Tumor-Infiltrating Lymphocyte Volume Is a Better Predictor of Disease-Free Survival Than Stromal Tumor-Infiltrating Lymphocytes in Invasive Breast Carcinoma

Elmira Vaziri Fard, MD; Yasir Ali, MD; Xiaohong I. Wang, MD, PhD; Karan Saluja, MD; Michael H. Covinsky, MD; Lei Wang, MD; Songlin Zhang, MD, PhD


Am J Clin Pathol. 2019;152(5):656-665. 

In This Article

Abstract and Introduction


Objectives: Tumor-infiltrating lymphocytes (TILs) have recently emerged as a prognostic factor in breast cancer. In our previous study, we proposed that tumor stroma should also be considered in the calculation of TILs and we introduced tumor infiltration lymphocyte volume (TILV) in triple-negative breast cancer.

Methods: We assessed the disease-free survival predictive value of TILV in all subtypes of invasive breast carcinoma and compared the predictive value of TILV with TILs. Differences between disease-free survival curves were determined by using the log-rank test, and Kaplan-Meier survival plots were generated for both groups.

Results: TILV was significantly correlated with disease-free survival in both invasive ductal carcinoma (P = .03) and all subtypes of invasive breast carcinoma (P = .043), whereas TILs failed to show a statistical significance.

Conclusions: Tumor-stroma ratio needs to be considered in estimation of tumor immunity, and TILV adds more predictive power to TILs.


Breast cancer is the most common cancer among US women (excluding skin cancer), accounting for 29% of newly diagnosed cancers. The lifetime risk of breast cancer in US women is 12.3% (one in eight women), and it is estimated that 231,840 women are diagnosed with invasive breast cancer and 40,290 women die due to breast cancer each year.[1] Based on the molecular subtypes of breast cancer (luminal A and B, triple negative, or human epidermal growth factor receptor 2 [HER-2] enriched), patients are treated with single or combined treatment modalities, including surgery, adjuvant/neoadjuvant chemotherapy, and/or radiation. These treatment modalities are not devoid of adverse complications for the patients and may significantly affect the patients' quality of life. Identifying pathologic markers that predict the response to therapy and the survival is necessary for optimization of treatment and reducing the potentially preventable adverse impacts on patients.

A growing body of study has demonstrated a vital role for the composition of the tumor microenvironment and stromal immune response to tumor cells with prognostic and predictive significance in many types of malignancies, including melanoma, head and neck, breast, bladder, urothelial, ovarian, colorectal, renal, prostate, and lung cancers.[2,3] Tumor-infiltrating lymphocytes (TILs) are considered to reflect the host immune response against cancer. Several studies have shown the prognostic value of stromal TILs in breast cancer.[4–8] Triple negative and HER-2–positive subtypes have been shown to have significantly higher TILs than other molecular subtypes and patients with an extensive immune infiltrate have better responses to treatment and improved survival.[7–10]

To develop a standardized methodology for visual assessment of TILs on H&E sections, the International TILs Working Group 2014 proposed a series of guidelines for grading of TILs.[11] Further studies showed that these criteria are reproducible and applicable to daily practice.[12] However, TILs assessment does not address the overall tumor-stroma ratio (the percentage of tumor stroma). In our previous study, we introduced the concept of tumor-infiltrating lymphocyte volume (TILV) to assess the tumor immune capacity by using the formula: TILV = % tumor stroma × % stromal TILs.[13] Our study showed that TILV was a better predictor for pathologic complete response and the overall survival than TILs in triple-negative breast cancer patients.[13] In the current study, we validated and compared TILV with TILs for the disease-free survival in invasive breast carcinomas including all subtypes.