Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients.

Stine L Figenschau,Elin S Mortensen,Kristin A Fenton,Silje Fismen,Christopher Fenton

doi:10.1186/s12885-015-1116-1

Abstract

BackgroundTertiary lymphoid structures (TLS) are highly organized immune cell aggregates that develop at sites of inflammation or infection in non-lymphoid organs. Despite the described role of inflammation in tumor progression, it is still unclear whether the process of lymphoid neogenesis and biological function of ectopic lymphoid tissue in tumors are beneficial or detrimental to tumor growth. In this study we analysed if TLS are found in human breast carcinomas and its association with clinicopathological parameters.MethodsIn a patient group (n = 290) who underwent primary surgery between 2011 and 2012 we assessed the interrelationship between the presence of TLS in breast tumors and clinicopathological factors. Prognostic factors were entered into a binary logistic regression model for identifying independent predictors for intratumoral TLS formation.ResultsThere was a positive association between the grade of immune cell infiltration within the tumor and important prognostic parameters such as hormone receptor status, tumor grade and lymph node involvement. The majority of patients with high grade infiltration of immune cells had TLS positive tumors. In addition to the degree of immune cell infiltration, the presence of TLS was associated with organized immune cell aggregates, hormone receptor status and tumor grade. Tumors with histological grade 3 were the strongest predictor for the presence of TLS in a multivariate regression model. The model also predicted that the odds for having intratumoral TLS formation were ten times higher for patients with high grade of inflammation than low grade.ConclusionsHuman breast carcinomas frequently contain TLS and the presence of these structures is associated with aggressive forms of tumors. Locally generated immune response with potentially antitumor immunity may control tumorigenesis and metastasis. Thus, defining the role of TLS formation in breast carcinomas may lead to alternative therapeutic approaches targeting the immune system.

Highlights

Tertiary lymphoid structures (TLS) are highly organized immune cell aggregates that develop at sites of inflammation or infection in non-lymphoid organs
The distribution of patient samples showed that 13.5% had no immune cell infiltration (Figure 1A), 49.8% had mild infiltration (Figure 1B), 31.1% had moderate infiltration (Figure 1C), and 5.6% were categorized as tumors with extensive infiltration of immune cells (Figure 1D and Table 1)
The immune cell aggregates which were TLS positive showed the presence of CD20+ B lymphocytes within the follicles, with areas of CD3+ T lymphocytes resembling the highly organized structures of secondary lymphoid organs (Figure 2B and C)

Summary

Introduction

Tertiary lymphoid structures (TLS) are highly organized immune cell aggregates that develop at sites of inflammation or infection in non-lymphoid organs. Immune responses may develop ectopically at sites of inflammation or infection independently of secondary lymphoid organs [2,3,4]. The development of ectopic lymphoid tissue, or tertiary lymphoid structures (TLS), in tumors has been described in several other neoplastic diseases such as lung cancer [10,11], colorectal cancer [12,13], malignant melanoma [14,15], as well as being a key feature of chronic inflammatory autoimmune and infectious diseases, including rheumatoid arthritis [16,17], Sjögren’s syndrome [18,19], and Helicobacter pylori-induced gastritis [20,21]

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Conclusion