Tertiary lymphoid structures in breast ductal carcinoma in situ correlate with adverse pathological parameters

Abstract

Aims: To investigate tertiary lymphoid structures (TLSs) in ductal carcinoma in situ (DCIS) of the breast and their correlation with pathological features, immune cell markers and clinical outcomes. Methods and results: Morphological identification of TLSs in 198 DCIS cases incorporated B and T cell zones with high endothelial venules. TLS positivity was defined as ≥ 1 TLSs in lesional areas, while TLS area percentage was divided into two categories: low (TLSs < 5%) and high (TLSs ≥ 5%). Previously reported biomarkers included ER, PR, HER2, CD68, CD163, CD4, CD8 and PD-L1. TLSs were observed in 24.7% (49 of 198) of cases, with a mean diameter of 0.44 mm (median = 0.4 mm, range = 0.12-1.43 mm). TLSs were significantly associated with higher nuclear grade, presence of necrosis, hormone receptor negativity/HER2 positivity, triple negativity, tumour infiltrating lymphocytes (TILs) and immune related biomarkers such as FOXP3, CD163, CD4 and CD4/CD8 ratio (all P < 0.05). There were no significant associations between TLSs and recurrence, but a combination of TLSs high with FOXP3 + , CD4 high , CD4/ CD8 ratio high and CD68 high individually, compared with all other combinations, disclosed significantly poorer disease-free survival (DFS) for ipsilateral invasive recurrence (IIR) on both Kaplan-Meier and multivariable Cox regression analyses (all P < 0.05). Conclusions: TLSs in DCIS were associated with unfavourable prognostic features, TILs and immune cell markers in our study. TLSs high /FoxP3 + , TLSs high / CD4 high , TLSs high /(CD4/CD8) ratio high and TLSs high / CD68 high were independent factors for poorer DFS for IIR. Further exploration of the pathological significance of TLSs may provide a clinical basis for their recognition as an important structure and functional unit in the tumour immune microenvironment.

Identification and Validation of a Prognostic Model Based on Three TLS- Related Genes in Oral Squamous Cell Carcinoma

“…This suggests that the patch-or tile-based approaches for image analysis used in many studies are inappropriate, which may lead to misestimation of the presence of TLSs. Zeng et al (21) reported that the percentage of TLS-positive breast ductal carcinomas was 24.7%, which is signi cantly different from the 60.3% reported in a Korean study (22).…”

Tertiary lymphoid structures in tongue cancer: Association with clinicopathological parameters, preoperative S‐1 chemotherapy response, and prognosis

“…In urothelial cancer, some studies included noninvasive urothelial carcinoma, although there is no description of the extent to which TLSs are contained in these noninvasive cancers and there is also no description of the correlation of intraepithelial carcinoma and TLSs. 24,25 One report describes that TLSs are also present in ductal carcinoma in situ of breast, 26 but further studies may be needed to better define the relationship between TLSs and carcinoma in situ.…”

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

“…The interactions between the immune component and other TME components such as stromal blood vessels or tumor stromal myofibroblasts are still less elucidated [ 31 , 32 , 33 , 34 ]. The TLSs impact on tumor progression, lymphovascular invasion, perineural invasion, and recurrence remain the most questionable and neglected chapters in the field [ 35 , 36 , 37 , 38 , 39 ].…”