Prognostic value of the immunohistochemical detection of cancer‐associated fibroblasts in oral cancer: A systematic review and meta‐analysis

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Oral squamous cell carcinomas (OSCC), representing more than 90% of cases of oral cancer, is the eleventh most commonly diagnosed cancer worldwide, accounting for 300 000 new cases and 145 000 deaths per year.1 The prognosis of OSCC is widely variable, depending largely on clinical stage (TNM classification) and localization in the oral cavity. Overall, the 5‐year survival rate is approximately 50%, which has remained unchanged over recent decades.2 Although advances in molecular biology have helped identify and characterize genes and molecular pathways involved in development and disease progression, little impact on predicting disease behavior, prognosis, and treatment response has resulted.3 Therefore, markers for early detection, differentiating low‐ and high‐risk groups, personalizing treatment plans, and post‐therapeutic monitoring are urgently required.
During OSCC invasion, tumor cells induce a series of modifications in the adjacent stroma, promoting a unique environment (commonly termed the tumor microenvironment) composed of an extracellular matrix scaffold, vascular structures, and cellular components including adipocytes, muscle cells, mast cells, immune and inflammatory cells, and fibroblasts. Some fibroblasts acquire an activated phenotype and are termed cancer‐associated fibroblasts (CAF; also known as peritumoural fibroblasts, activated fibroblasts, or myofibroblasts).4 CAF are thought to have a variety of origins, including transformation from resident fibroblasts, epithelial cells, and pericytes or differentiation from mesenchymal stem cells.5 There is no specific marker for CAF, but alpha smooth muscle actin (α‐SMA) is the most used and reliable marker for detecting CAF.6 CAF are found in approximately 60% of OSCC, frequently in close contact with the tumor islands,7 but are not found in tumor‐free tissues and in the adjacent stroma of potentially malignant disorders of the oral mucosa.9 Moreover, in vitro studies have demonstrated that transforming growth factor beta (TGF‐β) released by oral carcinoma cells induces CAF activation,8 suggesting that the emergence of CAF within tumor microenvironment is influenced by tumor cell invasion.
Previous studies have demonstrated that increased density of CAF in the stroma of OSCC correlated with higher mortality.7 Further analyses revealed that CAF promote tumorigenesis of OSCC cell lines via an enriched and specific secretome, which contains activin A, fibronectin type III domain‐containing 1 (FNDC1), serpin peptidase inhibitor type 1 (SERPINE1), stanniocalcin 2 (STC2), among other proteins putatively related to tumorigenesis.13 Importantly, Marsh and collaborators12 provided evidence that the presence of CAF in the stroma of OSCC is a stronger predictor of mortality than the classical TNM staging. However, other studies did not find a significant association between CAF and survival of patients with OSCC.15 The aim of this systematic review and meta‐analysis was to verify the value of CAF for the prognosis of patients with OSCC. The present study provides evidence that immunohistochemical detection of CAF (α‐SMA‐positive fibroblasts) is an independent marker of shortened disease‐free survival (DFS) and poor overall survival (OS) in patients with OSCC.
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