The strong causal link between tobacco use and OCSCC is well established. The carcinogenic effect of tobacco is due to its combination of nitrosamines, tars, and nicotine, which induce cell damage either directly or in a metabolite form. All forms of smoked tobacco, including cigarettes and cigars, are implicated. Multivariate analyses of risk factors for cancers of the oral cavity and oropharynx demonstrated that those who smoke six or more cigarettes per day had an odds ratio (OR) of 4.1 compared with minimal smokers, rising steadily to a maximum of 5.6 for those who smoked 26–35 cigarettes per day [5]. Longer duration and increased cumulative use of cigarettes were positively correlated as well. Former smokers who quit more than 10 years prior had a 50 % reduction in cancer risk compared to current smokers, suggesting a protective effect of smoking cessation.

While smoking is the most popular form of tobacco use in the West, variations of smokeless tobacco are used extensively throughout the world. This includes ground tobacco leaves (snuff) and chewing tobacco [6]. Carcinogenic compounds are directly absorbed through the oral mucous membrane leading to localized cellular damage and inflammatory changes. The risk of OCSCC in smokeless tobacco users is similar to that in tobacco smokers [7]. It is estimated that up to 90 % of smokeless tobacco use is in South Asia. It is not a coincidence that oral cavity cancer is one of the leading causes of death in many of these countries. Alcohol consumption has been implicated as another strong risk factor. Heavy drinkers have up to an eightfold risk of OCSCC compared to minimal drinkers. The type of alcoholic beverage may play a role, as mixed drinkers are at higher risk compared to beer or whiskey drinkers [5]. A significant proportion of the population that develops oral cavity cancer consumes both tobacco and alcohol. The combined effect is multiplicative, rising to a maximum OR of 98.4 in heavy users of both. A similar synergistic effect of tobacco and alcohol has been identified in all cancers of the upper aerodigestive tract.

Betel quid is a chewed preparation of betel leaf and areca nut, which is sometimes mixed with tobacco. It is extremely popular in India, Pakistan, and other Southeast Asian countries. Betel quid chewing has been recognized as the leading cause of oral cavity cancer in this part of the world [8]. It is believed that local mucosal inflammatory changes induced by betel quid progress to oral mucous fibrosis, which has a rate of malignant transformation as high as 19 % [9]. The mixing of betel quid with tobacco may pose an even greater risk than either substance alone [7].

Ultraviolet radiation (UVR) is strongly associated with skin cancers, which include malignant melanoma, basal cell carcinoma, and SCC. The main forms of UVR present in sunlight, and which were shown to be carcinogenic in animal studies, are UV-A and UV-B. A clear trend of increased nonmelanoma skin cancer in regions that receive more UVR based on geographical location has been found [10]. The risk of developing lip cancer is strongly related to lifetime solar radiation (OR = 13.5) and decreased sunscreen use [11].

Viruses are believed to cause 15–20 % of all cancers worldwide [12]. In head and neck cancers, Epstein-Barr virus (EBV) and human papillomavirus (HPV) are the main contributors. Since the discovery of its causal role in cervical cancer, HPV has been further implicated in SCC of the oral cavity, oropharynx, and hypopharynx as well as benign papillomas throughout the upper aerodigestive tract [13]. The rising number of oropharyngeal cancer diagnoses in the USA is attributed to increasing HPV prevalence, particularly of high-risk subtypes 16 and 18 [14]. HPV contains E6/E7 oncoproteins that inactivate important host tumor suppressor genes (i.e., p53 and Rb) and modify the cell cycle to enhance proliferation. Compared to traditional patients with head and neck SCC (HNSCC), HPV-associated disease has a tendency to affect younger populations. Caucasians, males, nonsmokers, nondrinkers, and those with a higher number of sexual partners are at greater risk [15]. HPV-associated HNSCC is increasingly seen as a clinically distinct entity from HPV-negative SCC and has a unique pathogenesis, prognosis, and management paradigm. It is too early to quantitate the impact of multivalent HPV vaccines, which cover both high-risk and low-risk subtypes on HNSCC.

Advanced age is strongly correlated with a number of malignancies, including OCSCC. The incidence is sixfold greater in those over the age of 65 years compared to those under 65, and the risk continues to rise well into the 80s [2]. The rising trend of HPV-associated HNSCC in younger patients may be lowering the average age of diagnosis. As such, malignancy should remain within the differential diagnosis in any patient with suspicious exam findings and an appropriate history.

The prevalence of OCSCC is two- to fourfold higher in males compared to age-matched females. It is unclear if this remains true independent of lifestyle choices such as tobacco and alcohol use. Among whites, the rate of HPV-related cancers is rising faster in males, which may reflect trends in sexual practices [16].

Dietary habits consistently demonstrate an effect on oral cavity and oropharyngeal cancer risk. Consumption of fruits and vegetables is protective, while red meats, dairy, and potatoes confer greater risk. Dietary intake may interact with tobacco and alcohol use in relation to cancer risk [17].

Individuals with a weakened immune system lose the ability to defend against infections and environmental toxins or eradicate abnormal host cells that have undergone malignant transformation. Within this population, transplant patients who remain on long-term immunosuppressive therapy are at the highest risk of developing malignancy, of which a small percentage develops in the head and neck. Immunosuppressive agents may also directly cause oncogenic threat. No specific therapy regimen has been shown to lower cancer risk [18]. Patients who undergo hematopoietic stem cell transplantation are at higher risk for OCSCC, which may be related to a high rate of graft-versus-host disease (GVHD) [19].

Some genetic syndromes predispose to cancer. Fanconi anemia, a rare inherited defect of DNA repair, is associated primarily with leukemias but may cause OCSCC. Xeroderma pigmentosum is another autosomal recessive defect of DNA repair, especially to damage from UV radiation. Patients are prone to developing cancers of the skin, lip, tongue, and buccal mucosa. Dyskeratosis congenita, also known as Zinsser-Cole-Engman syndrome, is a rare inherited disorder of telomere regulation. This disease clinically manifests as premature aging, oral leukoplakias, skin hyperpigmentation, nail dystrophy, and bone marrow failure. These patients are highly susceptible to many malignancies including those of the oral cavity.

Accurate staging provides important prognostic information and guides treatment. The American Joint Committee on Cancer (AJCC) establishes guidelines for staging of oral cavity and lip cancers using the TNM classification based on characteristics of the primary tumor (T), regional nodal metastases (N), and distant metastases (M) (Table 3.1) [25].

Direct examination of the upper aerodigestive tract with the patient under general anesthesia permits a thorough assessment of tumor size and extension for primary tumor (T) staging. This procedure, known as triple endoscopy or panendoscopy, consists of direct laryngoscopy, bronchoscopy, and esophagoscopy. Any suspicious lesions may be biopsied at this time. A coexisting malignancy of the head and neck discovered within six months of the initial malignancy is termed a synchronous second primary tumor (SPT). Synchronous SPTs are detected in 1–7 % of patients [26, 27]. OCSCCs may be associated with higher rates of SPTs compared to other head and neck sites, most often in the esophagus or elsewhere within the oral cavity [28].

Radiological imaging supplements panendoscopy by assessing deep tissue involvement to provide information for tumor (T), lymph node (N), and distant metastasis (M) staging. Computed tomography (CT) and/or magnetic resonance imaging (MRI) studies from the skull base to the thoracic inlet are performed with intravenous contrast to provide detailed images of the oral cavity and neck. CT provides information on primary tumor extension, bone erosion, and regional nodal metastases. MRI may be preferable in patients who have dental implants, involvement of deep tongue musculature, or with suspected perineural spread. Generally, malignant tumors appear on imaging as a poorly circumscribed mass with irregular borders that enhance with contrast and may invade rather than push on adjacent structures.

Radiological signs of nodal metastasis include pathological enlargement, central necrosis, loss of normal ovoid shape, loss of a fatty hilum, and extracapsular spread. Ultrasonography rather than CT imaging of the cervical lymph nodes is more commonplace outside in North America. Imaging of the chest with plain films or CT is recommended to detect distant metastasis. Spread to the abdomen or pelvis is uncommon, and imaging is not routinely performed, although liver function tests should be obtained. Positive emission tomography-computed tomography (PET-CT) has a positive predictive value of up to 89 % and a false-positive rate of 8.3 % [29]. PET-CT is valuable for detecting unknown primary tumors and recurrent tumor, but may also be considered for patients with Stage III–IV cancer, of whom up to 30.9 % may have their treatment altered. The overall accuracy of preoperative staging is approximately 66–76 % for CT, MRI, and ultrasonography [30].

Early-stage malignancies are less than 4 cm in maximum dimension, do not invade key structures, and do not spread to lymph nodes or distant organs (Table 3.1). Determination of lymph node metastases is critical because this necessarily classifies the cancer as advanced stage. Locally advanced tumors classified as T4b are surgically unresectable due to intimate involvement of critical structures and/or difficulty of obtaining negative surgical margins. Tumors within the masticator space, pterygoid plates, skull base, nasopharynx, prevertebral fascia, or encasing the internal carotid artery are considered unresectable. On initial presentation, 31 % are diagnosed with localized disease, 47 % with regional metastasis, and 18 % with distant metastasis. The primary site remains unknown in 5 % after clinical examination and imaging [2].

The National Comprehensive Cancer Network® (NCCN) publishes clinical practice guidelines for the workup, staging, and treatment of head and neck malignancies by site [31]. Current guidelines for workup of oral cavity cancer include obtaining a thorough history, performing a complete head and neck examination with mirror or fiberoptic exam as indicated, and obtaining a tissue biopsy to confirm the diagnosis. On the initial visit, smoking cessation counseling should be provided as indicated and the patient should be screened for depression. Patients should be referred for dental evaluation and possible imaging. Other referrals to consider include nutrition, speech, and swallowing evaluation as indicated. Early initiation of swallow evaluation and therapy is encouraged to maximize postoperative swallow function and quality of life. Patients with head and neck cancer are often of advanced age and have multiple medical comorbidities. Preanesthesia evaluation may be necessary to identify perioperative risks and determine candidacy for surgery. The nutritional and health status of the patient should be optimized. The next steps in the workup for clinical staging are panendoscopy under anesthesia with directed biopsies and radiological imaging of the primary, neck, and chest as indicated. PET-CT is an option for those with Stage III–IV diseases and may upstage. Clinical staging is based on the AJCC TNM classification system (Table 3.1) [25].