Tertiary Lymphoid Structures (TLSs) and Stromal Blood Vessels Have Significant and Heterogeneous Impact on Recurrence, Lymphovascular and Perineural Invasion amongst Breast Cancer Molecular Subtypes

SIMPLE SUMMARY: Immunotherapies for breast cancer (BC) are among the most promising treatments for mammary gland malignancies, but their tissue and cellular targets are heterogeneous and controversial. Hence, the effectiveness of immunotherapy varies. Tertiary lymphoid structures (TLSs) are paid the most attention among these therapies due to the favorable prognostic function they have been shown to play for several malignancies, but this has less investigated for BC because they are not at all connected to some BC molecular subtypes and the stromal vascular network. Moreover, research on the TLS’s impact on lymphovascular, perineural, and BC recurrence is inconsistent. In the current investigation, significant variations between TLS positive and TLS negative subgroups within the same BC molecular subtype were observed and had a significant impact on BC recurrence, lymphovascular invasion, and perineural invasion. By promoting quick blood vessel maturation followed by lowering lymphovascular or perineural invasion, and recurrence, BC-associated TLSs seem to have a local protective role against tumor spread. ABSTRACT: Background: Tertiary lymphoid structures (TLSs) mediate local antitumor immunity, and interest in them significantly increased since cancer immunotherapy was implemented. We examined TLS− tumor stromal blood vessel interplay for each breast cancer (BC) molecular subtype related to recurrence, lymphovascular invasion (LVI), and perineural invasion (PnI). Methods: TLSs were quantified on hematoxylin and eosin stain specimens followed by CD34/smooth muscle actin (SMA) double immunostaining for stromal blood vessel maturation assessment. Statistical analysis linked microscopy to recurrence, LVI, and PnI. Results: TLS negative (TLS−) subgroups in each BC molecular subtype (except to Luminal A) have higher LVI, PnI, and recurrence. A significant rise in LVI and PnI were observed for the HER2+/TLS− subgroup (p < 0.001). The triple negative breast cancer (TNBC)/TLS− subgroup had the highest recurrence and invasion risk which was also significantly related to tumor grade. PnI but not LVI significantly influenced recurrence in the TNBC/TLS+ subgroup (p < 0.001). TLS−stromal blood vessel interrelation was different amongst BC molecular subtypes. Conclusion: BC invasion and recurrence are strongly influenced by TLS presence and stromal blood vessels, especially for HER2 and TNBC BC molecular subtypes.