A link between poor oral hygiene and HNSCC has been suggested for over two decades [35–46] but the underlying mechanism of this association was not clear. Studies from our group have suggested that chronic periodontitis, an outcome of poor oral hygiene, is associated with oral premalignant lesions  and HNSCC [48, 49]. In a secondary analysis of the Third National Health and Nutrition Examination Survey (NHANES III), a large nationwide cross-sectional study, including 13,798 men and women of age 20 and older, a history of periodontitis, measured by clinical attachment loss (CAL), was significantly associated with the prevalence of oral premalignant lesions (OR = 1.55, 95% CI = 1.06–2.27) after adjusting for age, gender, race/ethnicity, education, tobacco, alcohol, and occupational hazard . Periodontitis was not associated with the presence of any oral soft tissue lesion (OR = 1.09, 95% CI = 0.91–1.31) (Table 2) .
Table 2: Risk of oral premalignant lesions from periodontitis.In a recent hospital-based case-control study with histologically confirmed 266 primary incident HNSCC cases and 207 controls in Upstate New York, ABL was significantly higher in cases compared to controls (4.04 mm versus 2.44 mm, ). After adjustment for age, gender, race/ethnicity, marital status, smoking status, alcohol use, and missing teeth, each millimeter of ABL was associated with >4-fold increased odds of HNSCC (OR = 4.36, 95% CI = 3.16–6.01). The strength of the association was greatest in the oral cavity (OR = 4.52, 95% CI = 3.03–6.75), followed by oropharynx (OR = 3.64, 95% CI = 2.54–5.22) and larynx (OR = 2.72, 95% CI = 1.78–4.16) (Table 3). Furthermore, patients with periodontitis were more likely than those without periodontitis to have poorly differentiated oral cavity SCC (32.8% versus 11.5%, ) .
The potential association between chronic inflammation and HNSCC is further supported by two recent case control studies suggesting a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAID) against HNSCC [50, 51]. In a hospital-based case control study among 529 patients with HNSCC and 529 control subjects matched by age, sex, and smoking status, Aspirin use was associated with a 25% reduction in the risk of HNSCC (OR = 0.75; 95% CI = 0.58–0.96). Risk reduction was observed across all primary tumor sites, with cancers of the oral cavity and oropharynx exhibiting greater risk reduction . In another more recent hospital-based case-control study among 71 incident HNSCC cases and 71 healthy controls, daily NSAID use was associated with 86% reduction in HNSCC risk (OR = 0.14; 95% CI = 0.04–0.54) after adjusting for educational level and marital status .
The biological mechanism of the association between chronic inflammation and cancer has been described extensively but is also evolving continuously since both inflammation and cancer are complex processes under the control of many driving forces [15–18]. Bacteria and their products, including endotoxins, enzymes, and metabolic by-products, may directly induce genetic and epigenetic changes in surrounding epithelial cells [52–54]. They also increase the production of carcinogenic acetaldehydes [55–57] and nitrosamines [58, 59]. However, the bulk of the available evidence supports an indirect association through stimulation of inflammation. Host cells, including neutrophils, macrophages, monocytes, lymphocytes, fibroblasts, and epithelial cells, respond to bacteria by generating (1) cytokines, chemokines, prostaglandins, growth factors, and other signals that provide an environment for cell survival, proliferation, migration, angiogenesis, and inhibition of apoptosis . This environment helps epithelial cells to accumulate mutations, and drives these mutant epithelial cells to proliferate and migrate and gives them a growth advantage; (2) reactive oxygen species (hydrogen peroxide and oxy radicals), reactive nitrogen species (nitric oxides), reactive lipids and metabolites (malondialdehyde, 4-hydroxy-2-nonenal), and matrix metalloproteinases (MMPs) which can act as endogenous mutagens. Numerous in vivo and in vitro studies have confirmed the associations of several genes and proteins involved in different stages of inflammation with carcinogenesis [61–71]. In addition to its independent association with HNSCC, chronic inflammation may also act synergistically with other carcinogens to increase the risk of HNSCC. For example, breaks in the mucosal barrier due to chronic inflammation may lead to enhanced penetration of other carcinogens such as tobacco, alcohol, and dietary metabolites
3. Chronic Inflammation and Oral HPV Infection
The steady increase in the incidence of oropharyngeal cancers over the last four decades has been mainly attributed to oral HPV infection which has been accepted as an etiological factor for a subset of HNSCC [10–14]. HPV is a commonly transmitted virus but the majority of the infections are cleared rapidly by the immune system. Rather than its mere presence at one time point, persistence of the virus seems to be the critical factor for the development of HPV-related diseases [74, 75]. Therefore, targeting factors associated not only with the acquisition but also with the persistence of oral HPV infection will contribute to both prevention and treatment.
HPV is a small DNA virus with a specific tropism for squamous epithelia. More than 120 different HPV types have been isolated to date. Low-risk HPVs, including HPV-6 and HPV-11, induce benign hyperproliferations of the epithelium such as papillomas or warts which rarely progress to cancer . High-risk oncogenic types such as HPV-16 and HPV-18 are associated with squamous cell carcinoma. HPV-16 and HPV-18 are capable of transforming epithelial cells. This transforming potential is largely a result of the function of two viral oncoproteins, E6 and E7, which inactivate two tumor suppressor proteins, p53 and pRb, respectively. Expression of E6 and E7 results in cellular proliferation, loss of cell cycle regulation, impaired cellular differentiation, increased frequency of mutations, and chromosomal instability [76, 77].
Population-based studies estimate that the prevalence of HPV DNA in normal oral mucosa is 5–10% [14, 76]. In contrast with cervical cancer, in which HPV is present 100% of the time, HPV is present at a smaller and variable percentage in HNSCC, depending on the subsite and the geographic region studied. In a review of 60 studies, the prevalence of HPV DNA was 23.5% in oral cavity SCC, 35.6% in oropharyngeal SCC, and 24.0% in laryngeal SCC . HPV-16 accounted for a larger majority of HPV-positive oropharyngeal SCC (86.7%) compared with HPV-positive oral cavity SCC (68.2%) and HPV-positive laryngeal SCC (69.2%). Conversely, HPV-18 was rare in HPV-positive oropharyngeal SCC (2.8%) compared with HPV-positive oral cavity SCC (34.1%) and HPV-positive laryngeal SCC (17.0%). Aside from HPV-16 and HPV-18, other oncogenic HPV DNAs were rarely detected in HNSCC . In a multi-national study conducted by the International Agency for Research on Cancer (IARC), only 18% of oropharyngeal tumors were HPV-positive . In the majority of recent studies, >50% of oropharyngeal SCC contained the HPV DNA [10–14]. Probability of HPV DNA being detected in the oral mucosa increases with increasing degree of dysplasia. Overall, HPV DNA is 2- to 3-times more likely to be detected in premalignant lesions and about 5-times more likely to be detected in HNSCC compared to normal oral mucosa .
HPV-positive HNSCCs have a unique risk factor profile. These tumors are more common in younger patients, have a male predominance, are often staged higher, yet have a survival advantage. These patients are less likely to have used tobacco and alcohol excessively . Pathologically, they are more likely to be basaloid type (poorly differentiated) and lack keratinization. The p16 protein, also known as cyclin-dependent kinase 4 (CDK4) inhibitor, is upregulated in HPV-positive HNSCC, and may serve as a surrogate marker for HPV transcriptional activity. Molecularly, these tumors expresses oncoproteins E6 and E7 demonstrate less chromosomal disruption than HPV-negative HNSCC. Tumor suppressor genes p53 and pRb are usually intact, but the expressed proteins are inactivated by the viral oncoproteins E6 and E7, respectively. In contrast, HPV-negative HNSCC, which is usually initiated by smoking and alcohol, shows considerable chromosomal aberration, including mutation of the p53 gene in 50% of cases [80–82