Atypical cytological presentation of granular cell tumour: Tumour‐associated fibrosis may affect fine‐needle aspiration cytology accuracy

Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.

Cancer-associated fibrosis is a critical component of the tumor microenvironment (TME) which significantly impacts cancer behavior. However, there is significant controversy regarding fibrosis as a predominantly tumor promoting or tumor suppressing factor. Cells essential to the generation of tissue fibrosis such as fibroblasts and mesenchymal stem cells (MSCs) have dual phenotypes dependent upon their independence or association with cancer cells. Cancer-associated fibroblasts and cancer-associated mesenchymal stem cells have unique molecular profiles which facilitate cancer cell cross talk, influence extracellular matrix deposition, and direct the immune system to generate a pro-tumorigenic environment. In contrast, normal tissue fibroblasts and MSCs are important in restraining cancer initiation, influencing epithelial cell differentiation and limiting cancer cell invasion. We propose this apparent dichotomy of function is due to 1) cancer mediated stromal reprogramming, 2) tissue stromal source, 3) unique subtypes of fibrosis and 4) the impact of fibrosis on other TME elements. First, as cancer progresses, tumor cells influence their surrounding stroma to move from a cancer restraining phenotype into a cancer supportive role. Second, cancer has specific organ tropism thus stroma derived from preferred metastatic organs support growth while less preferred metastatic tissues do not. Third, there are subtypes of fibrosis which have unique function to support or inhibit cancer growth. Fourth, depleting fibrosis influences other TME components which drives the cancer response. Collectively, this review highlights the complexity of cancer associated fibrosis and supports a dual function of fibrosis which evolves during the continuum of cancer growth.