Cancer‐associated fibroblasts are an infrequent finding in the microenvironment of proliferative verrucous leukoplakia‐associated squamous cell carcinoma

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Oral cancer (OSCC) represents 2.8% of all new cancer cases in the United States with an estimated 5‐year survival of 83% for localized disease, 47% for OSCCA that presents with lymph node metastasis, and 18% for OSCCA that presents with a distant metastasis 1. Increasing evidence seems to indicate that OSCCA is a heterogeneous disease rather than a single entity with clinically relevant subtypes 2.
Within the oral cancer community, there is a unique subgroup of patients who develop OSCCA with a prior history of proliferative verrucous leukoplakia (PVL). PVL, a ‘potentially malignant disorder’ is a unique type of oral leukoplakia that presents in multiple sites within the oral cavity and is highly difficult to treat, resulting in multiple recurrences over a time span of many years 4. PVL presents clinically in a progressive series of stages. Initially, the lesions appear innocuous and are indistinguishable clinically from leukoplakia. The second developmental stage is clinically exophytic lesions, diagnosed microscopically as verrucous hyperplasia and/or verrucous carcinoma 4. In the later stages, over 74% of patients with PVL will experience multiple and multifocal incidences of OSCCA, particularly on the gingiva, palate, and buccal mucosa 5. The diagnosis is retrospective because the early stages lack identifiable microscopic or clinical features that can distinguish PVL from other clinically similar lesions. In a previous study, we compared the clinicopathological features of OSCCA arising in PVL patients (p‐scca) with conventional buccal mucosa, gingival, and palatal OSCCA (c‐scca) and discovered that p‐scca patients seem to present with more favorable prognostic features and longer duration of illness (DOI). Based on the results of this earlier study, we suggested that p‐scca should be considered a separate clinical entity 6.
Current treatment strategies for treating OSCCA include wide tumor resection with supplement radiotherapy and/or chemotherapy for a subset of patients with negative clinical features such as lymph node metastasis and/or positive surgical margins 7. Designing new treatment strategies such as targeted and molecular‐based treatments may improve patient outcome. In the last two decades, we have discovered that cancer is a complex and heterogeneous disease that involves a complex network of communication between the malignant cancer cells and non‐malignant cells found within the supportive microenvironment surrounding the tumor. Heterotypic signals originating within the stroma activate a variety of growth factors that stimulate the resident fibroblasts into becoming ‘cancer‐associated fibroblasts’ (CAFs) 8. CAFs, a subpopulation of cells of various origins with diverse functions, are implicated in a variety of negative properties associated with cancer behavior 9. Unlike quiescent fibroblasts, activated fibroblasts (myofibroblasts) may be identified by their wide‐spread expression of alpha‐smooth muscle actin (α‐SMA) 8. Myofibroblasts are a rich source of chemokines, cytokines, inflammatory mediators, extracellular proteins, and extracellular matrix degrading proteases [matrix metalloproteinases (MMPs)] 8. In malignancies, these myofibroblasts, also known as CAFs, are capable of providing the necessary tools for inducing angiogenesis, local invasiveness, and metastasis 12. Practically, recent investigations have shown that (CAF)‐specific proteins serve as both prognostic markers and targets for anticancer drugs 15.
This study was initiated to explore the presence of CAFs in two subgroups of oral cancer patients (c‐scca and p‐scca) and correlate its expression with various clinicopathological characteristics to try and determine the role of the tumor microenvironment in driving PVL and non‐PVL‐related carcinomas.
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