Squamous cell carcinoma: characteristics and clinical management

Oral squamous cell carcinoma is one of the most important forms of oral cancers with unfortunately very poor prognosis rate. Surgery, radiation and chemotherapy constitute the mainstay treatment so far. With our progressing knowledge in molecular biology and the increasing understanding of the various signaling pathways there is no question of doubt that in the near future the prognosis for OSCC would be considerably improved. As with any other disease, prevention is better than cure. Avoiding the well-known risk factors, a well-balanced nutritional plan and regular dental health checkups are the most effective means of preventing Oral cancers.

Oral cancer continues to be one of the most dangerous forms of cancer worldover. While the fatality rate of cancer in general has declined over the last several years the survival rates for oral cancer has not shown a similar decline. In the United States alone more than 30000 people are diagnosed with oral cancer every year with an annual death rate of around 7500 people. [1] Squamous cell carcinoma is the single most important oral malignancy accounting for almost 90% of the oral cancers. [2] Oral cancer includes malignancy of the lip, tongue, salivary glands, gum, mouth, pharynx, oropharynx and the hypopharynx. [3] The poor prognosis of oral cancer is largely due to the very late stage diagnosis often identified only when the cancer has already metastasized into other regions of the body such as the neck and the upper digestive tract. Early diagnosis of oral cancer is important, as poor oral hygiene and periodontal disease have been implicated as high risk factors for developing neck, head and esophageal cancers. A brief overview of the epidemiology, etiology, and the treatment interventions would provide better insight into this important health issue.

Epidemiology of Oral Squamous cell Carcinoma

Oral cancers are among the top ten cancers in humans constituting around 3% of all cancers and oral Squamous Cell Carcinoma (OSCC) represents around 90 to 95% of all oral cancers. OSCC is more common among men compared to women with a ratio of 3:2. Though, known to have a very high incidence rate among those in the fifties and sixties recent data indicate a growing prevalence of OSCC among people under 40 years of age. Race wise, Caucasians and African-Americans have higher prevalence rates compared to Hispanics and Asians. While 46% of Caucasians presented with regional disease the comparable rate was higher in African-Americans at 57%. The survival rates also vary significantly between the races at 50% for whites and 31% for African-Americans for the regional form of OSCC. Clinical statistics also indicate that around 10 to 35% of the people with oral SCC develop secondary tumors in the aerodigestive tract. [4, pg 345]

Etiology and Pathogenesis

Oral SCC is clearly associated with tobacco and alcohol consumption. People who abuse alcohol and tobacco carry the highest risk factor for developing OSCC. Studies have shown that 75% of oral cancers are associated with tobacco and alcohol usage. While in south Asian countries chewing tobacco is a well-known risk factor, in the West cigarette smoking is clearly linked with OSCC. Tobacco chewing releases reactive oxygen species (ROS) that have a destructive effect on the oral mucosa. Studies have also confirmed that tobacco chewing increases the exposure to tobacco-specific nitrosamines (TSNA), which are well-known to be carcinogenic. Alcohol is also independently associated with an increased risk for OSCC. Alcohol metabolite such as Acetaldehyde is well-known as a tumor promoter. [5] An early research by Stephen et.al (2001) studied the association between alcohol consumption and Alcohol dehydrogenase 3 (ADH3genotypes) that convert alcohol to acetaldehyde. The results from this study confirmed the increased susceptibility of the ADH3 *2 to OSCC. [6]

Some studies have suggested a possible role of the Human Papilloma virus (HPV) in the pathogenesis of OSCC. The prevalence of HPV in around 23.5% of the OSCC patients has prompted more research into the potential link between HPV and OSCC. [4, pg 346] A research by Dzousa et.al (2007) studied 100 patients newly diagnosed with oropharyngeal cancer along with 200 control subjects to study the relationship between HPV and oral cancer. The study results indicated that oropharyngeal cancer was clearly associated with HPV type 16 (odds ratio 14.6; 95% CI, 6.3 to 36.6), with the HPV 16 gene detected in 72% (95% CI, 62 to 81) of the 100 tumor specimens that were analyzed. The study also indicated that 64% of the patients were seropositive for HPV-16 oncoprotein E6 and/or E7, implicating a clear role for the HPV virus in tumor pathogenesis. [7]

Clinical Features and Histopathology

Usually oral lesions tend to be unnoticed and asypmtomatic during the initial stages. This is the main reason why the survival rates are poor for oral cancers, as most patients are not diagnosed until they are in advanced stages of the disease. Routine dental screening would help in early diagnosis and intervention. Symptoms of Oral squamous cell carcinoma include abnormal lip or mouth sores that do not heal. A red (erythroplakia) or white patch (leukoplakia) on the inner cheek lining, lips or the mouth floor, swelling of the jaw, unusual bleeding, chronic sore throat with pain during swallowing, [8] Keratinization occurs in areas of physical or chemical trauma. Histopathology of the Oral lesions reveal large irregular granular mass protrusions of anaplastic squamous cells that destroy the normal anatomy. For example, study of the tongue affected by tumor would reveal abnormal surface growth with degenerated tongue skeletal muscles. Keratin pearl formation would be distinctly visible under microscopic examination. Unusually enlarged hyperchromatic nuclei with intercellular bridges can also be clearly observed. The different degrees of keratinization are used in the morphological classification of squamous cell carcinoma. [9]

A recent study by Rao et. al (2008) studied the expression pattern of cytokeratin 1, 5, 8,18 and Vimentin in 48 patients with diagnosed condition of oral squamous cell carcinoma. Immunohistochemical study was performed using monoclonal antibodies for CK 1, 5, 8, 18 and vimentin. The results from the study clearly attested abnormal expression of the CK1 30%, CK8 in 54%, CK18 in 44% and vimentin in 85% of the tumors. The researchers also observed that in 88% (7/8) of the subjects who had recurrence within 6 months there was a marked expression of CK 8 or 18 and vimentin clearly suggesting them as effective biomarkers for OSCC. [10] Another recent study by gang et.al (2008) focused on the expression of ?-Catenin in seventy six patients identified with oral sqamous cell carcinoma and 16 metastatic lymph node cases. Healthy oral epithelium has strong expression of ?-Catenin along the cell membranes but almost no expression at the cytoplasmic or nuclear sites. However, the researchers found reduced expression of ?-Catenin at the cell membrane in almost 71% of the cases (54 patients), cytoplasmic expression in 17 patients (22.4%) and three cases with nuclear ?-Catenin expression. In the patients with lymph node metastasis, cell membrane level expression was severely reduced in 13 of the 16 patients and very weak expression was noticed in the remaining three patients. These results indicate that ?-Catenin expression at the cell membrane maybe inversely associated with OSCC [11]

Treatment of OSCC