Two progressive pathways of microinvasive carcinoma: low-grade luminal pathway and high-grade HER2 pathway based on high tumour-infiltrating lymphocytes

J Clin Pathol. 2016 Oct;69(10):890-8. doi: 10.1136/jclinpath-2015-203506. Epub 2016 Mar 30.


Aims: While cancer immunity is involved in tumour progression from the very early stage, no detailed study has been reported on the relationship between 'early-stage' breast cancer and tumour-infiltrating lymphocytes (TILs). We focused on microinvasive carcinoma to investigate the relationship between histological tumour factors and immunity in 'early' breast cancer.

Methods: Of 2593 resected breast carcinomas, 46 microinvasive carcinomas (1.8%) were included. The relationships between tumour characteristics (invasive form, grade, comedo, subtype) and immunological characteristics (TIL, healing) were examined. The invasive form was divided into 'cluster-like' (ie, invasive foci consisted of a small number of cancer cells) and 'non-cluster-like' (ie, nested and classifiable into particular histological type).

Results: Among all cases, 34.8% were grade 1. ER+HER2-, ER+HER2+, ER-HER2+ and ER-HER2- accounted for 58.7%, 8.7%, 28.3% and 4.3%, respectively. Compared with ER+HER2-, ER-HER2+ cases had a significantly stronger association with grade 3 (92.3% vs 0%), comedo (100% vs 55.6%), high TIL (100% vs 29.3%), high CD8+ TIL (92.3% vs 33.3%) and healing (76.9% vs 14.8%) (p<0.001). Compared with 'non-cluster-like', 'cluster-like' carcinoma showed significantly higher rates of HER2 positivity (69.2% vs 24.2%), high TIL (92.3% vs 42.4%) and high CD8+ TIL (76.9% vs 39.4%) (p<0.01).

Conclusions: Our study revealed that microinvasive carcinoma has two progressive pathways; 'low-grade luminal pathway' and 'high-grade HER2 pathway'. HER2-positive cases showed the following unique characteristics: 'high-grade; comedo, high TIL and CD8+ TIL; healing; cluster-like invasion'. These results suggest that the cluster-like invasion might occur because of tumour immunity that leads to disruption of the duct and formation of microinvasive carcinoma in HER2-positive cases.


MeSH terms

  • Adult
  • Aged
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / surgery
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology*
  • Cohort Studies
  • Female
  • Humans
  • Japan
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology*
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism*


  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • Receptor, ErbB-2