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Thesis Format

Monograph

Degree

Master of Science

Program

Pathology

Supervisor

McCord, Christina

2nd Supervisor

Howlett, Christopher

Co-Supervisor

Abstract

Introduction: Glandular odontogenic cyst (GOC) is an uncommon, developmental cyst of the jaws making up less than 0.5% of odontogenic cysts. GOC is unique to most cysts found in the jaws in that it can have variation in clinical presentation and may behave aggressively. Although benign, aggressive lesions can cause local bony destruction and have a high rate of recurrence, demonstrating some similarity to neoplastic lesions. The molecular pathogenesis of GOC has rarely been investigated and remains unclear. This study aims to use targeted next-generation sequencing techniques to identify potentially pathogenic nucleotide variations in GOC, which may help in understanding the biologic behaviour of these lesions. Because of histopathologic overlap between GOC and other odontogenic lesions, diagnosis can be challenging. Multiple diagnostic criteria have been reported in the literature. As such, this study also aims to contribute histopathologic and clinical data of GOC found within our archives to the literature. We hypothesize that glandular odontogenic cyst shows distinct pathogenic nucleotide variations at both the DNA and RNA level.

Methods: All samples of GOC and odontogenic cysts with features of GOC from 2003-2022 were retrieved from the Western University and London Health Sciences Centre archives. Clinicopathologic data was gathered from the pathology reports and summarized. Histopathologic features were identified and frequency of known microscopic criteria were recorded and summarized. Cysts were regrouped as GOC or non-GOC based on different histologic criteria described in the literature. Targeted next-generation sequencing was used to interrogate a panel of 135 cancer driver genes and 49 fusion driver genes to identify potentially pathogenic mutations in GOC.

Results: A total of 99 specimens were identified from the archives. Histologic diagnosis of GOC was variable amongst the group. We found diagnostic criteria outlined by Fowler et al. to be the most accurate in the diagnosis of GOC in our cohort. When these histologic criteria were applied, we found 36 cases of GOC in our archives. The mean age was 51.6 years old with a male predilection. Most were found in the posterior mandible (44.4%). Histopathologic features most identified in GOC were eosinophilic cuboidal cells, clear cells, and variable thickness in the cyst epithelial lining. Tier I/II variants in NRAS and TP53 genes were identified in one case of GOC. No pathogenic RNA fusions were found.

Discussion: GOC is a challenging diagnosis both clinically and histologically given overlap with other odontogenic cysts and tumours. Correct diagnosis is important due to the higher potential for recurrence compared to other odontogenic cysts, and thus may influence treatment and follow-up. Application of a single classification method, such as that proposed by Fowler et al., may be more accurate in identifying true GOCs from non-GOC lesions than methods currently used. In our samples, we found a frequency of histopathologic features that differs from those found in the literature. Contribution of this data could influence diagnostic decision making in the future. This study is the first to identify potentially pathogenic mutations in NRAS and TP53 genes in glandular odontogenic cyst. This suggests that genetic changes of interest might be present in GOC. However, these findings need further validation. Future studies with a larger cohort of samples could help confirm the molecular pathogenesis of these lesions.

Summary for Lay Audience

Glandular odontogenic cyst (GOC) is a rare cyst that is found in the jaws. Unlike most jaw cysts, GOC can vary in how it appears and can sometimes act aggressively, causing bone damage and can recur after removal, similar to tumours. The exact reasons as to why GOC behave this way are not well understood. This study aims to use advanced genetic techniques, called Targeted Next Generation Sequencing, to identify possible genetic changes in GOC which might help explain its behavior. In addition, diagnosing GOC can be challenging because it shares clinical and microscopic features with other lesions in the jaws. This study also aims to add new data on GOC from our archives to the literature, which may help in diagnosis of these lesions.

We reviewed cases of GOC and cysts with features of GOC in our archives and collected the clinical and histologic data. We found one classification system, outlined by Fowler et al., to be the most useful in diagnosis of these lesions. We found that most lesions were found in middle aged males, most commonly in the posterior aspect of the lower jaw. We also found that certain microscopic criteria were more likely to be present in GOC compared to other cysts with features of GOC, which may aid in diagnosis.

We then used targeted next generation sequencing to examine specific genes in GOC. We found genetic mutations in NRAS and TP53 genes in one case, which suggests that genetic changes may be present in GOC. Future studies with more samples could help confirm these findings.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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