPV tumours. [ a16 ]

As these surveies revealed that there was a better forecast and survival rate on HPV positive OSCC patient, there should be better intervention and therapy profile optimized for them in hereafter. This besides rely on the development in prognostic markers and clinical diagnosing to located these HPV positive OSCC patients. [ 6, a8 ]

POSSIBLE CAUSES AND PREVENTIONS

Smoke and imbibing are the traditional etiologic factors of oropharyngeal malignant neoplastic diseases as already described in old surveies [ a6 ] , some surveies agreed with it [ a37 ] , whereas others did non [ # 4 ] . But the tendency of increasing of oropharyngeal malignant neoplastic diseases among both non-smoker and non-drinkers were observed worldwide [ b46 ]

Furthermore, HPV infection of oropharynx, was found to be associated with bad sexual behaviour, merely like those in cervical malignant neoplastic disease. [ b46, a38, a35 ] As suggested in the survey 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 behaviour. [ a35 ]

Further surveies reveal that addition in lifetime sex spouses, pattern unwritten sex and even unfastened oral cavity snoging were associated with the development of HPV related OSCC. [ a37, a38 ] Besides, get down sex at immature age as may be a aetiologic function for the development of HPV related OSCC as indicated by Anaya-Saavedra et Al. ( 2008 ) [ a37 ] This may be the ground why the patients are found tend to be younger in surveies [ a35, b46 ]

PREVENTION AND VACCINATION

Prevention can be achieve by instruction to the populace on the harmful of smoke and have cigarette control, as suggest in the survey of Sturgis ( 2007 ) which may assist to cut down the prevalence of caput and cervix malignant neoplastic disease. [ a11 ]

In add-ons, safe-sex instruction to immature people and cut down the life-time sex spouses should besides cut down the incidence of oropharyngeal malignant neoplastic diseases as it was found to be associated with sexual behaviour. But the more of import and to greater extent is the inoculation plan in protection populace against HPV induced malignant neoplastic diseases.

The Gardasil and Cervarix are two FDA approved vaccinums against HPV types 6, 11, 16 and 18 ( besides known as quadrivalent HPV vaccinum ) . They are non merely for protection adult females against cervical malignant neoplastic disease, but can besides be used to protect the populace against HPV related non-cervical malignant neoplastic disease. HPV 16 is the 1 that found strongly associated with oropharyngeal malignant neoplastic diseases and fundamentally these four HPV types in the vaccinums already covered most of the cervical and non-cervical malignant neoplastic disease etiologic HPV types [ a15, a40 ] .

The effectivity of the contraceptive vaccinums on cervical malignant neoplastic disease already show great promise as observed in many surveies [ a1, a2, a15 ] . In the survey of Munoz et Al. ( 2010 ) found that inoculation was up to 100 % effectual in HPV negative population in cut downing high class cervical, vulva, vaginal lesion and venereal warts. [ a2 ] But presently has few steps on the effectivity on non-cervical malignant neoplastic diseases.

It was besides suggested the HPV inoculation plan should be extremely promote to work forces and stripling, non merely covering the immature adult females, as those non-cervical HPV malignant neoplastic disease, anal, oropharyngeal and penial malignant neoplastic disease, are more likely found on work forces [ a15, a11 ] . And should be started at younger age.

The widespread HPV inoculation plan should finally cut down the load of HPV associated non-cervical malignant neoplastic disease, in add-on to the cervical malignant neoplastic diseases [ A15 ] , and ensuing in decrease of cytological abnormalcies, diagnostic and curative processs. [ a2 ]

Further suggestion to the inoculation plan as made by Gilison et Al. ( 2008 ) is to set up more effectual and widely used testing plans in non-cervical malignant neoplastic diseases [ a15 ] And the cost-effectiveness of HPV inoculation should be review as the benefit of forestalling non-cervical HPV malignant neoplastic disease are already included in the inoculation. [ a40 ]

Despite there is grounds of increasing HPV associated oropharyngeal malignant neoplastic diseases, it seem to be optimistic that HPV positive oropharyngeal tumours have better forecast and endurance rate, and hopefully can be impeded by the high coverage HPV inoculation if the effectivity is the same as in cervical malignant neoplastic disease.