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Thesis Format



Master of Science




Darling, Mark


Title: Evaluating the utility of S100A7 in identifying oral dysplastic lesions that will progress to oral squamous cell carcinoma Introduction: Recently, S100A7 has been shown to be a potential useful marker for identifying oral lesions at risk of transformation from dysplasia to squamous cell carcinoma. Our hypothesis is that high S100A7 protein expression predicts the transformation of oral epithelial dysplasia to malignancy. The objective of our study is to semi-quantitatively evaluate the level of S100A7 expression in dysplastic lesions which have transformed into oral squamous cell carcinoma using immunohistochemistry, and correlate these results with other methods of analysis including the standard 3-tier histopathological diagnosis, the 2-tier histopathological diagnosis, and S100A7 evaluation utilizing StraticyteTM, a digital proprietary technique designed to communicate S100A7 expression in dysplastic tissue as a 5-year risk of malignant transformation. In addition, a pilot study evaluating the utility of QuPath, an open source software for bioimage analysis, will be assessed to determine if it more reliably correlates with the known outcomes of the sample populations. MAPK pathway proteins ERK1/2, p38, and JNK, will also be assessed for dysregulated phosphorylation in each of the sample populations.

Methods: Formalin fixed paraffin embedded specimens from 48 patients with oral squamous cell carcinoma, where from the same site, a non-cancerous biopsy had been previously obtained, were included in the study. Thirty five (35) patients with multiple biopsies of dysplasia which had not advanced to squamous cell carcinoma, and 25


patients with a diagnosis of hyperkeratosis were included as control groups. In addition to the 3-tier dysplasia diagnoses of mild, moderate and severe, 2-tier diagnoses of low grade or high grade were assigned to each of the tissue samples. Specimens were stained for S100A7 protein using a standard immunohistochemistry protocol. Expression of S100A7 was assessed semi-quantitatively, using an intensity and proportion scale, as well as by image analysis using StraticyteTM and QuPath. As S100A7 is associated with activation of the MAPK signaling pathway activity, phosphorylated proteins ERK1/2, p38, and JNK were also evaluated via immunohistochemistry.

Results: Manual scoring of S100A7 stainingof epithelium in the three study populations was carried out and compared to the 3-tier and 2-tier grading schemes, StraticyteTM, and QuPath. Manual scoring had strong correlational relationships with QuPath and Straticyte based on Pearson correlation coefficients, and allowed differentiation of dysplastic from the Control groups. StraticyteTM, a test which utilizes a proprietary algorithm for the epithelial S100A7 stain assessment, allowed differentiation, of dysplastic tissue samples that progressed to OSCC, from those that did not (p < 0.05).

Conclusion: S100A7 holds potential for assisting in the identification of patients with oral premalignant lesions with dysplasia, that have an increased risk of malignant transformation as compared to those who do not.

Summary for Lay Audience

Despite increased awareness for the risk factors of oral cancer, there continues to be an increase in the number of cases globally and in Canada. Unfortunately, the prognosis is still grim and mortality also continues to rise. It is typical for cancerous lesions within the oral cavity to arise from pre-existing lesions, which as a group are called potentially malignant oral lesions. Therefore, in an attempt to identify and treat these lesions early, biopsies are conducted by health care practitioners and the tissue is viewed under microscopy to identify lesions that are potentially cancerous before they become invasive and spread to other parts of the body. However, it can be difficult to identify which of these lesions will progress to cancer, especially early. In this study we looked at a protein that is found within cells of the mucosa, called S100A7, to see if we could identify a change in its expression in lesions that progress to cancer as compared to those that do not. We looked at tissue from patient biopsies from three categories: Those that eventually developed cancer, those that did not, and those that had lesions that demonstrated relatively normal tissue. We looked to see if there were differences in S100A7 between these groups. Our evaluation consisted of a manual score, in which we evaluated the tissue samples under the microscope and scored the S100A7 expression, a commercially available digital scoring method called StraticyteTM in which a proprietary algorithm is used to evaluate and score S100A7 expression to determine a 5-year risk of progression to cancer, and a pilot study to see if an open-source bioimage analysis software, QuPathTM had utility in evaluating the tissue consistently as well. We looked to see if any method more reliably identified lesions likely to progress to cancer as compared to the conventional 3-tier and 2-tier methods of diagnosing tissue dysplasia.

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Pathology Commons