CHAPTER 2: LITERATURE REVIEW
2.13 Risk factors of head and neck cancer
2.13.2 Biological Factors
Cancer-causing viruses are gaining much interest among investigators since they represent an emerging area of research in the field of oncology (Javier and Butel, 2008). Human immunodeficiency virus (HIV), human papillomavirus (HPV), herpes simplex virus (HSV) and Epstein Barr virus (EBV) are recognized in the development of certain types of cancer including that of the head and neck region (Javier and Butel, 2008; Merten et al., 2016). These viruses act by altering the structure of DNA and cause proliferative changes at the chromosomal level (Javier and Butel, 2008).
2.13.2.1 Human immunodeficiency virus
With the effectiveness of antiretroviral therapy, the life expectancy of HIV-infected individuals has increased (Beachler and D’Souza, 2013). HIV increases the susceptibility of cancer- causing viruses like HPV, EBV and HSV (McLemore et al., 2010). This implies that malignancies associated with viruses are on the increase (Beachler and D’Souza, 2013). South Africa carries the highest incidence (7.1 million) of HIV infected individuals globally (Hoek, 2012). Kaposi sarcoma and non-Hodgkin lymphoma of the head and neck are the most common malignancies in HIV positive patients followed by squamous cell carcinoma of the head and neck region (McLemore et al., 2010; Hoek, 2012). Both Kaposi sarcoma and non-Hodgkin lymphoma are AIDS-defining malignancies while squamous cell and basal cell carcinomas of the head and neck and Hodgkin disease are not directly associated with HIV (Hoek, 2012).
HIV infections also increase the risk of oral cavity, laryngeal and non-HPV-related cancers (Beachler and D’Souza, 2013). Oral manifestations of HIV infections are xerostomia, aphtous ulcres, gingival and periodontal diseases (Hoek, 2012). Other head and neck manifestations include nasal obstruction, neck mass and parotid gland disease (Hoek, 2012).
50 2.13.2.2 Human papilloma virus
Human papilloma virus represents a serious concern to public health despite on-going development in vaccines and treatment approaches (Christensen, 2016). HPV exists in over one hundred and fifty fully sequenced genetically different types with fifteen among them being carcinogenic and includes HPV-16 and HPV-18 which have been mostly incriminated in malignancy of the head and neck, mainly that of the oropharynx (Chen et al., 2008; Boscolo- Rizzo et al., 2013; Christensen, 2016; Hernandez et al., 2017). HPV type-16 is present in 80%
of oropharyngeal cancers (Beachler and D’Souza, 2013). HPV has also been widely documented as an etiologic factor for cervical cancer (Cao et al., 2011). HIV positive individuals are at increased risk of developing HPV infections of the oral cavity and HPV- associated head and neck malignancies (Beachler and D’Souza, 2013). The risk of developing cancer of the tonsils in HIV-infected individuals is approximately two to four times more than the non HIV-infected population (Beachler and D’Souza, 2013). Its association to the development of cancer of the oropharynx, especially in the base of the tongue and the tonsils is expected to exceed the number of new cervical cancer cases by 2020 (Ha and Califano, 2004;
Mannarini et al., 2009; Gross et al., 2013; Marur and Forastiere, 2016; Dwojak and Bhattacharyya, 2017). Globally, its prevalence in head and neck cancer is 16% to 30%
(McLemore et al., 2010). It is an independent risk factor for cancer of the oral cavity and hence is not linked to any cancer-causing oral habits like betel nut chewing, tobacco smoking and alcohol consumption (Chen et al., 2008; Galbiatti et al., 2013).
HPV-associated oropharyngeal cancers have been shown to be have a wide geographical distribution worldwide with 56% in North America, followed by Japan with 52%, Australia with 45% and Europe with 39% (Marur and Forastiere, 2016). The incidence of oral squamous cell carcinoma in South Africa has been on the increase for the past 22 years and 90% of the cases were associated with type-16 human papilloma virus (Davidson et al., 2014).
2.13.2.2.1 Mechanism of Carcinogenicity of HPV
HPV, being a double stranded sexually transmitted DNA virus, is reported to be a high risk factor for malignancy in the mucosa of the head and neck region (Marur and Forastiere, 2016;
Wang et al., 2017). Infection with HPV is temporary, controlled and detected by the host immunity and clears within a short time, hence does not always progress to cancerous lesions
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(Christensen, 2016; Maura et al., 2017). However, persistent infection ensues when there is reduced or absence of immunity of the affected person to clear the virus resulting therefore in the latter being united into the host DNA to exert its oncogenic effects by altering the function of different tumour suppressor proteins namely p53 and retinoblastoma gene (Marur and Forastiere, 2016) . The oncoproteins which come into play in this process are E6 and E7 where E6 causes degradation of p53 while E7 integrates the retinoblastoma gene to disrupt the cell cycle mechanism by causing increased expression of p16 to give rise to malignant formation after accumulation of prolonged genetic damage (Marur and Forastiere, 2016; Wang et al., 2017). HPV-associated oropharyngeal cancers are more responsive to chemoradiation than alcohol or tobacco associated malignancies (Marur and Forastiere, 2016).
2.13.2.3 Herpes simplex and Epstein-Barr viruses
Herpes simplex virus (HSV), also known as human herpes virus (HHV), is associated with several malignancies, including that of the head and neck (McLemore et al., 2010). HSV-1 was demonstrated to have an oncogenic relationship to squamous cell carcinoma of the oral cavity (Ha and Califano, 2004). Kaposi Sarcoma is mainly caused by HSV-8 (McLemore et al., 2010).
HSV-2 antibodies are predominantly incriminated in cervical cancer (Kreimer et al., 2005).
Epstein Barr virus, human papilloma virus and other oncogenic viruses, when co-existed, have demonstrated to playing an important role in the transformation of healthy epithelial cells to cancerous ones (Al Moustafa et al., 2009). EBV is associated with cancer of the nasopharynx (Al Moustafa et al., 2009). Epstein Barr virus have also shown positivity in lymphoma of the parotid gland (Plummer and Masterson, 1971).
2.13.2.4 Syphilis
Syphilis is a sexually transmitted disease occurring as a result of unprotected sex with an infected individual, blood tranfusions, infected sharp object injury (Strieder et al., 2015). It is characterised by a chancre (painless ulceration) on the lips, but the soft palate and tongue may also be affected depending on the disease evolution (Ficarra and Carlos, 2009; Strieder et al., 2015). The syphilitic lesion on the lip may give rise to squamous cell carcinoma of the oral cavity (Strieder et al., 2015). Previously, arsenic compounds were used to treat syphillis and this was contributing to tongue cancer since they are carcinogenic (Ficarra and Carlos, 2009).
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Many cases of malignancies are preceded by pre-existing syphilitic glossitis and leukoplakia (Al Moustafa et al., 2009).