ArticleThe journal of pathology. Clinical research2026
The prognostic significance of the IASLC grading system in ALK-positive invasive non-mucinous adenocarcinoma of the lung: correlation with clinicopathological features.
Article in The journal of pathology. Clinical research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The prognostic value of the International Association for the Study of Lung Cancer (IASLC) grading system in anaplastic lymphoma kinase (ALK)-positive invasive non-mucinous adenocarcinoma (INMA) remains unclear, particularly in relation to the tumor immune microenvironment (TIME). This retrospective study included 108 patients with ALK-positive INMA. Tumors were graded according to the IASLC system. Clinicopathological features, progression-free survival (PFS), and overall survival (OS) were analyzed. Immunohistochemistry was used to assess PD-L1 expression and tumor-infiltrating lymphocytes (TILs), including CD4+, CD8+, and FoxP3+ regulatory T cells. Associations were evaluated using Kaplan-Meier analysis, Cox regression models, and correlation analyses. Higher IASLC grades were significantly associated with more aggressive pathological features, elevated PD-L1 expression, and shorter progression-free survival (PFS). Higher-grade tumors exhibited enhanced T-cell infiltration, predominantly driven by CD8+ T cells, while no significant difference in FoxP3+ Treg density was observed across grades. Notably, the CD4:CD8 ratio decreased, whereas the CD8:FoxP3 ratio increased with tumor grade, indicating a shift toward a CD8-dominant immune microenvironment. Importantly, this cytotoxic predominance occurred in parallel with elevated PD-L1 expression, suggesting an immune context consistent with adaptive immune resistance rather than effective anti-tumor immunity. The IASLC grading system effectively identifies a high-risk subgroup of ALK-positive INMA characterized by aggressive tumor behavior and a dynamically regulated immune microenvironment. High-grade tumors exhibit features of immune engagement coupled with checkpoint-mediated regulation, supporting a model of adaptive immune resistance. These findings underscore the necessity of combination therapeutic strategies that simultaneously target ALK and immune checkpoint modulation in high-grade INMA.
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