WHAT IS CANCER?Cancer is the end product of an

unregulated proliferation of cells resulting from the accumulation of sequential genetic alterations (mutations) in a precursor cell. The resultant "cancer" is a population of cells that continue to mutate and that secrete self‐perpetuating growth factors and angiogenic factors.

Evidence shows that cancers arise from the transformation of a single precursor cell into a clone consisting of many daughter cells with an accumulation of altered genes called "oncogenes."

Oral squamous cell carcinoma is something of a misnomer since the cancer‐generating cells are actually those within the basal cell layer of the mucosa. We call them squamous cell carcinomas only because the malignant squamous cell precursors (basal cells) undergo a partial squamous differentiation, making them look like squamous cells under the light microscope.

Evidence shows that cancers arise from the transformation of a single precursor cell into a clone consisting of many daughter cells with an accumulation of altered genes called "oncogenes."

Worldwide, oral carcinoma is one of the most prevalent cancers and is one of the 10 most common causes of death.

If oral cancers and cancers of the nasopharynx, pharynx, larynx, sinus, and salivary glands are combined, these sites represent more than 5% of total body cancers.

In males, oral cancer represents 4% of total body cancers; in females, 2% of all cancers are oral.

Oral cancer accounts for 2% of cancer deaths in males and 1% of cancer deaths in females.

The majority of oral cancers are squamous cell cancers.

Oral cancer is a disease of increasing age: approximately 95% of cases occur in people older than 40 years, with an average age at diagnosis of approximately 60 years.

The majority of oral cancers involve the tongue, oropharynx, and floor of the mouth.1–3 The lips, gingiva, dorsal tongue, and palate are less common sites.

Primary squamous cell carcinoma of bone is rare.

What distinguishes a malignant tumor from a benign tumor is generally agreed to be the potential of a malignant tumor to metastasize.

It is important to realize that the potential to metastasize is a property specific to each tumor related to the location and degree of its genetic alterations; it is independent of the histologic grade or the mitotic (growth) rate of the tumor.

Some of the recognized causes of oral squamous cell carcinoma are tobacco‐related products (particularly cigarettes), alcohol, several viruses (particularly human papillomaviruses 16, 18, and 32), irradiation, ultraviolet light, naturally occurring genetic defects such as are found in some syndromes, and random spontaneous genetic mutations.

Cancer etiology is very complex and is related to the type of carcinogen, its dose, its frequency, and its application. It is also related to the synergistic or additive actions of two or more carcinogens, the susceptibility of the host, and most importantly, the length of time a carcinogen has interacted with host tissues.

For a cancer to become "initiated," a cell must accumulate at least six of these genetic mutations. Each mutation must be passed along to a daughter cell at the basement membrane, which retains this mutation and passes it on to its own daughter cells, which, if further bombarded by carcinogens, pick up another nonlethal, non‐reproduction inhibiting, transferable mutation. Therefore, cancers are actually difficult to initiate and usually take years of repetitive carcinogen exposures before they develop. Because DNA turnover is greater during the growing years (0 to 20 years), DNA is more vulnerable to carcinogens in this time period. Once a cancer does develop, it represents a cell population with an unstable genome, which undergoes further self‐initiated mutations, making it more aggressive, invasive, and increasingly more likely to metastasize.

1) TUMOR LOAD is the most common, the slowest, and the gentlest pathway to death from oral cancers.

Most patients lose weight, become weak, lapse into a coma, and die from a cardiorespiratory arrest.

The very diabolic nature of cancer is not its replication rate, but the enzymes and growth factors it secretes. As the tumor load increases, the tumor secretes a greater amount of blocking factors and several vascular down‐regulating enzymes, known as anti‐angiogenic factors, which prevent normal cells from utilizing nutrients and metabolizing efficiently. These antiangiogenic factors, which were first discovered in cancer cells, prevent normal tissues from recruiting new capillaries and instead promote the formation of new capillaries into the cancer.

2) Infection (Pneumonia)As the tumor load increases and causes

systemic weakness, infections, specifically pneumonia, become more likely. Individuals are often anemic, hypoproteinemic, and possibly malnourished by the secretory products of the tumor load and/or by the tumor‐related dysfunction of the oral cavity and the effort required to eat or to be fed by someone else. This weakness and subsequent sedentary existence promotes atelectasis, which progresses to pneumonia.

3. Complications of Treatment A smaller percentage of patients die from direct

complications of treatment or from side effects of therapy. Chemotherapy occasionally produces a severe marrow suppression, reducing white blood cell counts to less than 500/mm3 and resulting in a fatal systemic infection.

Surgery has produced events such as the "carotid blow‐out" or internal jugular vein exsanguination. It also poses the threat of upper airway obstruction, where patients die after the attachments of the tongue are removed or bulky flaps are placed in the airway.

Radiotherapy rarely produces life‐threatening complications during its treatment. However, the delayed effects of radiotherapy can be a significant factor in the patient's death. Progressive later dysphagia from fibrosis in the pharyngeal musculature reduces nutritional intake and promotes aspiration.

From a biologic viewpoint, carcinomas of the lower lip are separated from carcinomas of the upper lip. Carcinomas of the lower lip are far more common than upper lip lesions.

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 over 90% of patients alive after 5 years.

By contrast, the prognosis for upper lip lesions is considerably 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 often than women.

Some components of lipstick may have sunscreen properties and account, in part, for this finding. Lesions arise on the vermilion and typically appear as a chronic nonhealing ulcer or as an exophytic lesion that is occasionally verrucous in nature.

Deep invasion generally appears later in the course of the disease.

Metastasis to local submental or submandibular lymph nodes is uncommon but is more likely with larger, more poorly differentiated lesions.

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, and eighth decades.

However, lesions may uncommonly be found in the very young. These lesions often exhibit a particularly aggressive behavior.

Lingual carcinoma is typically asymptomatic. In later stages, as deep invasion occurs, pain or dysphagia may be a prominent patient complaint.

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 are more often advanced or have metastasized regionally by the time they are discovered, reflecting a significantly poorer prognosis than for lesions of the anterior two thirds.

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 on the ipsilateral (same) side.

The first nodes to become involved are the submandibular or jugulodigastric nodes at the angle of the mandible.

Uncommonly, distant metastatic deposits may be seen in the lung or the liver.

The floor of the mouth is the second most common intraoral location of squamous cell carcinomas, accounting for 15% to 20% of cases.

Again, carcinomas in this location occur predominantly in older men, especially those who are chronic alcoholics and smokers.

The usual presenting appearance is that of a painless, nonhealing, indurated ulcer. It may also appear as a white or red patch.

The lesion occasionally may widely infiltrate the soft tissues of the floor of the mouth, causing decreased mobility of the tongue.

Metastasis to submandibular lymph nodes is not uncommon for lesions of the floor of the mouth.

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 group affected. The presenting clinical appearance varies from a white patch to a nonhealing ulcer to an exophytic lesion.

In the last-mentioned group is the clinical pathologic entity verrucous carcinoma. This subset of squamous cell carcinoma, some associated with the use of smokeless tobacco, presents as a broad-based, wartlike mass. It is slow growing and very well differentiated, rarely metastasizes, and has a very favorable prognosis.

There is some justification for the separation of cancers of the hard palate from those of the soft palate. In the soft palate and contiguous faucial tissues, squamous cell carcinoma is a 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 are relatively common 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 initially appear as nonulcerated masses). Metastasis to cervical nodes or large lesions signify an ominous course.