Nature and Significance of Stromal Differentiation, PD-L1, and VISTA in GIST: Shifting Current Paradigms

Abstract The nature and significance of stromal differentiation (SD), program death-ligand 1 (PD-L1), and v-domain Ig suppressor of T cell activation (VISTA) in gastrointestinal stromal tumor (GIST) is largely unknown. Looking forward, the assessment of SD and immune check point inhibition will become more ubiquitous in surgical pathology. Immature, myxoid stroma has been found to be a poor prognostic signature in many cancer subtypes (colon, breast, cervix, esophagus, stomach); although little is known regarding its significance in GIST. For immune check-point inhibition, studies have demonstrated high PD-L1 and expression to be associated with patient outcomes in numerous cancer subtypes. The present body of work aims to discover the role of SD, PD-L1 and VISTA: both in terms of its nature, and its significance in a clinical setting. Here we found PD-L1 expression in immune cells (IC) and immature SD to be associated with worse cancer free survival, while positive VISTA expression was found to be associated with improved outcomes. High-grade immature SD had the highest propensity for death/recurrence and was the only variable found to have prognostic significance on multivariate analysis. Our findings support the evaluation of SD, PD-L1 and VISTA in GIST, with clinical practice implications for pathologists. Ultimately, we hope our findings lead to improved prognostication, further optimization of therapeutics, and improved outcomes in a true clinical environment. For GIST, tumoral differentiation (TD) may be performed in isolation by pathologists, but cautiously; PD-L1 and VISTA could be on the cutting edge of an immunotherapeutic revolution, and SD may be the answer to clinical heterogeneity in GIST. We hope that this work can serve as a lexicon and a guide for discovering the essence of stroma in GIST, while also being a catalyst for pathologists to shoulder the adoption of SD in cancer.