Cancer-Associated Fibroblast Density, Prognostic Characteristics, and Recurrence in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis

Alexander M Knops; Andrew South; Ulrich Rodeck; Ubaldo Martinez-Outschoorn; Larry A Harshyne; Jennifer Johnson; Adam J Luginbuhl; Joseph M Curry

doi:10.3389/fonc.2020.565306

Cancer-Associated Fibroblast Density, Prognostic Characteristics, and Recurrence in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis

Front Oncol. 2020 Nov 27:10:565306. doi: 10.3389/fonc.2020.565306. eCollection 2020.

Authors

Alexander M Knops¹, Andrew South², Ulrich Rodeck², Ubaldo Martinez-Outschoorn³, Larry A Harshyne⁴, Jennifer Johnson³, Adam J Luginbuhl⁵, Joseph M Curry⁵

Affiliations

¹ Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
² Department of Dermatology, Thomas Jefferson University, Philadelphia, PA, United States.
³ Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States.
⁴ Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA, United States.
⁵ Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, United States.

Abstract

Introduction: The progression and clinical course of head and neck squamous cell carcinoma (HNSCC) relies on complex interactions between cancer and stromal cells in the tumor microenvironment (TME). Among the most abundant of these stromal cells are cancer-associated fibroblasts (CAFs). While their contribution to tumor progression is widely acknowledged, and various CAF-targeted treatments are under development, the relationship between CAF density and the clinicopathologic course of HNSCC has not been clearly defined. Here we examine the published evidence investigating the relationship of cancer-associated fibroblasts to local recurrence and indicators of prognostic significance in HNSCC.

Methods: We conducted a meta-analysis of existing publications that compare the relationship between CAF density, local recurrence, and clinically significant pathologic criteria of disease development (T stage, nodal positivity, clinical stage, vascular invasion, perineural invasion, Ki67 expression, and differentiation). Thirteen studies met the selection criteria, providing a total study population of 926 patients. Forest plots and risk ratios were generated to illustrate overall relationships.

Results: Higher CAF density within the tumor microenvironment is associated with advanced T stage, nodal infiltration, clinical stage, vascular invasion, perineural invasion, Ki67 expression, and differentiation (p <0.05). High CAF density is also associated with increased rates of local recurrence (p <0.001).

Conclusions: Across multiple studies, increased CAF density is correlated with histopathological criteria of poor prognosis in HNSCC. These findings highlight that CAFs may play a pivotal role in HNSCC development and progression. Staining for CAFs may represent a valuable addition to current pathologic analysis and help to guide prognosis and treatment. Understanding the mechanisms by which CAFs reciprocally interact with cancer cells will be crucial for optimization of TME-focused treatment of HNSCC.

Keywords: CAF; alpha-smooth muscle actin; cancer-associated fibroblasts; head and neck squamous cell carcinoma; myofibroblast; prognosis; tumor microenvironment.

Publication types

Systematic Review