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

1Department of Oral Diagnosis, School of Dentistry, University of Campinas2Unit of Cancer Research and Translational Medicine, Faculty of Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu3Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasília

4Department of Pathology, Institute of Oral and Maxillofacial Disease, HUSLAB, Helsinki University Hospital, University of Helsinki5Integrated Biosciences, School of Clinical Dentistry and Sheffield Cancer Centre, University of Sheffield

Abstract

Aim: To perform a meta-analysis to assess whether the presence of cancer-associated fibroblasts (CAF) is a prognostic marker of oral squamous cell carcinomas (OSCC).

Methods: Immunohistochemical studies assessing the prognostic relevance of CAF (alpha smooth muscle actin (α-SMA)-positive fibroblasts) in patients with OSCC were systematically reviewed using Cochrane, Lilacs, PubMed, Scopus, and Web of Science databases. The outcomes assessed were overall survival (OS) and disease-free survival (DFS). The meta-analysis was performed using the random- and fixed-effects model with adjusted hazard ratio (HR) and 95% confidence intervals (95% CI) as effect measures. The methodological quality of the included studies was assessed using the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system.

Results: The presence of high levels of CAF in the stroma of OSCC predicted shortened time to DFS (HR = 3.32, 95% CI: 2.09–5.26, P < .00001) and an overall decrease in survival (HR: 2.16, 95% CI: 1.60–2.92, P < .00001). Moreover, high presence of CAF was frequently reported in association with parameters that worsen the prognosis in OSCC, including advanced disease stage (TNM classification), recurrence, tumor grade, depth of invasion, vascular, lymphatic and neural invasion, and extranodal metastatic spread.

Conclusion: The presence of CAF, as assessed by α-SMA-positive fibroblasts in the stroma, indicates poor prognosis in patients with OSCC.

MRD is supported by grants from the Coordination for the Improvement of Higher Education Personnel-CAPES, Brasilia, Brazil, and Medical Research Center, University of Oulu, Finland. Research in Coletta's laboratory is funded by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo-FAPESP, São Paulo, Brazil; and Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq, Brasília, Brazil.