Abstract
PURPOSE: The presence of a high degree of tumor-infiltrating lymphocytes (TIL) has been proven to be associated with outcome in patients with non-small cell lung cancer (NSCLC). However, recent evidence indicates that tissue architecture is also prognostic of disease-specific survival and recurrence. We show a set of descriptors (spatial TIL, SpaTIL) that capture density, and spatial colocalization of TILs and tumor cells across digital images that can predict likelihood of recurrence in early-stage NSCLC. EXPERIMENTAL DESIGN: The association between recurrence in early-stage NSCLC and SpaTIL features was explored on 301 patients across four different cohorts. Cohort D(1) (n = 70) was used to identify the most prognostic SpaTIL features and to train a classifier to predict the likelihood of recurrence. The classifier performance was evaluated in cohorts D(2) (n = 119), D(3) (n = 112), and D(4) (n = 112). Two pathologists graded each sample of D(1) and D(2); intraobserver agreement and association between manual grading and likelihood of recurrence were analyzed. RESULTS: SpaTIL was associated with likelihood of recurrence in all test sets (log-rank P < 0.02). A multivariate Cox proportional hazards analysis revealed an HR of 3.08 (95% confidence interval, 2.1-4.5, P = 7.3 × 10(-5)). In contrast, agreement among expert pathologists using tumor grade was moderate (Kappa = 0.5), and the manual TIL grading was only prognostic for one reader in D(2) (P = 8.0 × 10(-3)). CONCLUSIONS: A set of features related to density and spatial architecture of TILs was found to be associated with a likelihood of recurrence of early-stage NSCLC. This information could potentially be used for helping in treatment planning and management of early-stage NSCLC.See related commentary by Peled et al., p. 1449.