Squamous cell carcinomas and preneoplastic lesions of the oral cavity : biological factors and prognosis

University dissertation from Stockholm : Karolinska Institutet, -

Abstract: In Sweden, squamous cell carcinoma of the oral cavity comprises only 0.8% of the total cancer incidence. However, this disease often has a poor prognosis and the treatment frequently means some degree of disfiguration of the patient. The TNM classification, defined by UICC (International Union Against Cancer), together with the histopathological evaluation of the tumor, grade of differentiation according to Broders, and the performance status of the patient, serve as the basis for the decisions regarding the treatment of each individual patient. However, this system is a blunt instrument for optimization of treatment and it is well known that a tumor might possess features that are much more aggressive than the evaluation gives the impression of. Some mucosal lesions in the oral cavity are burdened with a risk of cancer development: preneoplastic lesions. Macroscopic appearance and microscopic evaluation of grade of dysplasia, serve as the basis for selection of treatment of these lesions. Again, these decisions are hampered by the subjectivity of the methods and the unpredictable course of the disease. Our general hypothesis is that biological characteristics closer to the genotype of the carcinomas and the preneoplastic lesions could provide information that could be used for optimizing the treatment of the individual patient. Measurement of nuclear DNA content, through Image Cytometry, is a method to estimate genetic instability in tumor cells. The tumor suppressor gene p53 regulates the cell cycle via protein p53, the WAF1 gene and its protein p21. p53 and p21/WAF1 proteins were studied through immunohistochemistry and the p53 gene was screened for mutations, using CDGE (Constant Denaturant Gel Electrophoresis). A tumor cell population depends on neovascularization (angiogenesis) for its survival. This phenomenon, which was studied through immunohistochemistry, is considered to take place as a result of tumor-host interaction. Morphological characteristics of the tumor cell population and tumor-host relationships can be described through microscopic interpretation and measured in a malignancy grading system according to Jakobsson or tumor front grading system according to Bryne. Previous studies on the prognostic value of biological actors hav often shown contradictory results and no marker has emerged as superior to TNM classification. This was also our experience when oral carcinomas of different subsites and of different stages were included. However, when the materials were compiled with an effort to control confounding factors, such as stage, site and treatment, subgroups of patients could be identified through biological factors. In stage I tongue carcinomas, a severe DNA deviation was found to correlate with the risk of local recurrence in the tongue. The DNA deviation of the recurring tumors was comparable to the DNA deviation of advanced tongue carcinomas. Overexpression of the p53 protein correlated with the appearance of cervical metastases (regional recurrence), which also could be predicted through the Jakobsson malignancy grading system. But, when the presence of p53 mutations were investigated through CDGE and sequencing (exons 5-8) no significant prognostic impact could be detected for stage I tongue carcinomas. Preneoplastic lesions with a later development of carcinoma or carcinoma in situ on the same localization, revealed the same nuclear DNA content and frequency of p53 protein overexpression as the subsequent carcinomas, irrespective of the grade of dysplasia. Dysplastic lesions prior to carcinomas on the same localization displayed a more severe DNA deviation than dysplastic lesions without further progression.

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