Abstract
Tumor-infiltrating lymphocytes (TILs) provide prognostic value in invasive breast cancer and guidelines for their assessment have been published. This study aims to evaluate: (a) methods of TILs assessment, and (b) their prognostic significance in breast ductal carcinoma in situ (DCIS). Hematoxylin and eosin sections from two clinically annotated DCIS cohorts; a training set (n = 150 pure DCIS) and a validation set (n = 666 comprising 534 pure DCIS and 132 cases wherein DCIS and invasive breast carcinoma were co-existent) were assessed. Seven different scoring methods were applied to the training set to identify the most optimal reproducible method associated with strongest prognostic value. Among different methods, TILs touching ducts' basement membrane or away from it by one lymphocyte cell thickness provided the strongest significant association with outcome and highest concordance rate [inter-cluster correlation coefficient = 0.95]. Assessment of periductal TILs at increasing distances from DCIS (0.2 , 0.5 , and 1 mm) as well as percent of stromal TILs were practically challenging and showed lower concordance rates than touching TILs. TILs hotspots and lymphoid follicles did not show prognostic significance. Within the pure DCIS validation set, dense TILs were associated with younger age, symptomatic presentation, larger size, higher nuclear grade, comedo necrosis and estrogen receptor negativity as well as shorter recurrence-free interval (p = 0.002). In multivariate survival analysis, dense TILs were independent predictor of shorter recurrence-free interval (p = 0.002) in patients treated with breast conservation. DCIS associated with invasive carcinoma showed denser TILs than pure DCIS (p = 9.0 × 10−13). Dense TILs is an independent prognostic variable in DCIS. Touching TILs provides a reproducible method for their assessment that can potentially be used to guide management
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.The incidence of ductal carcinoma in situ (DCIS) of the breast has dramatically increased after introduction of mammographic screening programs [1, 2]
To mimic the three-tier prognostic classification system of Tumor-infiltrating lymphocytes (TILs) in melanoma [20] and based on the outcome analysis, TILs were further defined into three-groups; absent/very scanty, sparse (6–20 cells/DCIS duct) and dense (>20 cells/DCIS duct) TILs
This was based on counting TILs around DCIS ducts, in up to 20 ducts per case, and the total number of TILs was divided by the number of DCIS ducts resulting in the mean TILs number
Summary
In previous studies on invasive breast cancer, dense TILs were shown to augment effect of chemotherapy providing better prognosis mainly in triple-negative breast tumors [12, 13]. Following demonstration of their prognostic significance in invasive breast carcinoma and their potential clinical application, guideline recommendations for TILs evaluation have been published [14, 15]. Despite the reported role of TILs in DCIS [5, 16], studies utilizing the invasive carcinoma guidelines for TILs assessment in the context of DCIS did not find any association with outcome [15, 17]. This study aims to identify the optimal method of TILs evaluation in DCIS in terms of reliability, reproducibility and prognostic significance with recurrence through utilization of a large well-annotated DCIS cohort with long-term follow-up
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