Diagnostic significance of intratumoral CD8+ tumor-infiltrating lymphocytes in medullary carcinoma

Invasive ductal carcinomas of breast with marked stromal lymphocytic infiltration have come to be classified as lymphocyte-predominant breast cancer (LPBC) because it obtains high pathological complete response rates with neoadjuvant chemotherapy. Medullary carcinoma (MC), which is independent from LPBC, is a rare histological subtype of invasive breast carcinoma accompanied by abundant lymphoplasmacytic infiltration as LPBC. Although MC shows marked cellular and structural atypia, it usually has a favorable outcome. It is occasionally difficult to distinguish MC from LPBC because both subtypes have nonspecific morphological features according to the present diagnostic criteria. Herein, we adopted multiplexed fluorescent immunohistochemistry to perform quantitative and simultaneous analyses of tumor-infiltrating lymphocytes (TILs) considering their spatial distribution and examined focal immune reaction differences between MC and LPBC. We found that CD8+ TILs are predominant in the intratumoral region, whereas CD4+ TILs are less common in MC. In non-luminal-type cancers, the numbers of stromal and intratumoral CD8+ TILs were significantly higher in MC than in LPBC. Stratified analyses by CD4+ TIL subsets showed robust infiltration of intratumoral CD8+ TILs in non-luminal-type MC even in suppressive environments, such a low T helper 1-to-regulatory T cell ratio. Our results suggest that extensive intratumoral CD8+ TIL infiltration might well be a promising biomarker for distinguishing MC from LPBC, especially in non-luminal-type cancers. Intratumoral CD8+ TILs and nonluminal intrinsic subtypes may serve as diagnostic characteristics allowing reliable histological criteria to be established for reproducibly diagnosing MC.