fnVulvar squamous cell carcinoma (vSCC) is a gynecologic malignancy associated with devastating morbidities, high risk for tumor recurrence, and frequent nodal metastasis. Tumor features that lead to aggressive behavior in vSCC are not well-defined, leaving a gap in knowledge that impacts the clinical approach to diagnosis and treatment of this cancer. The aim of this dissertation was to understand the pathologic and molecular features of vSCC that predict adverse clinical outcomes.
Tumors from a cohort of vSCC patients were classified based on the pattern of tumor invasion and stromal response. Initial analysis demonstrated that infiltrative vSCCs with fibromyxoid (FMX) stroma are associated with higher risk for tumor recurrence, nodal metastases, and extracapsular extension (ECE) than pushing or nested tumors with lymphoplasmacytic (LPC) stroma. Based on these results, I investigated the pathologic and molecular features that distinguish infiltrative vSCC with FMX stroma from pushing or nested vSCC with LPC stroma and the association of these features with patient outcomes.
Using immunohistochemistry, I determined that perineural invasion (PNI) is highly associated with tumor recurrence, and that infiltrative tumors with FMX stroma are more likely to exhibit PNI than the pushing or nested variants with LPC stroma. My results further indicate that epithelial-mesenchymal transition (EMT) is significantly associated with tumor recurrence and more likely to occur in infiltrative tumors. These data implicate invasion of the local nerves and altered tumor cell phenotype as contributors to the aggressive nature of the infiltrative tumor variant.
To better understand the role of stromal response in tumor behavior, I examined the immune response in vSCC. My results indicate that relative to tumors with a FMX stroma, tumors with LPC stroma have a more robust T-lymphocyte-mediated immune response and an immune suppressive profile as defined by higher proportions of FoxP3+ T-regulatory cells and increased expression of the immune-suppressive protein PD-L1. These results suggest a role for immune evasion as a mechanism of progression from a less aggressive to more aggressive tumor phenotype.
Finally, I used an unbiased, label-free LC-MS/MS proteomics approach to profile differences in protein expression between infiltrative and pushing or nested tumor variants. Results from this proteomic study identified proteins that were differentially expressed in these tumors and were associated with different outcomes. In addition, bioinformatics analyses of these differences indicate that signaling pathways involved in the immune response differed between infiltrative and pushing or nested tumors, which is consistent with the differences observed using an immunohistochemical approach.
Overall, my findings demonstrate the heterogeneous nature of vulvar tumors and identify specific pathologic and molecular features that contribute to aggressive tumor behavior in vSCC. Based on my results, I propose a tumor progression model suggesting that PNI, EMT, and lack of host immune response contribute to aggressive behavior in infiltrative tumors with FMX stroma. In contrast, a robust inflammatory response and lack of PNI or EMT result in less aggressive behavior in pushing or nested tumors with LPC stroma. Recognizing and understanding features such as PNI, EMT, and immune evasion could alter the diagnostic and treatment approach for this cancer. In addition, by identifying pathways involved in the aggressive behavior of vSCC, my results should stimulate further investigation into the mechanisms underlying tumor development and progression.
|Advisor:||Post, Steven R., Quick, Charles M.|
|Commitee:||Chambers, Timothy, Gottschall, Paul, Kelly, Thomas, Post, Steven R., Quick, Charles M.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 77/11(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Pathology, Oncology|
|Keywords:||Gynecology, Invasive patterns, Oncology, Prognostic indices, Stromal response, Vulvar carcinoma|
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