Oral malignancies diagnosed in their initial stages can be treated more conservatively than their larger, metastatic counterparts. Unfortunately, the most common oral malignancy, squamous cell carcinoma, usually remains undetected until it is in its advanced stages. Pain, numbness, swelling, loss of function, and difficulty swallowing, which may appear later in disease progression, often do not accompany the beginnings of oral malignancies. The five-year survival rate of only 68% reflects the trend of late diagnosis [3].

Most patients with oral cancer have used tobacco products for prolonged periods of time [4]. Cigarettes, with their multitude of carcinogens, are the most frequent form of tobacco used. However, cigars, pipes, and smokeless tobacco also contain carcinogens; these should not be considered safe alternatives to cigarettes.

Although many more people smoke than develop oral cancer, the majority of oral cancers may be attributed to tobacco and/or alcohol use, either individually or together [4,5]. The use of alcoholic beverages by those who use tobacco products may enhance the negative effect upon the oral tissues [4]. The desiccating effects of alcohol provide a prolonged exposure of the carcinogens within tobacco on these tissues. This additional contact time increases the risk of the development of an oral malignancy, such as squamous cell carcinoma, 100 fold [4]. Factors such as immunosuppression and immunocompromise, a family history of cancer, nutritional considerations, alcohol abuse, systemic disease, and the duration and amount of tobacco used are possible reasons some tobacco users develop oral cancer and others do not. Because the majority of patients with oral cancer have a history of tobacco use, the implication of this product's carcinogens as agents that can cause malignant transformation in the oral tissues is strongly correlated.

Increasing age is another risk factor in the development of oral cancer, with a peak incidence in individuals 63 years of age; however, it is now occurring more frequently in younger individuals [2,6]. The exact causes for this are not yet clear, but there appear to be associations between young men and women who use conventional "smokeless" chewing or spit tobacco [2]. Historically, the incidence of oral cancer in the African American population has been twice that of the white population, but 2020 data from the National Cancer Institute indicates that the incidence in the white population has surpassed that of the African American population for both men and women [2,3]. A strong gender differentiation has also been noted historically, as men developed oral cancer with a frequency that was more than six times that of women. The ratio is now one woman to every three men, likely due to the increase in women who smoke since the 1950s [2]. It is thought that lifestyle choices (e.g., tobacco use, particularly in combination with the consumption of alcohol), rather than genetics, are responsible for these various disparities.

Chronic tissue trauma from ill-fitting prostheses, such as dentures or partial dentures, may predispose tissues to malignant change, though as a whole, there is no heightened risk for those with dentures [4]. However, patients who utilize these devices should be educated that any area of irritation should be examined and the corresponding adjustment should be made by a dentist. Sore spots that cannot be eliminated after adjustments, relines of the existing prosthesis, or the fabrication of a completely new prosthesis should be monitored very closely. If the prosthesis is not worn and the sore spot remains, a biopsy of the area is indicated.

In one study, HPV type 16 (HPV16) was found to account for approximately 55% of oral cancer cases in the absence of any other risk factors [7]. While HPV16 and HPV18 infections are widely recognized as a main cause of cervical cancers in women, they are also increasingly linked to oral cancer in those younger than 40 years of age [3,4]. The increase of oral cancer cases in this population is associated with the spread of HPV and is strongly correlated to having multiple oral sex partners [2,3,7]. Autoimmune factors, complex genetic mechanisms (individually or collectively), and other viral agents, such as herpes simplex virus, may also be etiologic risk factors in this group (Table 1).

Excessive, chronic ultraviolet light exposure has been linked to cancers of the lip, particularly in individuals who work outdoors [4]. Other documented or researched causes include poor nutrition (i.e., lack of fruits/vegetables), lichen planus, and graft-versus-host disease. Oral cancer may also develop in the absence of known risk factors. Approximately 25% of patients with oral cancer have no identified risk factors for the disease [10]. Most of these patients are younger than 40 years of age, well below the age distribution for this disease [2,11].

The oral mucous membrane does not have the same surface consistency throughout the oral cavity. The oral mucosa is classified into three types:

Common to all three mucosal types is an outermost cellular layer composed of stratified squamous epithelium. Some of the stratified squamous epithelium, specifically the masticatory mucosa, may be keratinized. All of these surface cells are produced from a deeper layer of cells called basal cells. This cellular layer consists of cells that are active in deoxyribonucleic acid (DNA) synthesis and undergo mitosis. The cells that replace the outer squamous layer every three to four days originate here. When radiotherapy or chemotherapy causes ulcerations anywhere in the oral mucosa, it is because the mitotic sequence of the basal cells has been interrupted. A small membrane beneath the basal cells, called the basement membrane, is what malignant cells perforate to invade the underlying tissue and begin the growth of a malignant lesion [12].

There is no universal appearance of malignant lesions. It is recommended that an oral lesion of unknown origin that does not heal within two weeks should be submitted for an expedited referral [2]. Patients should be advised that lesions that appear harmless may be malignant, while those that appear aggressive may be benign. Whether benign or malignant, oral lesions span a remarkable array of clinical presentations.

Leukoplakic (white) lesions are much more common than their erythroplakic (red) counterparts. Clinically, the latter group of lesions is more difficult to see amidst oral mucous membranes of a similar color, especially in areas of tissue inflammation or hypertrophy. A prominent vascular supply causes erythroplakic lesions to appear red and to bleed easily upon palpation. These lesions occur with less frequency than leukoplakic lesions but have a 91% probability of being dysplastic or malignant [14]. Therefore, it is essential that any erythroplakic lesion is biopsied. Among leukoplakic lesions that have undergone histologic examination, 20% are found to be malignant or premalignant [14]. However, this rate is more than doubled for leukoplakic lesions that are found in the floor of the mouth [14]. Healthcare professionals should perform thorough oral soft tissue exams as these lesions may be difficult to detect and patients are usually asymptomatic. It is also important to remember that lesion color cannot be used as a feature to distinguish a malignant lesion from one that is innocuous.

Leukoplakic (white) lesions are much more common than their erythroplakic (red) counterparts. Clinically, the latter group of lesions is more difficult to see amidst oral mucous membranes of a similar color, especially in areas of tissue inflammation or hypertrophy. A prominent vascular supply causes erythroplakic lesions to appear red and to bleed easily upon palpation. These lesions occur with less frequency than leukoplakic lesions but have a 91% probability of being dysplastic or malignant [14]. Therefore, it is essential that any erythroplakic lesion is biopsied. Among leukoplakic lesions that have undergone histologic examination, 20% are found to be malignant or premalignant [14]. However, this rate is more than doubled for leukoplakic lesions that are found in the floor of the mouth [14]. Healthcare professionals should perform thorough oral soft tissue exams as these lesions may be difficult to detect and patients are usually asymptomatic. It is also important to remember that lesion color cannot be used as a feature to distinguish a malignant lesion from one that is innocuous.

The oral malignancy responsible for more than 90% of the total cases of oral cancer is squamous cell carcinoma [26]. Squamous cell carcinoma is the result of uncontrolled differentiation of surface squamous cells of the oral mucosa into malignant cells. This is an aggressive lesion whose nests of malignant cells penetrate the basement membrane and the underlying connective tissue. Infiltration into the vascular and lymphatic circulation may occur early and facilitate metastasis. Continued proliferation can extend into the musculature and the supporting bone, with the capacity to destroy both. Upon histologic confirmation of a squamous cell carcinoma, surgery and radiotherapy should be scheduled as quickly as possible, because growth of the primary lesion and metastasis both occur rapidly; combined therapy may also include chemotherapy in later stages [26].

Squamous cell carcinoma can occur anywhere in the oral cavity. However, there are some areas of the mouth where these lesions occur more frequently than others. As noted, the most common sites of involvement are the tongue, lip, and floor of the mouth [21]. Many squamous cell carcinomas are located in areas that preclude visualization by the patient and can grow to larger sizes asymptomatically (Image 1).

The remaining types of oral malignancies affect tissues within the oral cavity or the adjacent salivary glands. Kaposi sarcoma, mainly associated with late-stage human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), is one such malignancy. A rarity in the United States until the AIDS epidemic, Kaposi sarcoma has been identified as an AIDS-defining illness.

The initial presentation of these lesions is usually on the skin, but oral manifestations occur frequently. The palate, gingiva, and tongue are the primary sites of the appearance of these lesions; however, they may occur anywhere in the mouth. The human herpesvirus-8 (HHV-8) is considered to be the etiologic agent of this malignancy [9]. The lesions of Kaposi sarcoma may be red, violet, dark blue, or black-blue and usually begin asymptomatically. This vascular malignancy is typically flat at its onset but progresses to form nodules that develop a spongy consistency. Their growth can interfere with swallowing and eating, and larger lesions bleed easily. Treatment is usually a combination of surgery and radiation therapy, which is taxing for patients with an advanced stage of immunosuppression (Image 2).

Radiation in adequate doses is cytotoxic to malignant cells because it causes free radical damage to the cellular components that are required for cell division and replication. Unfortunately, healthy tissues in the area of the radiation beam will undergo the same cellular damage. So, the goal is to destroy the malignant cells with as little damage to healthy cells as possible.

Oral mucositis is the most common intraoral side effect of radiotherapy and usually has an onset in the second week of therapy [43,44]. Mucositis affects nearly 80% of all patients who undergo head and neck radiotherapy and occurs in four phases [43]. The inflammatory phase is begun as ionizing radiation causes the generation of free radicals. The disruption of the normal sequence of turnover and stratification from the basal cell layer is a continuum into the epithelial phase. The ulcerative phase features ulcerations of varied dimensions on any mucosal surface. The consequent pain can be so intense that patients may have difficulty eating at a time when adequate nutrition is life sustaining. Patients with removable complete or partial dentures may be unable to wear them, further complicating their ability to masticate and swallow. The denuded mucosal surfaces also are a portal of entry for organisms of an altered oral microflora. This, coupled with a host whose immunocompetence is challenged, can lead to systemic bacterial or fungal infections that may be fatal. Severe mucositis mandates that radiotherapy be postponed until adequate healing of the epithelium occurs. The healing phase may take several weeks after the last radiotherapy treatment [45].

The changes that occur in the oral environment after radiotherapy portals have damaged the salivary glands may cause rapid and widespread destruction of teeth that previously had no dental pathology [65]. It is postulated that radiation alters the organic and inorganic matrix of enamel and the remaining tooth structure [47]. Decalcification may be favored over remineralization as an initiator of the carious process. The decrease in pH levels, which is commensurate with the amount of damage to the salivary glands, begins the creation of a caries-prone oral environment. When the serous component of saliva decreases and the viscosity increases, adherence of cariogenic bacteria to tooth structure increases. These organisms thrive in the more acidic oral environment that develops after radiotherapy.

These factors, coupled with the difficulty patients have with their oral hygiene maintenance amidst sensitive teeth and soft tissues, create a problem known as "radiation caries." This is an aggressive and rapid form of dental decay, targeting parts of the tooth that are usually not prone to decay. The smooth buccal (outer) and lingual (inner) walls of the tooth become involved with rapidly advancing carious lesions. The area of the tooth that is closest to the gingival tissues, the cervical area, is a frequent point of origin. The process can also affect the incisal edges of anterior teeth and the cusp tips of posterior teeth. Within weeks or months, the process renders teeth that were previously devoid of any dental pathology completely destroyed.

A complete clinical and radiographic examination of the teeth and soft tissues should be completed as far in advance as possible from the surgical phase of oral cancer therapy. This will allow sufficient healing time for the extractions of teeth with unrestorable decay and advanced periodontal disease. Partially erupted wisdom teeth should be removed if they are in an area to be irradiated. Teeth with dental caries should be restored to optimal clinical condition. Teeth in which the carious process has extended into the pulp and has caused irreversible inflammation or necrosis should undergo root canal therapy or be extracted. Those teeth that cannot have deep periodontal pockets reduced to levels that will facilitate oral hygiene should be extracted. Prosthetic appliances should be adjusted so that their use will not promote tissue trauma. The goal is definitive treatment, avoiding a "watch and wait" approach. Patients should be informed that dental problems may exist without any symptoms and that lack of treatment will contribute to infections and even ORN after the completion of oral cancer therapy.

When the number of platelets produced or the quality of those in existence are diminished, oral bleeding can occur. The normal range of platelets is 150,000–450,000 per mm³of blood. Spontaneous bleeding occurs when the platelet count decreases to 20,000–50,000 per mm³of blood [78]. When platelets contact a damaged blood vessel, they increase in size and adhesiveness and form a plug upon the damaged vessel. Some chemotherapeutic agents alter the ability of platelets to adhere to each other in the formation of a fibrous plug, which is required for hemostasis. Others may interfere with actual platelet production and decrease the number of platelets available. Regimens that use more than one chemotherapeutic agent may affect both platelet quality and production.

Interference with coagulation causes oral manifestations, including petechiae, ecchymoses, or oozing of blood [79]. The most common areas in which petechiae are found intraorally include the palate, gingiva, lips, and tongue. Petechiae are small areas of bleeding within the tissue that occur because of a decreased platelet count. Similarly, bleeding submucosally or subcutaneously due to platelet deficiencies in quality or quantity may produce ecchymoses. These lesions can occur anywhere within the oral tissues and appear as a dark red or reddish-blue area submucosally. They are exacerbated by accidental trauma or by prostheses that irritate the tissues. The most disconcerting problem for the patient is hemorrhage, which occurs spontaneously or with actions such as eating, brushing, or flossing. This problem is exacerbated in patients who have chronically inflamed gingival tissues characteristic of gingivitis and periodontal disease. Ideal depth of the gingival sulcus in health is 3 mm or less. As gingivitis and periodontal disease progress, destruction of the epithelial attachment causes this sulcus to become deeper. Cleansing the pocket depth becomes increasingly difficult, with a resultant state of chronic inflammation. As alveolar bone is lost during the progression of periodontal disease, the gingival tissues become poorly attached to the tooth and bone.

Oral infections of fungal origin (with the potential to spread systemically) occur in as many as 38% of patients receiving chemotherapy [80]. As mentioned, C. albicans is a resident fungal organism in the oral microflora. This opportunistic pathogen thrives in the oral environment of a host who is immunologically compromised. Oral candidiasis has different manifestations and degrees of severity. Angular cheilitis occurs when these organisms infect the commissures of the lips and the surrounding skin. The affected areas are sore and can crack and bleed easily. Treatment with a topical antifungal (such as miconazole) that is usually successful in the immunocompetent patient may not be successful in patients with cancer.

The activation of herpes simplex virus or varicella zoster virus (shingles) is a common occurrence in immunocompromised patients [84]. These viruses reside and lie dormant in the ganglia of neurons until a triggering event or stressor stimulates their activation. In immunocompromised patients, these viral infections are more susceptible to systemic or organ dissemination [85]. Because they reside in the actual nerve, these viruses cannot be destroyed by any medical procedure.

Systemic chemotherapy can have oral manifestations that are dependent on the agent(s) used, their dosage, and the duration of therapy. As with any medication, there is a considerable variability in the tolerance for a given pharmacotherapeutic regimen as well as any side effects. As noted, one such effect may be xerostomia. This problem is associated with some chemotherapeutic agents more than others. The parotid glands, with their serous secretions, are the glands most frequently affected. Because chemotherapeutic agents are administered as a systemic therapy, these substances course through all salivary glands. With the serous component reduced, the saliva develops a mucus-laden, ropey consistency. The decreased lubrication exacerbates the pain associated with concurrent areas of mucositis and makes it difficult to wear any dental prostheses. Eating, speaking, and swallowing may become difficult, and the taste of foods may be altered.

While radiotherapy-induced xerostomia and all of the problems associated with it are long-term or permanent, those associated with chemotherapy dissipate after the completion of the regimen. Chemotherapy is usually given in an incremental fashion, with several days or weeks separating the appointments. Xerostomia may be a continuous problem until enough time has elapsed after the last session. A 2015 Cochrane Review concluded that cryotherapy (i.e., holding ice chips or ice water in the mouth from 5 minutes prior to 30 minutes after treatment) is effective in reducing mucotoxicity [96]. A simple act to palliate the symptoms associated with this xerostomia and mucositis is to frequently suck on ice chips. Being that the cost and risks of this preventative measure are virtually nonexistent, cryotherapy should always be considered.

Neurologic effects may be seen in some patients on chemotherapy. Vincristine sulfate is the chemotherapeutic agent most commonly associated with this problem [51,97]. Chemotherapeutic agents exert varied effects on any nerve. The most commonly affected nerves that serve the oral and maxillofacial complex are the facial and trigeminal nerves. The facial nerve is the major source of motor innervation for the muscles of facial expression. Transient neural toxicity manifests as weakness of these muscles and decreased facial muscular coordination. The trigeminal nerve is another cranial nerve that provides sensory innervation to many portions of the face and for those structures within the oral cavity. Symptoms of neural toxicity present in a variety of ways. Pain that mimics that of dental origin may affect both the maxillary and the mandibular arches. There may be temporary paresthesia in the soft tissues or in the teeth. Pain in the temporomandibular joint (TMJ) may mimic TMJ problems. Patients should be reassured that these problems will regress after chemotherapy is completed.