Risk factor
Unique features of associated tumor
Tobacco
OSCCs retain many molecular characteristics of tobacco-induced malignancies at other sites such as lung; features that likely reflect the robust carcinogen metabolism present in human oral epithelia
Alcohol
Human papillomavirus
More sensitive to selective chemotherapeutics and radiation; multimodal treatment has achieved higher success rates for this OSCC variant
Diet
Immune status
If iatrogenic immunosuppression, tumor immunity will improve with reduction/elimination of immunosuppressant drugs
Heritable conditions
With the specific molecular mutations and deficiencies identified, targeted therapy to address these issues is now feasible
Not surprisingly, in addition to the African-American/Caucasian disparities revealed from the analysis of the SEER and BRFSS data, there are also substantial differences for OPC incidence in other ethnic groups. Nasopharyngeal cancers (NPC) are elevated in Chinese immigrants from the Szechuan province [9]. Interestingly, nasopharyngeal cancer rates from Szechuan province immigrants are intermediate between US-born Chinese and those persons who remain in the Szechuan province, findings which imply a combination of both genetic and environmental factors in the pathogenesis of this disease [9]. NPCs are also unique from standard oropharyngeal squamous cell carcinomas via the well-recognized contribution of Epstein–Barr virus and the accompanying heavy lymphocytic infiltrate [10]. As additional SEER and BRFSS data are compiled, disparities in the incidence and mortality in diverse ethnic groups are expected.
Furthermore, the previous studies did not characterize demographic changes with regard to cancer type or location (e.g., oral SCC or pharyngeal SCC – i.e., as separate entities). Stratifying the data by tumor location shows an increase in pharyngeal cancers in Caucasian males, without concomitant increases in oral cavity cancers [11]. These changing trends within this specific demographic group have been associated with an increasing prevalence of human papillomavirus infections in the oropharynx [11]. These data highlight the importance of demographic-specific risk factors, of which additional studies investigating race- and geographic-related differences in OPC incidence and mortality could provide valuable insight for the education and prevention in specific populations.
1.2 Risk Factors
Identifying and understanding the contributing factors to the development of OPC will facilitate the detection and prevention of disease. Numerous behavioral and physical factors are associated with the development of OPC and, more specifically, oral and pharyngeal squamous cell carcinoma. Age is frequently considered a risk factor for OPC, as it historically occurs in persons over the age of 40, indicating a temporal component for the accumulation of cellular damage resulting in malignant transformation potential. In spite of the contribution of age to cancer development, a paradigm shift in OPC development is actively underway with increasing incidence of OPCs in nonsmokers under the age of 60 and in nontraditional anatomical locations [11].
Cancers of the anterior oral cavity (i.e., anterior of tonsillar pillars) are most commonly associated with alcohol and tobacco use, which are routinely monitored on the state level by the Centers for Disease Control’s Office on Smoking and Health via the National Health Interview Survey (NHIS) and Behavioral Risk Factor Surveillance System (BRFSS). These surveys provide valuable data regarding use patterns, but do not establish associations between these patterns and cancer incidence. Furthermore, alcohol and tobacco use in the United States have decreased over the past several decades, but race and location-specific trends have developed [8]. These changes in the demographic affected by OPC are likely due to shifting risk behaviors and new, emerging risk factors. Specifically, the human papillomavirus serotypes 16 and 18 (i.e., high-risk oncogenic HPV16 and HPV18) are directly responsible for the increasing incidence of pharyngeal cancers in Caucasian males under the age of 60 [11, 12]. In addition to these prominent risk factors, dietary habits, sun/ultraviolet exposure (lip cancers), betel quid use (common in Eastern countries), immunosuppression, and genetic predisposition are all considered risk factors for the development of oral and pharyngeal squamous cell carcinoma.
1.2.1 Tobacco and Alcohol
The development of OPC is linked to numerous risk factors, representing a multifaceted etiology, with tobacco and alcohol consumption generally considered the primary risk factors. Over the last several decades, the US government has causally linked tobacco use to the development of cancer at eight major anatomical sites, and it is related to increased mortality in several others [13]. While other risk factors play a role in OPC etiology, historically, tobacco represents the most important, yet preventable cause of OPC.
The majority of tobacco-related carcinogens are by-products of pyrolysis, of which over 4000 chemical constituents are produced [13]. Smokeless tobacco varies widely based on the production process but favors the formation of carcinogenic tobacco-specific N-nitrosamines [14–19]. In addition, studies have shown interpatient heterogeneity with regard to an individual’s capacity to bioactivate carcinogens present in smokeless tobacco (e.g., N′-nitrosonornicotine and 4-(methylnitrosamino)-1-3-pyridyl-1-butanone) [16–20]. More specifically, the presence of phase I and II metabolic enzymes within the oral epithelium predisposes the individual to the production of carcinogens from compounds present in smokeless tobacco [20, 21]. Burnt tobacco releases an additional group of chemicals, i.e., the polycyclic aromatic hydrocarbons. The fate of these chemicals in the mouth is also contingent upon the smoker’s oral epithelial metabolic profile [22, 23]. Cytochrome p450 enzymes 1A1, 1B1, and 1A2 which are present in human oral epithelia can bioactivate benzo(a)pyrene to the ultimate carcinogen benzo(a)pyrene diol epoxide [22]. Persons with a preponderance of phase II enzymes, such as GSH-s-transferases and UGT glucuronosyl transferases that are also present in human oral epithelia, have greater inherent protective potential [24]. These enzymes convert the reactive oxygenated polycyclic aromatic hydrocarbons to more polar compounds for excretion in the urine [23, 24]. Collectively, these data demonstrate the carcinogenic potential of both smokeless and smoked tobacco products (i.e., cigarettes, pipe, and cigars), with a greater predilection toward smoked tobacco by-products and OPC. In addition, during concurrent alcohol and tobacco use, alcohol acts as a solvent for tobacco carcinogens, enhances their penetration through the surface epithelium, and enables access to critical oral epithelial stem cell populations [25, 26].
While numerous studies have established tobacco use and alcohol consumption as independent risk factors (i.e., increasing risk for OPC by up to 27-fold), combined use results in synergistic development of OPC [7]. A recent study (2004) evaluating 137 cases of OPC demonstrated a synergistic effect of tobacco and alcohol use [27]. The authors identified the multivariate odds ratios (OR) for developing OPC in heavy smokers (OR: 20.7), heavy drinkers (OR: 4.9), and combined use (OR: 48) [27]. A similar study separated risk by anatomical site, showing synergistically elevated risk of OPC development in the oral cavity (OR: 228) and/or pharynx (OR: 100) in individuals consuming more than 77 drinks per week and smoking more than 25 cigarettes per day [28]. Interestingly, increased alcohol consumption with stable tobacco use correlated with an increase of oral cavity, but not pharyngeal, cancer development [28]. Finally, a large case–control study (1114 OPC cases and 1268 controls) in the United States found similar synergism between tobacco and alcohol consumption (estimating that combined use accounts for roughly 75 % of OPC in the United States), with those individuals smoking more than 2 packs and consuming more than 4 drinks per day increasing their odds 35-fold for developing OPC [29]. Taken together, these studies demonstrate the substantial role of tobacco and alcohol use in the development of OPC.
1.2.2 Oncogenic Strains of Human Papillomavirus
The human papillomavirus, principally HPV subtypes 16 and 18, has been definitively associated with the development of OPC, particularly in the oropharynx, base of tongue, tonsillar pillars, and tonsils [12]. HPV is a common, sexually transmitted virus, with over 100 serotypes, which have infected an estimated 40 million Americans [11, 12]. While most Americans will be exposed to HPV in their lifetimes, by either oncogenic or non-oncogenic serotypes, an estimated 1 % lacks the immune response to HPV16, resulting in an increased risk of developing OPC [11, 12]. Over the past several decades, changing sexual behaviors in young adults are increasing the spread of HPV and, thus, resulting in a pronounced increase of OPC incidence in the younger demographic without prominent alcohol/tobacco histories [30, 31]. These sexual behaviors include young age at first intercourse, history of genital warts, and number of sexual partners (greater than 26 for vaginal sex and greater than 6 for oral sex – indicating that oral sex is strongly associated with a risk of HPV infection and OPC development) [31, 32]. Other prominent factors associated with HPV infection include the male sex, husbands of females with a history of cervical carcinoma, a history of sexually transmitted diseases, human immunodeficiency virus infection, and immunosuppression [31–34].
In 1985, Löning et al. identified a causal relationship between HPV and OPC [35]. Since this discovery, the link between high-risk HPV subtype 16 and OPC has been elucidated (both molecularly and epidemiologically) as a significant etiological factor, accounting for up to a 15-fold increase in the development of OPC [36–38]. Unfortunately, HPV-positive OPCs often present at an advanced stage (i.e., cervical lymph node involvement), but unlike OPCs associated with traditional risk factors, HPV-positive OPCs are seemingly more sensitive to chemoradiotherapy resulting in improved progression-free survival rates (approximately 70 % greater than non-HPV OPC survival rates) [39–42]. Interestingly, studies in patients with OPC have shown a 15-fold increase of HPV-positive cancers in nonsmokers than smokers [41]. Collectively, these results demonstrate HPV as a distinct risk factor for OPC, which is shifting toward a younger demographic.
1.2.3 Dietary
Dietary factors, and a generally healthy lifestyle, play a significant role in decreasing the risk of preventing numerous cancer types, including OPC. The scientific evidence, however, does not provide the definitive association that has been shown with tobacco/alcohol and HPV, which is likely attributed to confounding variables with regard to lifestyle that diminish dietary associations.
Several studies have investigated vitamin intake relative to OPC risk; demonstrating diets low in beta-carotene, vitamin C, vitamin D, and vitamin E increased the risk of developing OPC, while diets high in these factors imparted a protective effect by reducing risk by nearly 50 % [43–49]. Specifically, vitamin C consumption greater than 745 mg/week exhibited a protective effect in two separate studies, decreasing risk of developing OPC with odds ratios of 0.39 and 0.63 [43, 50]. Similarly, regular use of vitamin D and E supplements reduced OPC risk to 0.76 and 0.5, respectively [46, 51]. In general, studies evaluating vegetable and fruit consumption have shown a protective effect against OPC [52–54]. In contrast, a case–control study in Uruguay with 4000 participants demonstrated that diets high in red meat significantly increased the odds of developing OPC (OR: 3.65) [55]. In general, these studies demonstrate that diets high in vegetable and fruit consumption exhibit a protective effect, while the converse enhance OPC risk.
1.2.4 Immunosuppression
Immunocompromised patients are at high-risk for several forms of cancer, including OPC. This group includes those infected with human immunodeficiency virus (HIV) and those recipients of iatrogenic immunosuppression (e.g., transplant recipients).
While HIV-positive patients are at an increased risk of developing oral and pharyngeal SCCs (OR: 1.4–2.6 relative to non-HIV population in the United States), they are also historically prone to the development of Kaposi’s sarcoma and non-Hodgkin’s lymphoma within the oral cavity [56, 57]. Studies evaluating SEER data from the 1980s, coinciding with the HIV epidemic in the United States, demonstrated a 14-fold increase of oral Kaposi’s sarcoma and non-Hodgkin’s lymphoma in 20–54-year-old males in the San Francisco, California (high-density of HIV positive patients), area relative to other SEER combined sites [58]. In addition, recent studies suggest that up to 26 % of HIV-infected individuals are coinfected with the oncogenic HPV16, compared to roughly 1 % of the non-HIV population [59]. The increased incidence of HPV infection combined with the high prevalence of tobacco use in the HIV-positive population is expected to result in the increased incidence of OPC in the near future [59].
Prolonged iatrogenic immunosuppression, such as that following hematopoietic stem cell transplantation (HSCT), can be complicated by the development of chronic graft versus host disease (cGVHD) and the subsequent increased risk of developing solid tumors, including OPC. Common immunosuppression regimens include combination treatment with cyclosporine, tacrolimus, azathioprine, and corticosteroids [60]. In 1997, Curtis et al. conducted a multi-institute database study of 19,229 patients who had received HSCT and concluded that the male sex, cGVHD, and greater than 24-month treatment with azathioprine were strongly linked to an increased risk of developing OPC (OR: 11.1) [60, 61]. Specifically, a combination of cyclosporine, azathioprine, and corticosteroids resulted in a fivefold increased risk of developing OPC [60]. Collectively, immunosuppressed individuals and those with a history of HSCT or cGVHD are at an elevated risk for developing OPC and require periodic, thorough oral evaluations.
1.3 Heritable Conditions Associated with the Development of OSCC
While efforts to elucidate a “genetic fingerprint” indicative of the development of oral squamous cell carcinoma (OSCC) have not yet been successful, inroads into genetic and epigenetic contributing factors have been made. Identification that loss of heterozygosity at specific tumor suppressor loci heralds malignant transformation of premalignant oral epithelial lesions enhanced the predictability of OSCC development [62]. Furthermore, demonstration of the extensive heterogeneity of human oral cavity xenobiotic-metabolizing enzymes provides insights regarding the varied sensitivities of human oral mucosal epithelia to recognized carcinogens [20–22, 24]. The integral role of genetics in OSCC development, however, is most clearly manifest by two heritable conditions, i.e., Fanconi anemia (FA) and dyskeratosis congenita (DC). Both of these conditions are associated with a dramatically higher risk (1000-fold) and at a younger age for OSCC development [63, 64]. While the specific genetic perturbations of FA and DC are unique, there are also striking similarities between these diseases [63, 64]. Both FA and DC belong to the “inherited bone marrow failure syndromes” that include other heritable diseases such as Diamond–Blackfan anemia and severe congenital neutropenia [64]. Although all of these heritable syndromes carry an increased risk for acute myeloid leukemia, FA and DC are uniquely also susceptible to solid cancers [65, 66]. Marked chromosomal instability – attributable to faulty DNA repair (FA) and telomerase function (DC) – is a predominant common feature of FA and DC [65, 66]. Furthermore, both FA and DC patients experience immunosuppression attributable to bone marrow suppression, which enhances their tumor susceptibility [67, 68]. A final commonality is the nature of the tissues that undergo malignant transformation [63, 64]. Both FA and DC cancers arise in tissues with rapid cell turnover that mandates high replication rates such as bone marrow and throughout the gastrointestinal track (predominantly oral cavity) and skin [63, 64]. (Please see Table 1.2 for a summary of clinical and genetic features.) A recently published science article substantiates these clinical observations. This study employed a rigorous mathematical model to compare the estimated number of stem cell divisions at a tissue site with cancer risk [69]. Similar to these clinical observations in FA and DC patients, the authors concluded that tissues with higher rates of stem cell divisions experienced higher cancer incidence [69]. The longevity of stem cells – including mutated stem cells – and their potential to pass these mutations to daughter cells were an underlying premise for their observations [69].
Table 1.2
Features, genetic mutations, and associated diseases in persons with Fanconi anemia and dyskeratosis congenita
|
Clinical manifestations
|
|
|
Fanconi anemia
|
Developmental defects that can include short stature, cardiac and renal abnormalities, endocrinopathies, hyperpigmentation
Most consequential: bone marrow failure or aplastic anemia at a young age
|
|
Dyskeratosis congenita
|
“Classic triad” which consists of dystrophic nail changes, oral leukoplakia, reticulated skin pigmentation. May also note pulmonary fibrosis, hypogonadism, alopecia, cirrhosis, canities prematura
Most consequential: bone marrow failure at a young age
|
|
Patterns of inheritance
|
|
|
Fanconi anemia
|
Autosomal recessive (majority)
X-linked (1–2 %)
|
|
Dyskeratosis congenita
|
Autosomal dominant
X-linked
|
|
Diagnostic criteria
|
|
|
Fanconi anemia
|
Chromosomal instability and sensitivity to cross-linking agents. Positive results not pathognomonic as may reflect other syndromes associated with unstable DNA
Conclusive tests entail screening for mutation in the known FA genes (15 distinct “complementation groups” recognized)
|
|
Dyskeratosis congenita
|
Genetic analyses reveal mutations in gene that codes for telomerase RNA (autosomal dominant), mutations in DKC1 (X-linked)
|
|
Genetic mutations
|
|
|
Fanconi anemia
|
Genes affected: FANCA, CANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, GANCG, FANCJ (BRIP1), FANCL, FANCM/Hef
FANC proteins function in a myriad of roles in DNA repair that include formation of a nuclear complex necessary for ubiquitination and others that support endonuclease and helicase functions. FA proteins associate with other DNA repair complexes
|
|
Dyskeratosis congenita
|
Genes affected: DKC1 (X-linked, codes for the telomerase RNA-associated protein dyskerin), hTR (autosomal dominant, gene that codes for human telomerase RNA), NOLA3 (autosomal recessive, telomerase maintenance)
The associated genetic mutations cause telomerase erosion and deficiency, which ultimately result in chromatin instability
|
|
Cancer risk
|
|
|
Fanconi anemia
|
Acute myeloid leukemia (may be preceded by myelodysplastic syndrome)
Head and neck squamous cell carcinoma (HNSCC)
Esophageal carcinomas
Genitourinary cancers in women
|
|
Dyskeratosis congenita
|
Acute myeloid leukemia
Head and neck squamous cell carcinoma. May experience multiple primary tumors. If multiple tumors, HNSCC almost always present
Skin and gastrointestinal carcinomas, Hodgkin’s and non-Hodgkin’s lymphoma
|
1.3.1 Fanconi Anemia
FA is a rare (approximately 1 in 200,000–400,000 live births) heritable condition that exhibits both autosomal recessive (majority ~98 %) and X-linked patterns of inheritance [70, 71]. Sophisticated genetic analyses have revealed up to 15 unique “complementation groups” or genetic subtypes in FA: FA-A, FA-B, FA-C, FA-D1, FA-D2, FA-E, FA-F, FA-G, FA-I, FA-J, FA-L, FA-M, FA-N, FA-O, and FA-P [72–74]. In 2002 Howlett et al. discovered that FANCD1 is BRCA2 and determined that mono-allelic mutations resulted in breast cancer whereas bi-allelic mutations were associated with FA [75]. Despite the diversity of genetic subtypes, chromosomal instability is the hallmark feature of all FA complementation groups. In health, FA proteins form multi-protein nuclear complexes that collectively form the FA pathway [76]. Healthy FA proteins perform a variety of roles in DNA repair including homologous recombination and contribute to ubiquitin ligase function [63]. Of note, FA proteins also interact in a cooperative fashion with other DNA repair pathways [63]. In addition, a role for FA proteins in monitoring oxidative stress and initiating protective responses has been identified [77]. Provided the oral cavity’s high levels of exposure to xenobiotics, inflammation, and associated reactive species, the need for timely cytoprotective responses to reduce reactive oxygen species-mediated genetic damage is readily apparent.
While development of aplastic anemia between the ages of 5 and 10 is the most common FA presentation, FA-attributable developmental anomalies such as small stature could prompt an earlier diagnosis [63]. The “chromosomal breakage test,” which entails challenge of suspected FA patients’ peripheral blood lymphocytes with DNA clastogenic agents, remains the most common test to evaluate for FA [78]. Formerly, FA chromosomal fragility was formerly attributed exclusively to FA cells’ loss of “caretaking genes” needed for DNA repair. A retrospective analysis, however, that questioned which evolutionary pressures might mandate protection from completely man-made reagents, has revised this assessment [79]. The evolved concept combines reduced DNA repair capacity with susceptibility to the redox stress that arises from metabolism of DNA interstrand cross-linking agents [79]. These authors have concluded that a prooxidant state exists in at least three FA subtypes, A, C, and G [79]. Other investigators have confirmed mitochondrial dysfunction and impaired ROS degradation [80]. Provided the oncogenic potential of reactive species-mediated nuclear and mitochondrial and DNA damage and inappropriately sustained intracellular signaling, the prooxidant cancer-permissive phenotype is understandable [81].
As a result of early diagnosis, successes of allogenic bone marrow transplantations, and improvements in graft versus host management, many FA patients now live into adulthood [82]. This enhanced life span – combined with the inherent cancer susceptibility – has redirected the focus to early detection and management of solid tumors [82]. While only 6 % of all worldwide malignancies are head and neck squamous cell carcinomas (HNSCC), HNSCCs represent the predominant solid cancers found in FA patients [83]. Approximately 50 % of nontransplanted FA patients will develop HNSCC by age 45 while 100 % of FA transplant recipients will develop HNSCC by 45 [84]. Furthermore while the majority of FA head and neck squamous cell carcinomas occur in the oral cavity, about 33 % develop in non-visibly detectable sites including oropharynx, nasopharynx, and larynx, which create challenges for early detection [85].
The etiology of FA OSCCs is distinct from the general population. While tobacco and alcohol use are the primary initiators of OSCC, FA patients’ tumors most frequently arise in very young patients with negative social histories [86]. Oncogenic human papillomavirus (HPV) subtypes have more recent been implicated in some FA OSCCs [83]. Oncogenic HPV infection initiates the FA pathway in normal epithelial cells while genomic instability becomes accentuated in FA keratinocytes [83]. Furthermore, the absence of an intact FA pathway increases the susceptibility of FA cells to oncogenic HPV infections [83]. Notably, conflicting data regarding the contribution of oncogenic HPV in FA OSCCs has arisen from the European (HPV absence) and US (HPV presence) FA patient cohorts [83, 85]. Evaluations of US patients’ FA OSCC tumors demonstrated the presence of oncogenic HPV in 84 % (21 of 25 tumors) evaluated [85]. In contrast European FA OSCCs did not reveal any high-risk HPV subtypes [24]. As both studies employed comparable HPV detection methodology, these clinical differences were thought to reflect geographic variations in the prevalence of HPV infections [83, 85]. The European studies also assessed surrogate HPV markers, i.e., elevation of p16, p53 silencing as a result of HPV E6 protein, and evaluated p53 mutations [83]. Interestingly, the data revealed that non-HPV-containing FA OSCC tumors demonstrated comparable TP53 allelic losses as seen in sporadic OSCCs [83]. Current guidelines for FA patients recommend close clinical follow-up, with oral cavity evaluations to be conducted by a health professional every 3 months beginning at 10 years of age [83].
1.3.2 Dyskeratosis Congenita
As previously mentioned dyskeratosis congenita (DC) and FA are unique among the bone marrow failure syndromes by virtue of their increased susceptibility to solid tumors. Like FA, DC is also heritable by an X-linked recessive pattern, an autosomal recessive pattern, and unlike FA also an autosomal dominant pattern of inheritance [64]. In addition, sporadic cases, presumed to reflect dominant de novo gene mutations, are also fairly frequent [66]. The incidence of solid cancer susceptibility in DC patients is only surpassed by persons with FA [64]. Comparable to FA, the majority of DC patients with multiple tumors develop at least one HNSCC [64]. The actuarial cancer risk for persons with DC is ~40 % by age 50 and over 60 % by age 68 [64]. DC, like FA, is a rare condition, with a prevalence of approximately 1 in 1,000,000 births [66]. While bone marrow failure may be the presenting manifestation, early in life persons with DC often develop “dyskeratotic” features that entail dystrophic nails, reticular skin pigmentation, and precancerous oral epithelial lesions [66, 87]. A diagnosis of DC can be made of the basis of two of three of the “diagnostic triad” [66]. In addition, clinical presentations of DC can vary in accordance with the extent of expression, a feature that is most notable in patients with the autosomal dominant form [64].
The underlying deficit in DC patients’ cells is defective telomerase activity [66]. The specific proteins affected, however, are unique depending upon the inheritance patterns [66]. The DKC1 gene, which is responsible for production of dyskerin, is mutated in persons with X-linked DC [64]. Major functions of dyskerin include RNA processing, conversion of rRNA uridine residues to pseudouridine, and maintenance of the telomerase enzyme complex through RNA binding [64–66]. Nonfunctional dyskerin has appreciable consequences, most notably faulty telomerase function and premature telomere shortening [64
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