Doctor of Philosophy in Craniofacial Science (PhD)
The role of the immune microenvironment in oral carcinogenesis
I owe sincere gratitude to my amazing supervisor Dr. Denise Laronde for her continuous support, encouragement, and the long, late nights she puts into helping her students. She is the perfect combination of supervisor, mentor, and friend. Not only does she support her own students, but has been known to offer advice, support and encouragement to other grad students who seek her out. She leads with a collaborative approach, versus a "top down" approach. To quote another grad student in our faculty, "She is a great leader, because she is not afraid to create new leaders." This is truly a meritorious and extraordinary quality.
A major barrier to oral cancer prevention is the lack of risk predictors for the malignant progression of oral potentially malignant lesions (OPML). OPML with evidence of dysplasia are at risk of progressing to oral cancer. However, not all will progress and predicting which low- grade dysplasia (LGD; mild/moderate dysplasia) are at risk of progression is challenging. The overall goal of this thesis was to advance risk stratification and to improve the prediction of malignant progression in LGD. Three research projects were developed to accomplish this goal. Each identified important insights into the phenotypic changes associated with malignant transformation and advanced risk prediction by exploring the association between histological, clinical and molecular biomarkers and malignant progression. The first project revealed that dysplasia with or without lichenoid mucositis (LM) had similar cancer risk and that pathologists and clinicians should not discount dysplasia in the presence of LM. The second project compared the clinical and molecular features of LGD in smokers in contrast to those of non-smokers (NS) and confirmed that NS possess an increased risk of progression, and progressed more quickly, than smokers. These findings emphasize the need for clinicians to consider smoking history (or the lack thereof) and molecular profiles in the triage and management of LGD. The final project aimed to advance a risk prediction model using microsatellite analysis for loss of heterozygosity (LOH) and repeated measures of clinicopathological features. Multivariable analysis showed that after LOH risk category, temporal repeated measures of toluidine blue status was the most significant predictor of progression. Two risk prediction models are presented and provide a systematic decision-making process for these very heterogeneous group of lesions. Patients at higher risk could be offered intensified surveillance or targeted interventions based on their predicted risk of disease, while patients at low risk would be spared from excessive screening and treatment. This body of work has advanced the risk stratification of LGD and presents an important framework to give scientists and clinicians a better view into the natural history of the disease and a novel approach to integrate repeated measurements of change over time into risk models.
Objectives: While oral cancer is one of the most common malignancies across the globe, the vast majority of cases arise in South Asian countries. Currently in British Columbia, nearly 10% of the population is of South Asian ethnicity. Evidence suggests that risk factors within this population play a significant role in oral cancer incidence and clinical presentation. As a significant subgroup, it is crucial to gain insight into the trends of oral precancerous and cancerous lesions in this population. This thesis aims to explore differences in oral cancer, dysplasia and hyperplasia between South Asians and the general population, as well as differences in anatomical lesion sites and access to care. This thesis also examines biopsy activity by dental practitioners across the province. Methods: Data from the British Columbia Oral Biopsy Service (OBS) and the British Columbia Cancer Registry (BCCR) were used to identify cases of squamous cell carcinoma, carcinoma in situ, dysplasia, and hyperplasia in the oral cavity in British Columbia in 2007 and 2013. Name recognition software programs were utilized to determine ethnicity. Results: Oral cancer, dysplasia, and hyperplasia trends vary between South Asians and the general population. There are more cases among South Asian males than males in the general population. South Asian cases are diagnosed at younger ages than in the general population, with a mean age at diagnosis below the age of sixty years. While common lesion sites among South Asians include the gingiva and buccal mucosa, these lesion sites are common within the general population as well. The number of biopsies received by the OBS increased by 36% from 2007 to 2013. The number of dental practitioners performing biopsies also increased, as well as the overall number of South Asian cases seen in the OBS. Conclusion: Results from this thesis provide current information regarding trends and risk factors for hyperplasias, dysplasias, and oral cancers in the South Asian population in BC. These findings, along with spatial analysis of biopsy trends, provide a basis for tailored screening programs and oral cancer prevention initiatives in British Columbia.
One reason for the poor survival rate of oral cancer is the high rate of recurrence (REC). The objective of this study is to investigate how fluorescence visualization (FV) may play in the prediction of oral cancer REC at a site previously treated for oral cancer. We will confirm previously identified clinical factors for REC such as lesion presence and TB status, and analyze if any combinations of these three factors at varying follow-up time intervals can suggest a higher risk for REC. Information for this study will come from patients enrolled in the BC Oral Cancer Prediction Longitudinal study. Patients are eligible if: 1) they had a primary tumour diagnosis of SCC or CIS; 2) were treated with curative intent; and 3) had at least one recall visit within one year after completion of initial treatment. Data analyzed: 1) demographic and lifestyle habit information; 2) primary tumour information; 3) oral clinicopathological features during follow-up at 6, 12, 18, and 24 months. For this thesis, 232 patients have been identified that fit the inclusion criteria. Of those, 34 patients developed recurrence, and 198 patients remained tumour free throughout their follow-up period. Demographic, smoking, alcohol and FV status were not found to be associated with a recurrence. Of significance, OPL status at all follow-up intervals (P
Oral squamous cell carcinoma (SCC) has a poor survival rate mainly due to late stage diagnosis and the high risk of developing second primary tumours (SPTs). Risk factors associated with progression of primary oral premalignant lesions (OPLs) to SCC have been validated; however, little research has been done on the risk predictors of SPTs. The objective of this thesis was to identify the demographic, clinicopathological and molecular risk factors associated with oral SPTs as well as those associated with second oral premalignant lesion (SOPL) progression to an oral SPT. From a cohort of the Oral Cancer Prediction Longitudinal study, data collected included: 1) demographic and habit information; 2) primary tumour information; 3) clinicopathological features during follow-up; and 4) toluidine blue (TB) and florescence visualization results. SOPL biopsy samples were analyzed for loss of heterozygosity (LOH) at regions previously identified as high risk for primary OPL progression. Of 296 patients who were followed-up subsequent to curative primary tumour treatment, 23 (8%) developed SPTs. Sixty-seven (23%) patients developed SOPLs, of which nine (14.5%) progressed to SPTs. Patients with primary tumours located on low-risk sites had an increased risk of SPTs (P=0.004) and SOPLs (P=0.009). Tobacco (P=0.046) and alcohol consumption (P=0.019) were each associated with the presence of SOPLs. The presence of an SOPL was associated with risk for SPT development, independent from histopathological diagnosis (P