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. 2023 Apr 17;12(8):1176.
doi: 10.3390/cells12081176.

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

Alina Cristina Barb  1   2   3 , Mihaela Pasca Fenesan  1   2   3 , Marilena Pirtea  2 , Madalin Marius Margan  4 , Larisa Tomescu  2   5 , Eugen Melnic  6 , Anca Maria Cimpean  1   7
Affiliations

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

Alina Cristina Barb et al. Cells. .

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.

Keywords: TLS; breast cancer molecular subtypes; immature blood vessels; lymphovascular invasion; mature blood vessels; perineural invasion; recurrence; tertiary lymphoid structure.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Figure 1
Figure 1
(A–J) Comparative TLS assessment distribution from normal to malignant breast cancer tissue. (A) No TLSs were detected inside normal breast tissue. (B) TLS complex interrelations with tumor tissue (upper left) but also with several TME components such as stromal blood vessels and adipose tissue. (C) General overview of TLS topography in mammary gland stroma related to its neighborhood with adipose tissue. (D,E) TLSs in direct contact with adipose tissue or (F) surrounded by stroma. (G,J) Intratumor TLSs are smaller in size ((G), inset 1) and surrounded by tumor cells ((G), inset 2). (H) Sometimes, TLSs are invaded by tumor cells (arrows) in a manner mimicking lymph node metastasis or (I) are highly vascularized (arrows) without any tumor cells inside. (A–J) Double stain for CD34 positive reaction for endothelial cells highlighted in brown with diaminobenzidine and smooth muscle actin (SMA) for perivascular cells highlighted in red with permanent AEC chromogen.
Figure 2
Figure 2
Correlation matrix showing the interrelation between BMI and TLS stromal blood vessels in BC tissues (p = 0.014 was significant). BMI significantly influenced the TLS presence (a) while TLSs are highly correlated with both immature (IBV_CD34+/SMA−, p = 0.008) and mature tumor (MBV_CD34+/SMA+, p = 0.003) stroma blood vessels (b).
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