Relative to the incidence of all cancers, oral and oropharyngeal (is a middle part of the throat that includes the base of the tongue, the tonsils, the soft palate, and the walls of the pharynx) squamous cell carcinomas (cancer in epithelium) represent about 3% of cancers in men and 2% of cancers in women. Annually, more than 36000 new cases of oral and oropharyngeal cancer are expected to occur in men and women in the United States. The ratio of cases in men and women is now about 2 to 1. Previously, this ratio was 3 to 1; this shift has been attributed to an increase in smoking by women and to their longer life expectancy.
Death resulting from oral and oropharyngeal cancer represent approximately 2% of the total in men and 1% of total in women. The total number of estimated annual deaths resulting from oral and oropharyngeal cancer is as high as 7880 in United States, although a decrease of slightly more than 1.8% was noted in cancer death rates between 1991 & 2006 for this site.
The trend in survival of patients with this malignancy has been rather disappointing, although recently slight but significant improvement has been reported. Survival rates for African Americans have been lower than for other races. Geographic variation in oral & oropharnygeal carcinoma survival rates exist in the United States and around the world and are most likely attributed to genetic and environmental differences unique to local populations.
In India and some other Asian countries, oral cancer is the most common type of malignancy and may account for more than 50% of all cancer cases. This finding is generally linked to the high prevalence of a unique smokeless tobacco habit. The tobacco, typically mixed with areca (betel) nut, slaked lime, and spices, is known as the quid, or paan, and is held in the buccal vestibule for long periods. This combination of ingredients, which may vary from one locale to another, is more carcinogenic than tobacco used alone.
- Tobacco smoking
- Smoking of cigars and pipes
- Cigarette smoking
- “Reverse smoking,” the habit of holding the lighted end of the cigarette inside the mouth, as may be the habit in India and some South American countries.
All these forms have high risk of developing oral cancer which is due to the intensity of tobacco combustion adjacent to palatal (roof of mouth) and lingual (tongue) tissues.
Added to the list causes is smokeless tobacco, & alcohol consumption of which all contribute to the development of oral cancer.
Although poor nutritional status has been linked to an increased rise in oral cancer, the only convincing nutritional factor that has been associated with oral cancer is iron deficiency of Plummer-Vinson syndrome (Patterson-Kelly syndrome, sideropenic dysphagia). Typically affecting middle-aged women, the syndrome includes a painful red tongue, mucosal atrophy (waste away of tissue), dysphagia (discomfort or inability to swallow) caused by esophageal webs, and a predisposition to the development of oral squamous cell carcinoma.
Ultraviolet (UV) light is known carcinogenic agent that is significant factor in basal cell carcinomas of the skin and squamous cell carcinomas of the skin and lip.
A compromised immune system puts patients at risk for oral cancer. This increased risk has been documented for bone marrow and kidney transplant recipients, who are iatrogenically (induced inadvertently by a physician or surgeon or by medical treatment or diagnostic procedures) immunosuppressed. The total-body radiation and high-dose chemotherapy that are used to condition patients for bone marrow transplants also put patients at lifelong risk for solid and lymphoid malignancies. It has long been suspected that AIDS predisposes patients to oral cancer, but evidence is mixed and has yet to be convincingly proven.
Chronic irritation is generally regarded as a modifier rather than an initiator of oral caner. Mechanical trauma from ill-fitting dentures, broken fillings, and other frictional rubs is unlikely to cause oral cancer. If however, a cancer is started from another cause, these factors will probably hasten the process. Poor oral hygiene is regarded as having a comparable modifying effect, although many patients with poor oral hygiene have other important risk factors for oral cancer, such as tobacco habits and alcohol consumption.
Oral cancer, similar to most other malignancies, arises from accumulation of a number of discrete genetic events that lead to invasive cancer. These changes occur in genes that encode for proteins that control cell cycle, cell survival, cell motility, and angiogenesis (development of new blood vessels). Each genetic mutation confers a selective growth advantage, permitting clonal expansion of mutant cells with increased malignant potential.
Conceptually, oral cancers progress through two important biological stages. The first is loss of cell cycle control through increased proliferation and reduced apoptosis (programmed cell death). Histologically, the impact of the molecular alterations is most obvious in patients with in situ carcinoma, in which an increased number of diving cells can be seen in all levels of epithelium. The second stage is increased neoplastic (cancer) cell motility, leading to invasion and metastasis. Here, neoplastic epithelial cells penetrate the basement membrane and invade underlying tissues, eventually reaching regional lymph nodes.
Both stages result from activation (upregulation) of oncogenes (a gene that in certain circumstances can transform a cell into a tumor cell) and inactivation (downregulation) of tumor suppressor genes (antioncogenes). Oncogenes, or proto-oncogenes under normal circumstances, encode proteins that positively regulate critical cell growth functions, such as proliferation, apoptosis, cell motility, membrane and internal cell signaling, and angiogenesis. If these agents are altered through one of several mechanism (e.g., mutation), overexpression of the encoded protein occurs, giving rise to a clone of cells with a growth/motility advantage. Tumor suppressor genes encode proteins that negatively regulate or suppress proliferation.
Oral Cancer Pathogenesis
Oncogenes and tumor suppressor genes
- Mutation, amplification, or inactivation
Loss of control of:
- Cell cycle (proliferation vs. inhibition, signaling)
- Cell survival (apoptosis vs. antiapoptosis)
- Cell motility
The biological antithesis of proliferation is apoptosis (programmed cell death). If cells live longer, they may have a biological advantage that favors the development of neoplasia (cancer). Some genes that controls apoptosis are altered in cancers. In oral cancers, several proteins that regulate apoptosis are often dysregulated.
Several other oncogenes that function in regulating cell growth and transporting signals from the cell membrane to the nucleus are frequently altered in many oral cancers.
Many oral cancers pass through a premalignant phase (dysplasia “the enlargement of an organ or tissue by the proliferation of cells of an abnormal type, as a developmental disorder or an early stage in the development of cancer” or in situ carcinoma” is a group of abnormal cells”), whereas other appear arise de novo without clinical or microscopic evidence of a preexisting lesion. Invasive carcinomas have developed the ability to penetrate basement membrane and connective tissue, as well as enter the vascular system.
Most head and neck carcinomas have telomerase (enzyme that adds DNA sequence repeats) activity through neoexpression of the enzyme, giving the neoplastic cell extended life.
- Clinical Features
Carcinoma of the lips. From a biological viewpoint, carcinomas of the vermilion portion of the lower lip (normally sharp demarcation between the lip “red colored” and the adjacent normal skin) are separated from those of the upper lip. Carcinomas of the lower lip are far more common than upper lip lesions (Figure 1 & 2).
UV light and pipe smoking are much more important in the cause of lower lip cancer than in the cause of upper lip cancer. The growth rate is slower for lower lip cancers than for upper lip cancers. The prognosis for lower lip lesions is generally very favorable, with more than 90% of patients alive after 5 years. By contrast, the prognosis for upper lip lesions is considerable worse.
Lip carcinomas account for 25% to 30% of all oral cancers. They appear most commonly in patients between 50 and 70 years of age and affect men much more than women. Some components of lipstick may have sunscreen properties that account, in part, for this finding, although occupational exposure to sunlight is more of a factor in men. Lesions arise on the vermilion and typically appear as chronic nonhealing ulcers or as exophytic lesions (tending to grow outward beyond the surface epithelium from which it originates) that are occasionally verrucous in nature. Deep invasion generally appears later in the course of the disease. Metastasis (the development of secondary malignant growths at a distance from a primary site of cancer) to local submental (below the chin) or submandibular (below the lower jaw) lymph nodes is uncommon but is more likely with larger, more poorly differentiated lesions.
Carcinoma of the Tongue. Squamous cell carcinoma of the tongue is the most common intraoral malignancy. Excluding lip lesions, it accounts for between 25% and 40% of oral carcinomas. It has a definite predilection for men in their sixth, seventh, & eighth decades. However, lesions may be found uncommonly in the very young. These lesions often exhibit particularly aggressive behavior.
Lingual (tongue) carcinomas is typically asymptomatic. In later stages, as deep invasion occurs, pain or dysphagia (difficulty swallowing) may be prominent patient complaint. Similar to other oral cancers, these present in one of four ways: as an indurated, nonhealing ulcer; as a red lesion; as a white lesion; or as a red-and-white lesion (Figure 3,4,5,& 6).
The neoplasm (cancer) may occasionally have a prominent exophytic, as well as endophytic (growing inward), growth pattern. A small percentage of leukoplakias of the tongue represent invasive squamous cell carcinoma or eventually become squamous cell carcinoma. Most erythroplakic patches that appear on the tongue are in situ (on site) or invasive squamous cell carcinomas at the time of discovery.
The most common location of cancer of the tongue is the posterior-lateral border, accounting for as many as 45% of tongue lesions. Lesions very uncommonly develop on the dorsum or on the tip of the tongue. Approximately 25% of tongue cancers occur in the posterior one third or base of the tongue. These lesions are more troublesome than the others because of their silent progression in an area that is difficult to visualize. Accordingly, these lesions more often are advanced or have metastasized regionally by the time they are discovered, reflecting a significantly poorer prognosis.
Metastases from tongue cancer are relatively common at the time of primary treatment. In general, metastatic deposits from squamous cell carcinoma of the tongue are found in the lymph nodes of the neck, usually ipsilateral (same) side. The first nodes to become involved are the submandibular (below the lower jaw) or jugulodigastric nodes at the angle of the mandible (lower jaw). Uncommonly, distant metastatic deposits may be seen in the lung or the liver.
Carcinoma of the Floor of Mouth. The floor of mouth is the second most common intraoral location of squamous cell carcinoma, accounting for 15% to 20% of cases. Again, carcinomas in this location occur predominately in older men, especially those who are chronic alcoholics and smokers. The usual presenting appearance is that of a painless, nonhealing, indurated ulcer (Figure 7).
It may appear as a white or red patch (Figure 8).
The lesion occasionally may widely infiltrate the soft tissues of the floor of mouth, causing decreased motility of the tongue (Figure 9 & 10).
Metastasis to submandibular lymph nodes is not uncommon for lesions of the floor of mouth.
Carcinoma of the Buccal (cheek) Mucosa and Gingiva (gums). Lesions of the buccal mucosa and lesions of the gingiva each account for approximately 10% of oral squamous cell carcinomas. Men in their seventh decade typify the affected group. The presenting clinical appearance varies from a white patch to a nonhealing ulcer to an exophytic lesion (Figure 11).
In the latter group is the clinical pathologic entity verrucous carcinoma. This subset of squamous cell carcinoma, sometimes associated with the use of smokeless tobacco, presents as a broad-based, wartlike mass. It is slow growing and is very well differentiated, rarely metastasizes, and has a very favorable prognosis.
Carcinoma of the Palate (Roof of Mouth). There is some justification for separation of cancers of the hard palate (Anterior part of roof of mouth) from those of the soft palate (posterior part of roof of mouth). In the soft palate and contiguous faucial tissues (The passage from the back of the mouth to the pharynx, bounded by the soft palate, the base of the tongue, and thepalatine arches), squamous cell carcinoma is fairly common occurrence, accounting for 10% to 20% of intraoral lesions. In the hard palate, squamous cell carcinomas are relatively rare. By contrast, salivary gland adenocarcinomas (a malignant tumor formed from glandular structures in epithelial tissue) are relatively in the palate. However, palatal carcinomas are commonly encountered in countries such as India, where reverse smoking is common.
Palatal squamous cell carcinomas generally present as asymptomatic red or white plaques or as ulcerated and keratotic masses (adenocarcinomas initally appear as nonulcerated masses) (Figure 12).
Metastasis to cervical nodes or large lesions signifies an ominous course (Figure 13).
- Differential Diagnosis.
When oral squamous cell carcinomas present in their typical clinical form of chronic, nonhealing ulcers, other ulcerative conditions should be considered. An undiagnosed chronic ulcer must always be considered possible infectious until biopsy finding prove otherwise. It may be impossible on clinical grounds to separate TB, syphilis, and deep (invasive) fungal infections expressing oral manifestations from oral cancer. Chronic trauma, including factitial or self-induced injury, may mimic squamous cell carcinoma. Careful history taking is especially important, and biopsy findings confirm the diagnosis. In the palate and contiguous tissues, midline granuloma (a mass of granulation tissue, typically produced in response to infection, inflammation, or the presence of a foreign substance) and necrotizing sialometaplasia* would be serious diagnostic considerations.
*Necrotizing Sialometaplasia is a benign, ulcerative lesion, usually located towards the back of the hard palate. It is thought to be caused by ischemic necrosis (death of tissue due to lack of blood supply) of minor salivary glands in response to trauma. Often painless, the condition is self-limiting and should heal in 6–10 weeks.
Although entirely benign and requiring no treatment, due to its similar appearance to oral cancer, it is sometimes misdiagnosed as malignant. Therefore, it is considered an important condition, despite its rarity.
Treatment is directed on whether a surgery or radiotherapy can be implicated or both.
If radiation was appropriate for your case, there are some complications that may come with it (dose-dependent side effects). Some of these are reversible, whereas others are not (Figure 14, 15, 16, & 17).
Radiation-induced mucositis and ulcers and the accompanying pain, xerostomia, loss of taste, and dysgeusia (alterations in taste) are common side effects. Radiation mucositis is a reversible condition that begins 1 to 2 weeks after the start of therapy and ends several weeks after termination of therapy. Oral candidiasis often accompanies the mucositis. Use of antifungals, chlorhexidine rinses, or salt-soda rinses helps reduce morbidity.
Permanent damage to salivary gland tissue situated in the beam path may produce significant levels of xerostomia.
Some recovery is often noted, especially at lower radiation levels. Xerostomia is frequently a patient’s chief complaint during the postradiation period. Frequent use of water or artificial saliva is of minimal benefit to these patients. Pilocarpine, used during the course of radiation, may provide some protective measure of salivary function. With the dryness also comes the potential for the development of cervical, or so-called radiation, caries. This problem can be minimized with regular follow-up dental care and scrupulous oral hygiene. Custom-fitted soft trays are made for the fully or partially dentate patient to permit the nightly application of neutral pH fluoride directly to the teeth. This treatment is initiated at the start of cancer treatment and continues for the remainder of the patient’s life. It has been shown significantly reduce the incidence of cervical caries and there by the need for future dental extractions.
Skin in the path of radiation beam also suffers some damage. Alopecia (loss of hair) is temporary at lower radiation levels but permanent at the higher levels required in the treatment of squamous cell carcinoma. Skin erythema is temporary, but the telangiectasias and atrophy that follow are permanent. Cutaneous pigmentation in the line of therapy is also a late complication, and it, too, may be permanent.
A more insidious problem lies in the damage that radiation causes to bone, which may result in osteoradionecrosis (Figure 18 & 19).
Radiation apparently has deleterious effects on osteocytes*, osteoblasts,** and endothelial cells***, causing reduced capacity of bone to recover from injury. Injury may come in the form of trauma (such as extractions), advancing periodontal disease (disease affecting supporting tissues of the tooth), and periapical inflammation associated with nonvital teeth (inflammation around the apices of the roots of the tooth). Once osteoradionecrosis occurs, varying amounts of bone (usually in the mandible “lower jaw”) are lost. This may be an area as small as a few millimeters to as large as half the jaw or more. The most important factor responsible for osteonecrosis is the amount of radiation directed through a bone on the path to the tumor. Oral health is also of considerable significant. Poor nutrition and chronic alcoholism appear to be influential in the progression of this complication. Conservative surgical removal of necrotic bone may assist in the healing process. Also, if available, the use of a hyperbaric oxygen chamber may provide patients with a healing advantage.
Because osteoradionecrosis is a danger that is always present after radiation, tooth extractions should be avoided after therapy. If absolutely necessary, tooth removal should be performed as atraumatically as possible, using antibiotics coverage. It is preferable to commit treatment plan that schedules tooth removal before radiation therapy begins. Initial soft tissue healing before therapy is begun reduces the risk of nonhealing of the extraction sites. Prosthetic devices such as dentures and partial dentures, if carefully constructed and monitored, can be worn without difficulty. Xerostomia does not seem difficulty in the wearing of these prostheses. Continued careful surveillance of the patient’s oral health, during and after radiation therapy, helps keep complications to an acceptable minimum.
*Osteocyte: Bone cells.
**Osteoblasts: Bone forming cells.
***Endothelial cells: cells lining the walls of arteries.
- Therapeutic Radiation Side Effects
Temporary Side Effects
- Mucosal pain/mucositis
- Taste alterations
- Candidiasis (fungal infection in mouth)
- Erythema (superficial reddening of the skin, usually in patches, as a result of injury or irritation causing dilatation of the blood capillaries)
- Focal alopecia (hair loss)
Permanent Side Effects
- Xerostomia (dry mouth)
- Cervical caries
- Osteoradionecrosis (is a possible complication following radiotherapy where an area of bone does not heal from irradiation. Irradiation of bones causes damage impairs the blood supply)
- Epithelial atrophy
- Focal alopecia
- Focal hyperpigmentation
*Telangiectasias Are small dilated blood vessels near the surface of the skin or mucous membranes (Figure 18).
Prognosis. Similar to other cancers, the prognosis for patients with oral SCC is dependant on both the histologic subtype and the clinical extent (stage) of the tumor. Of the two, the clinical stage is significantly more important. Other, more abstract factors that may influence the clinical course include the patient’s age, gender, general health, immune system status, and mental attitude.
If the neoplasm is small and localized, the 5-year cure rate may be as high as 60% to 70%. However, if cervical nodes metastasis are present at the time of diagnosis, the survival figures drop precipitously to about 25%.
Reference: Oral Pathology, Sixth Edition, By Regezi, Sciubba, & Jordan.
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