Diffuse distribution of tumor-infiltrating lymphocytes is a marker for better prognosis and chemotherapeutic effect in triple-negative breast cancer

  • Akira I. HidaEmail author
  • Takahiro Watanabe
  • Yasuaki Sagara
  • Masahiro Kashiwaba
  • Yoshiaki Sagara
  • Kenjiro Aogi
  • Yasuyo Ohi
  • Akihide Tanimoto
Preclinical study



High-density tumor-infiltrating lymphocytes (TILs) are a prognostic marker for triple-negative breast cancer (TNBC). However, lymphocytic infiltration is heterogeneous in its pattern. We aimed to explore the utility of TIL distribution patterns against TIL density for predicting TNBC prognosis and chemotherapeutic effects.


Primary invasive TNBC cases were retrieved from a single institutional cohort, and archived samples were reviewed by two board-certificated pathologists. We used 154 consecutive surgical specimens from patients with standard adjuvant therapy, and 80 biopsies taken before primary systemic chemotherapy. The average density of stromal TILs was scored at 10% intervals, while the distribution pattern of TILs was evaluated as diffuse or non-diffuse. The association between TILs and prognosis or pathological complete response (pCR) was statistically analyzed.


A diffuse pattern of TILs at primary surgery correlated with better prognosis (relapse-free survival [RFS], hazard ratio [HR] 3.71, 95% confidence interval [CI] 1.60–8.57; overall survival [OS], HR 3.87, 95% CI 1.46–10.27), as well as high TIL density (≥ 50%; RFS, HR 4.51, 95% CI 2.06–9.90; OS, HR 3.28, 95% CI 1.32–8.14). Diffuse TIL pattern and nodal status were independent prognostic factors in multivariate analysis. Diffuse TIL pattern upon biopsy was associated with higher pCR rate (diffuse, 46%; non-diffuse, 21%; P = 0.032). All high TIL cases had diffuse patterns and the best outcome. Interobserver concordance was moderate (k = 0.53–0.55; distribution pattern) to good (weighted k = 0.67–0.69; density), and it was faster to assess the distribution pattern than to assess the density of TIL.


Showing similar clinical impacts to the TIL density, diffuse TILs could be a predictive marker for better prognosis and higher pCR. The assessment of TIL distribution pattern is simple, faster, and practical. Heterogeneous tumor immunity may contribute to further stratification of TNBC treatment.


Tumor-infiltrating lymphocytes Triple-negative breast cancer Heterogeneous tumor immunity Pathological complete response Interobserver concordance 



Tumor-infiltrating lymphocyte


Triple-negative breast cancer


Estrogen receptor


Progesterone receptor


Human epithelial growth factor receptor 2


Relapse-free survival


Overall survival


Pathological complete response




Primary systemic chemotherapy


Lymphocytic-predominant breast cancer



The authors would like to thank S. Haraguchi at the research center of Sagara Hospital for extracting the necessary information from the database, and the technicians at the Department of Pathology at Sagara Hospital for their assistance in dealing with archived samples. We thank H. Nikki March, PhD, from Edanz Group ( for editing a draft of this manuscript.

Authors’ contributions

AH, KA, and YO planned the study. AH and TW conducted pathological assessments. Yasuaki S., Yoshiaki S., and MK performed biopsies and/or surgeries, and provided oncological treatment. KA supervised the whole study. The manuscript was mainly written by AH, and amended by YO and AT. All authors read and approved the final manuscript.


This study was funded by the Division of Clinical Research Promotion at the National Hospital Organization Shikoku Cancer Center.

Compliance with ethical standards

Conflict of interest

AH received personal fees as honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, and Novartis Pharma. YS received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Pfizer, Eisai, Novartis Pharma, Taiho Pharmaceutical, and Takeda Pharmaceutical. MK received personal fees as honoraria from Chugai Pharmaceutical, Eisai, AstraZeneca, Pfizer, Taiho Pharmaceutical, Novartis Pharma, Takeda Pharmaceutical, Daiichi Sankyo, Kyowa Hakko Kirin, Shionogi, and Asashi Kasei. KA received personal fees as honoraria from Chugai Pharmaceutical, Eisai, AstraZeneca, Taiho Pharmaceutical, Novartis Pharma, Daiichi Sankyo, Mochida Pharmaceutical, Ono Pharmaceutical, and Eli Lilly Japan, and his institution received research funds from Chugai Pharmaceutical, Eisai and Sanofi. The other authors have no competing interests to declare.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee (No. 14-06 & 17-33) and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Formal consent was not required for this type of study.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology, Field of OncologyKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  2. 2.Department of PathologyHyogo College of MedicineNishinomiyaJapan
  3. 3.Department of Breast Surgical OncologyHakuaikai Sagara HospitalKagoshimaJapan
  4. 4.Department of Breast OncologyNational Hospital Organization Shikoku Cancer CenterMatsuyamaJapan
  5. 5.Department of PathologyHakuaikai Sagara HospitalKagoshimaJapan
  6. 6.Department of PathologyMatsuyama Shimin HospitalMatsuyamaJapan

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