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

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.

Reassessing Breast Cancer-Associated Fibroblasts (CAFs) Interactions with Other Stromal Components and Clinico-Pathologic Parameters by Using Immunohistochemistry and Digital Image Analysis (DIA)

“…The interrelation between TLSs and tumor stroma blood vessels was recently reported by our team [72] and together with the findings from the present study may sustain the expansion of BC stroma research by integrating as many stromal components as we have for a better understanding of tumor stroma heterogeneity.…”

Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

“…111 Although the presence of TLS reduced BC invasion and metastasis, this correlation was heterogeneous between different molecular subtypes. 112 A cross-sectional study showed that TLS was most frequently observed in the HR (−) /HER2 (+) subtype and in the base-like subtype. 113 In addition, Bertucci et al 114 reported that in triplenegative BC treated with neoadjuvant chemotherapy, the high TLS score group had a significantly higher pathological complete response.…”

“…Although the presence of TLS reduced BC invasion and metastasis, this correlation was heterogeneous between different molecular subtypes. 112 A cross‐sectional study showed that TLS was most frequently observed in the HR (−) /HER2 (+) subtype and in the base‐like subtype. 113 In addition, Bertucci et al.…”

Advances in the study of tertiary lymphoid structures in the immunotherapy of breast cancer

“…TLSs have been shown to have a favorable prognostic function in a variety of malignancies, but have been less well studied in breast cancer. In the available studies, significant differences were found between TLSs-positive and TLSs-negative subgroups within the same molecular subtype of breast cancer, with significant effects on breast cancer recurrence, lymphovascular infiltration and perineural infiltration ( 88 ). TLSs in the breast cancer stroma have been associated with activation of tumor angiogenesis, suggesting that this may be a factor favoring breast cancer metastasis, but most of these studies have been performed in animal models and there are no data on human tissues ( 89 ).TLSs were detected in 60% of breast cancer tumors and correlated with higher infiltration of TILs by Buisseret.…”