Effect of automated TIL quantification in early-stage melanoma on accuracy of standard T staging using AJCC guidelines.

Abstract

10076 Background: Patients diagnosed with early stage melanoma are at risk of recurrence and death. Adjuvant therapy decreases risk but incurs toxicity and expense. While tumor-infiltrating lymphocytes (TILs) improve prognosis, studies have shown conflicting results due, at least in part, to inter-observer variability. Thus, TILs are not included in standard American Joint Committee on Cancer (AJCC) staging. Here, we quantitatively analyze TILs in hematoxylin and eosin (H&E) melanoma images using two machine learning algorithms. Methods: H&E images were evaluated by two methods for patients with resectable stage I-III melanoma from Columbia (N = 81) and validated using samples from Geisinger and Moffitt (N = 128). For both methods, H&E images were manually annotated using open source software, QuPath, to specify tumor regions. For Method A, images were divided into patches and, for each patch, a probability was generated to detect lymphocytes. Patches above a set threshold were considered to be “TIL positive”. Ratio of TIL positive patches to total patches was assessed for every image. For Method B, a classifier was manually trained in QuPath and then applied on each image to determine the ratio of the areas of all immune cells to all tumor cells as previously published. Cutoff values to define high and low risk groups were established based on a test set and then validated in an independent cohort. Results: Both methods distinguished patients with visceral recurrence from those without for the Columbia training set (Method A p = .0015, Method B p = .043). Using Method A, Kaplan-Meier curve at the selected cutoff also correlated significantly with disease specific survival (DSS) for Columbia (p = .022) and was validated in the Geisinger/Moffitt (p = .046) cohort. Cox analysis using Method A showed that TIL status predicted DSS in the validation set (p = .047) and added significantly to depth and ulceration (HR = 3.43, CI: 1.047-11.257, p = .042). Conclusions: Both open source machine learning algorithms find significantly higher TILs in patients who do not develop metastasis. Notably, Method A may add to standard predictors, such as depth and ulceration. These results demonstrate the promise of computational algorithms to enhance visual grading, and suggest that digital TIL evaluation may add to current AJCC staging. [Table: see text]