The oral cavity refers to a collection of subsites of the upper aerodigestive tract that play a key role in mastication, articulation, swallowing and breathing(1). The oral cavity consists of the oral cavity proper (the space between the upper and lower dental arcades) and the oral vestibule (the space between the lips, cheeks, teeth and gums). The oral cavity extends from the skin vermillion border of the lips to the junction of the hard and soft palate superiorly, and to the circumvallate papillae on the tongue inferiorly(2). The circumvallate papillae also define the border between the oral tongue (anterior two-thirds of the tongue) and the base of tongue (posterior one-third)(1). The major subsites of the oral cavity are the lips, buccal mucosa, maxillary and mandibular alveolar ridges, floor of mouth (FOM), oral tongue, retromolar trigone and hard palate (Fig. 1)(1, 3). Apart from the oral cavity, the other subsites of head and neck cancer include the nasopharynx, oropharynx, hypopharynx and larynx (Fig. 2)(4).
The lips (labium superioris (upper) and labium inferioris (lower)) have both cutaneous and mucosal portions. The upper and lower lips are continuous at the angles of the mouth (oral commissures) and are separated from the cheeks by the nasolabial grooves, and from the chin by the labiomental groove(5). The orbicularis oris muscle complex underlies the lips and is composed of four interlacing muscle constituents, giving the appearance of a circular muscle (sphincter)(5). The true ‘oral cavity’ portion of the lips is that which comes in contact with the opposing lip. This region of the lips is the anterior-most portion of the oral vestibule and serves a critical role in both oral intake, as well as speech articulation(1). The major blood supply to the lips is derived from the labial artery, which is a branch of the facial artery, off of the external carotid artery(5). Motor innervation is supplied by the facial nerve (cranial nerve (CN) VII) and sensory innervation is supplied by the maxillary nerve (CN V2) (upper lip) and the mental nerve (a branch of the mandibular nerve, CN V3) (lower lip)(5). The lips are the most common subsite for oral cavity cancers (OCC)(2).
The remainder of the oral vestibule—apart from the region formed by the lips—is made up by the buccal mucosa. The buccal mucosa lines the inner lips and cheeks (Fig. 1)(1). The buccal mucosa is supplied by the facial artery and receives sensory innervation from the buccal nerve (a branch of the mandibular nerve (CN V3))(5). Integrity of the buccal mucosa is important for maintaining oral competence and managing secretions(1).
The alveolar ridges are extensions of the maxilla (upper jaw) and mandible (lower jaw) that hold the sockets for teeth (Fig. 1)(5). The alveolar ridges include the mucosa of the gums on both the buccal (outer) and lingual (inner) surfaces of the jaw(1). Neoplasms of the alveolar ridges tend to have a high rate of bony involvement which can complicate their management(2).
The retromolar trigone is a triangular-shaped mucosal region located posterior to the last lower molar, overlying the mandible (Fig. 1)(1, 2). The lower gum serves as its base. Pain in this site can be referred to the ipsilateral ear due to sensory innervation of the retromolar trigone by branches of the glossopharyngeal nerve (CN IX), which also provides sensory innervation to the middle ear(5). Ipsilateral otalgia, in combination with other signs or symptoms, may therefore signal retromolar trigone OCC(1). Neoplasms originating in the retromolar trigone often present in an advanced stage and tend to involve the mandible early in their course(1, 2).
The floor of mouth (FOM) extends from the alveolar ridge of the mandible up to the undersurface of the tongue (ventral tongue) and along each side under the tongue to the anterior tonsillar pillar(1). The FOM is divided by the lingual frenulum below the tongue (Fig. 1)(5). Mucosa lining the FOM enables significant tongue flexibility and the movements required for speech articulation and swallowing(1). The sublingual salivary glands also lie below the mucous membrane in this region(5). The FOM is innervated by the lingual nerve (a branch of CN V3) and is a dependent site for both alcohol and chewing tobacco (2, 5).
The ‘oral tongue’ extends anterior to the circumvallate papillae and constitutes approximately two-thirds of the tongue(1). The remainder of the tongue (posterior one-third) is considered the ‘base of tongue’ and is classified as part of the oropharynx (Fig. 3). The oral tongue consists of four anatomic regions: the apex, lateral borders, dorsal tongue (top) and ventral tongue (undersurface)(1). The oral tongue is mobile and muscular(2, 5). It functions to ingest and prepare food for digestion via chewing, bolus formation, and release of saliva. It receives blood supply from the lingual artery, a division of the external carotid artery(5). The hypoglossal nerve (CN XII) provides motor innervation to the entire tongue (with the exception of the palatoglossus muscle, which is innervated by the vagus nerve), while the lingual nerve (a branch of CN V3) supplies sensation and the chorda tympani (a branch of the facial nerve, CN VII) supplies taste to the oral tongue(3). The sensory and taste innervation of the base of tongue is supplied by the glossopharyngeal nerve (CN IX).
Lymphatic drainage of the oral cavity can be divided into drainage to superficial regional lymph nodes and drainage to deep lymph nodes. In terms of superficial lymph nodes, the submandibular nodes are located on the lateral wall of the submandibular gland and drain the upper and lower lips, upper and lower teeth, oral tongue, FOM, oral vestibule, gums and maxillary sinus(5). The submental nodes sit below the chin and drain the tip of the tongue, the anterior-most FOM, the central lower lip and the skin of the chin(5). The superficial cervical nodes are located in the neck along the external jugular vein and drain the skin over the angle of the jaw(5).
In terms of deep lymph nodes, the jugulodigastric node sits posterioinferiorly to the jaw and drains the tongue and tonsils, while the jugulo-omohyoid node drains the tongue(5). The identification of anomalies in the lymph nodes of the head and neck can greatly help oncologists identify potential tumours at early stages, which increase the likelihood of a better prognosis.
In addition to the superficial and deep lymph nodes described, the lymph nodes in the neck should be examined for all patients presenting with head and neck malignancies(2). The neck can be divided into six lymph node levels (Fig. 4)(2). Level I is divided into IA (submental) and IB (submandibular) regions(2). The submental nodes are defined by a triangular area from the mandible to the hyoid bone between the bellies of the digastric muscles. The submandibular nodes are located in the area bounded by the submandibular gland, mandible, and digastric muscles. Levels II, III, and IV are known as the upper, middle, and lower jugular nodes, respectively. These levels are located deep to the sternocleidomastoid muscle. Level II extends from the inferior aspect of transverse process of C1 to the hyoid. Level III extends from the hyoid to the caudal edge of the cricoid cartilage. Level IV extends from the caudal edge of the cricoid cartilage to 2cm above the sternoclavicular joint. Level V includes the area referred to as the posterior triangle which is the area anterior to the trapezius and posterior to the sternocleidomastoid extending superiorly from the hyoid to the transverse cervical vessels inferiorly. Level VI is the anterior neck compartment extending from the caudal edge of the thyroid cartilage to the manubrium.
These anatomic levels are associated with drainage from various primary sites(2). For instance, the oral cavity is mainly drained by levels IA and IB. Drainage can continue from level I into levels II, III, and IV. The submental nodes drain the skin of the chin, lower lip, tip of tongue, and anterior FOM. The submandibular nodes drain the alveolar ridges, buccal mucosa, lips, and tongue. Primary drainage to level II can occur with lesions arising from the hard palate or tongue. Therefore, clinical examination of the lower lip, chin, anterior FOM and anterior third of the tongue should be performed for lymphadenopathy of submental nodes. Further examination of the alveolar ridge, lips, FOM, tongue and facial skin should be performed for lymphadenopathy in the submandibular region(5). A summary of cervical lymph node locations and drainage patterns is included in Table 1.
Of note, OCCs located along the midline (for instance midline of the lip, FOM or tongue) are at increased risk for metastasizing to lymph nodes in the contralateral neck; in these cases, both necks may require treatment(1).
The oral mucosa is the mucous membrane lining the oral cavity. It comprises stratified squamous epithelium ("oral epithelium") and an underlying connective tissue (lamina propria). Over 90% of malignant lesions in the oral cavity are squamous cell carcinomas(2, 3). Non-mucosal malignancies make up the remaining <10% of OCCs(1). Non-mucosal malignancies include basal cell carcinomas (often seen on the upper lip, due to sun exposure), minor salivary gland cancers (e.g. adenoid cystic carcinoma, mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma), Kaposi sarcoma, primary mucosal melanoma, lymphomas and sarcomas(1). While minor salivary gland cancers are considered uncommon, mucosal melanomas, lymphomas and sarcomas are generally considered rare oral cavity lesions.
The majority of head and neck cancers occur in the oral cavity, as compared to other sites (e.g. nasopharynx, oropharynx, hypopharynx, larynx)(2, 4). Worldwide, the annual incidence of OCC is around 358,000 cases(4). The mean age at the time of diagnosis is 50–60 years and men are more often affected than women (~2:1)(1). The incidence of tobacco-related head and neck cancers—including OCCs—has decreased in recent years due to increased awareness around the harmful effects of smoking and second-hand smoke(1). However, sun exposure and use of carcinogenic substances such as chewing tobacco and betel quid contribute to the ongoing prevalence of these cancers(1, 6).
The primary risk factors for the development of OCC are tobacco and alcohol use(1). These agents account for up to approximately 75% of cases(1). Further, chronic exposure to tobacco and alcohol together has been found to be synergistic and increases the risk of OCC exponentially(1). Additional risk factors for the development of OCC include sun exposure, chewing tobacco and betel nut chew (which primarily affect dependent areas, such as the gums, buccal mucosa and lips), previous radiation exposure, past cancer history, family history of head and neck cancer, poor oral hygiene and chronic oral inflammation(1, 2, 7-9). A summary of modifiable and non-modifiable risk factors for the development of oral cavity cancer is shown in Table 2.
Several lesions seen in the oral cavity have been found to have premalignant potential(1). Leukoplakia (white, well-defined keratotic patches) and erythroplakia (red mucosal plaques with ill-defined borders) are both considered premalignant lesions in the oral cavity(2). Leukoplakia can result from chronic irritation of the oral mucosa and has been documented to convert into invasive carcinoma in up to 18% of cases(10). Erythroplakia does not result from mucosal irritation but has a higher (~25%) risk of converting to a malignant lesion(2). Lichen planus (lacey-looking lines along the buccal mucosa) has also been found to have premalignant potential for OCC(1).
In line with the known risk factors for OCC, avoidance of exposures (tobacco, alcohol, betel quid, sun) is the primary means for preventing OCC(1). Additionally, maintaining good oral hygiene and seeking routine dental care may help minimize the risk of cancer development and/or allow suspicious lesions or masses to be identified early(1). Finally, while human papillomavirus (HPV) infection is not a major driving cause of OCC, it is worth mentioning that HPV infection is a significant cause of oropharyngeal cancers (e.g. base of tongue, tonsils, soft palate). As such, HPV vaccination is recommended for boys and girls starting at age 11–12 as a preventative measure against head and neck cancer, as well as cervical cancer(1).
Presentation of OCC will vary according to the specific location and extent of the tumour(1). Most often, individuals with OCC will present with a painful oral lesion or mass. They may also experience bleeding from the oral cavity, loose teeth or ill-fitting dentures(1). For some patients, an asymptomatic lesion (for instance, leukoplakia or erythroplakia) may be identified during a routine dental or medical exam, or by the patient themself. A non-healing ulcer or wound noted after a minor dental trauma may also point to an OCC(1).
Other signs and symptoms of OCC include dysphagia, odynophagia, trismus, halitosis, numbness of the lower teeth, asymmetry on tongue extension and/or fixation of the tongue(1). FOM cancers may obstruct salivary outflow from the submandibular ducts, leading to tenderness and/or enlargement of the submandibular glands. A strong odor from the oral cavity can also point to OCC, as ulcerating cancerous lesions may be colonized by bacteria, producing a foul smell(1). Symptoms suggestive of hypoglossal nerve (CN XII) involvement include tongue deviation towards the side of the affected nerve and tongue fasciculations. Referred otalgia can occur due to irritation of the ipsilateral auriculotemporal nerve (branch of CN V3). A palpable neck mass may indicate regional lymph node spread(1). A new cough, hemoptysis, or weight loss can suggest metastatic disease.
Initial evaluation of a patient with suspected OCC requires a thorough history and physical exam, imaging studies to evaluate metastasis and a tissue biopsy.
A detailed timeline of symptoms should be sought from patients, including information regarding the onset, duration, severity and consistency of symptoms. Specific inquiry should be made into whether or not the patient experiences pain, as this has been found to be an important factor in distinguishing benign versus malignant lesions(1). Patients should be asked about dental issues, including changes in their ability to close their jaw, changes in denture fit and the presence of loose teeth. Social factors, including use of tobacco and alcohol should be explored and quantified (e.g. pack years for smoking) as these are the primary risk factors for OCC. A history of sun exposure (recreational or occupational) should be taken and risk factors for exposure to HPV (e.g. number of sexual partners, age of first sexual encounter, participation in oral sex) should be noted (11, 12).
Patients should also be asked about past cancer history, as well as family history of cancer, particularly in first-degree relatives. If the patient has previously had a head and neck cancer, past radiation treatments are important to document. Other important information includes general medical and surgical history, family medical history and other social and occupational history. A review of systems may be used to garner a thorough understanding of the patient’s overall health. Finally, constitutional symptoms (e.g. weight loss, fevers, hyperhidrosis) should be reviewed and documented.
The physical exam for a patient with suspected OCC should begin with a complete head and neck evaluation. Careful inspection of the oral cavity should be performed bimanually, with the assistance of a headlight(1). A description of the appearance, size and location of the lesion should be documented, as well as whether or not it crosses the midline or appears to involve other surrounding structures. Palpation is essential to assess the depth of the lesion as well as the involvement of deeper muscles or bone. Fiberoptic pharyngolaryngoscopy should be performed to evaluate oropharyngeal structures and rule out synchronous lesions or compromises to the patient’s airway(2). A thorough lymph node exam should also be performed, including palpation of all levels of the neck. The presence of enlarged cervical lymph nodes in the setting of primary OCC carries important prognostic and therapeutic implications(1). Any neck masses identified should be assessed for their size, location, consistency, tenderness and mobility(1).
A biopsy specimen should be obtained at the time of the patient’s initial visit(1). Most oral cavity lesions are accessible for biopsy in the clinic under local anaesthesia. Typically an incisional biopsy is done, in which a small piece of tissue is cut from the lesion. All biopsy samples are reviewed by pathologists who will confirm the presence and type of cancer.
Imaging is ordered to evaluate the primary tumour, as well as the cervical lymph nodes. Computed tomography (CT) with contrast and magnetic resonance imaging (MRI) are both used to examine OCCs and offer different advantages. CT is most often used, as it can be done quickly and at a lower cost. CT is able to assess depth of invasion and the involvement of adjacent structures(1). MRI can be helpful in determining base of tongue, deep musculature, or nerve involvement. Workup for metastases includes chest imaging (via x-ray or non-contrast CT) and sometimes positron emission tomography (PET)/CT(1).
Staging of OCC follows the tumour, node, metastasis (TNM) system from the American Joint Committee for Cancer (AJCC) Cancer Staging Manual (8th Edition, 2017) and the Union for International Cancer Control (UICC), which includes information from clinical examinations and imaging studies (1). OCC stage is used to guide treatment as well as to apply statistics such as prognosis and likely treatment effectiveness. The earlier the stage, the less the cancer has spread. Stage 0 is the earliest stage and describes carcinoma in situ. The stages then range from Stage I through Stage IV. Three primary features are used to stage the cancer: the size of the tumour (T), the presence or absence of metastases to cervical lymph nodes (N) and the presence or absence of distant metastases (M) (Table 3). These features are combined to generate a TNM status, which correlates to a stage of OCC according to Table 4.
Management of OCC and other head and neck malignancies requires the efforts of a multidisciplinary team, including head and neck surgeons (otolaryngologists), radiation oncologists, medical oncologists, dedicated head and neck pathology and radiology specialists, dentists, speech/swallowing pathologists and dieticians(2). The main treatment options for OCC are surgery and/or radiation. Overall, upfront surgical management is preferred in most cases. Chemotherapy is not typically used as a primary treatment modality but may be used concurrently with radiation to increase its efficacy(1).
Stage I and II OCC tumours can be treated with either surgery or radiation alone(1). In early stage OCC, definitive surgical management is preferred if feasible. However, the choice of treatment modality will depend on several factors: patient comorbidities, ability to undergo general anesthesia, social supports (for instance, the ability to attend daily radiation treatments), predicted loss of function following either surgical intervention or radiation and patient preference. Advanced-stage tumours (Stage III and IV) typically require multi-modal therapy with upfront surgery followed by post-operative radiotherapy (with or without concurrent chemotherapy)(1).
Owing to the essential functions performed by the constituents of the oral cavity (e.g. mastication, articulation, swallowing, breathing) and the aesthetic role of the lips, cheeks and jaws in the structure of the face, functional and cosmetic outcomes are key considerations for patients undergoing surgery for OCC. Decisions to operate must focus on optimizing cancer cure, while simultaneously minimizing functional and cosmetic morbidity(1). Most early-stage OCC can be removed using a transoral approach. The wound may be closed primarily, left to heal by secondary intention or skin-grafted(1). Although at least 1 cm margins of normal-appearing tissue are typically removed surrounding any oral cavity mass, speech and swallowing are usually unaffected(1). However, as the extent of surgical resection increases, the risk of disruption to these functions increases and in some cases surgery may not be considered if it would result in significant morbidity for the patient(1). Other contraindications to surgery for OCC include encasement of the internal carotid artery, the presence of either dermal or distant metastases and the involvement of the masticator space (a deep neck compartment) or prevertebral fascia(1).
If there is clinical evidence of cervical metastases, the patient should undergo a modified radical neck dissection to remove all cervical lymph nodes at the time of their primary surgery. As compared to a radial neck dissection, a modified radical neck dissection spares more neck tissue, and usually preserves major nerves, vessels and muscle in the neck(1, 13). Patients who have primary tumours situated proximal to or crossing the midline should undergo bilateral neck dissection(1). Of note, selective neck dissection (removal of a subset of cervical lymph nodes) is often performed even for early-stage OCC without evidence of metastases. This is because up to 35% of patients without palpable cervical lymph nodes have been found to have pathologic evidence of metastases at the time of surgery(13). An elective neck dissection is therefore recommended as it has been shown to improve overall survival(13).
Radiation therapy may be delivered as traditional external beam radiation therapy (EBRT) or with interstitial radiation implants (brachytherapy)(1). EBRT can be delivered with intensity modulation which has been shown to maximize the radiation dose delivered to the tumour, while minimizing the dose delivered to surrounding structures (including the salivary glands, spinal cord and laryngopharynx)(1). As a primary treatment for OCC, radiation is generally administered daily over the course of 6–7 weeks, to a total dose of 65–75 Gy. The dose may be reduced if radiation is given in the adjuvant setting(1).
As mentioned, early-stage OCCs may be treated solely with radiation; this is particularly advantageous for patients unable to undergo general anesthesia. For more advanced-stage tumours (generally Stage III and IV), patients usually undergo upfront surgery followed by post-operative (adjuvant) radiotherapy(1). Indications for adjuvant radiotherapy include pT3-4, pN2-3, perineural invasion (PNI), lymphovascular invasion (LVI), and close surgical margins (<5mm). Chemotherapy is sometimes added to adjuvant radiotherapy for patients with positive surgical margins or extranodal extension (ENE).
The side effects of radiation therapy can be divided into acute and late side effects. Acute side effects include fatigue, skin reaction of neck, xerostomia, dysgeusia, mucositis resulting in odynophagia and weight loss. Occasionally patients may need a feeding tube to maintain caloric intake during and shortly after radiotherapy. Late effects can include submental lymphedema, skin fibrosis, xerostomia, dysgeusia, carotid atherosclerosis increasing the risk of stroke, sensorineural hearing loss and hypothyroidism(1). Long term xerostomia can increase the risk of dental caries. Mandibular osteoradionecrosis is a rare but significant complication that can occur, particularly after dental extractions following radiotherapy(1). Full-dose radiation can typically only be given once, owing to the significant side effects seen with subsequent doses (for example, weakening of the carotid artery that can lead to carotid blowout)(14). Patients who recur after initial radiation may be re-treated with lower doses, especially if there has been a long disease-free interval allowing for normal tissue repair, but alternative means (e.g. surgery) are usually recommended first(1).
As mentioned, chemotherapy is primarily used as an adjunct to radiation—as a radiosensitizer(1). This may be the case for advanced-stage tumours that are unresectable, or post-operatively along with radiation for patients with positive surgical margins or extranodal extension(1). In both these settings, chemotherapy treatment has been found to lead to significant improvement in survival and locoregional control, as compared to giving radiation alone(1, 15-17).
The most common chemotherapeutic agents used to treat OCC are platinum-based agents (e.g. cisplatin or carboplatin), paclitaxel and 5-fluorouracil (5-FU)(1). Post-operatively, cisplatin is the most commonly used, either alone or in combination with radiation therapy(18). Notable side effects of chemotherapy include myelosuppression, neuropathy, renal dysfunction and ototoxicity(19).
Apart from standard chemotherapy, a number of targeted therapies continue to be investigated for their use in treating head and neck cancers. Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is approved as both a monotherapy and as a combination agent for patients with recurrent and/or metastatic disease and those with locoregionally advanced disease(4, 20).
The role of immunotherapy in metastatic head and neck squamous cell carcinoma is evolving. This includes Nivolumab and Pembrolizumab which are monoclonal antibodies to the programmed cell death 1 protein (PD-1) on T cells. This prevents binding between PD-1 (on T cell) and programmed cell death 1 ligand (PD-L1) on tumour cells which would inhibit T cell killing (Fig. 5).
The prognosis of OCC is determined by the stage of disease. T1/T2 disease has a 5-year survival rate of approximately 70%(21). In contrast, more advanced disease (T3/T4) has a 5-year survival rate of approximately 55%(1). Important prognostic factors include: greater depth of tumour invasion, close surgical margins, positive cervical nodes and extracapsular spread(7).
Follow-up management of OCC may be conducted by otolaryngology, radiation oncology, medical oncology or primary care. Dentistry and speech/swallow therapists are also usually involved and these aspects of post-treatment care can substantially impact patients’ quality of life(23, 24).
Long-term surveillance is very important in the management of OCC. Patients are at risk of disease recurrence following treatment, as well as the development of a new primary tumour(1).
The follow-up schedule for patients will vary according to the practitioner they are seeing. The American Cancer Society recommends follow-up appointments every 1–3 months during the first year, every 2–6 months during the second year and every 4–8 months during the third through fifth years following the completion of treatment(1).
During follow-up appointments, a complete head and neck examination should be performed as described, including pharyngolaryngoscopy(1). Baseline post-treatment imaging (CT, PET/CT or MRI) should be obtained 3 months after treatment completion. Additional imaging is only required as clinically indicated(1).
Side effects from surgery and/or radiation should be addressed and managed during follow-up appointments where possible. Xerostomia (dry mouth), for example, can be managed with salivary replacements and frequent hydration(1). Where indicated, smoking and alcohol cessation should be discussed and counselling/interventions should be made available if the patient is willing and then have not already been initiated(1). If the neck was irradiated, TSH testing should be done annually to screen for hypothyroidism.
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