Lymphocyte-predominant triple-negative breast carcinomas in premenopausal patients: Lower expression of basal immunohistochemical markers

Highlights

• Lymphocyte-predominant breast cancer is a subset of triple-negative carcinomas.

• Lymphocyte-predominant breast carcinomas are mostly of non-basal phenotype.

• Basal cytokeratin expression is lower in triple-negative tumors rich in lymphocytes.

• EGFR expression is lower in triple-negative tumors rich in lymphocytes.

• Stromal expression of ALDH1 is associated with tumor-infiltrating lymphocytes.

Abstract

Objectives

Triple-negative breast carcinomas (TNBCs) correspond to a molecular heterogeneous disease defined by lack of estrogen and progesterone receptor expression, and the absence of overexpression and/or amplification of HER2. Recent data indicate that clinical outcome in TNBC is affected by tumor-infiltrating lymphocytes, suggesting that they can benefit from immunotherapies. We selected 116 consecutive premenopausal patients with TNBC to compare the immunohistochemical profile of the group rich in tumor-infiltrating lymphocytes with those without this characteristic.

Materials and methods

We reviewed all the original histological sections to assess pathological features, and to select a representative area for tissue microarrays and immunohistochemical study. Estrogen and progesterone receptors, HER2 and Ki-67 were evaluated in whole histological sections. The following markers were analyzed in tissue microarrays sections: androgen receptor, cytokeratin 5/6, cytokeratin 14, epidermal growth factor receptor (EGFR), vimentin, p16, claudin-3, -4, and -7, p63, and aldehyde dehydrogenase isoform 1 (ALDH1). Lymphocyte-predominant breast cancer (LPBC) was defined by the presence of more than 50% of lymphocytes in the intratumoral stroma.

Results

Twenty-six (22.4%) patients present tumors classified as LPBC and 90 (77.6%) as non-LPBC. The two groups were similar regarding age of patients, tumor grade and Ki-67 positive cells. LPBC cases presented lower frequency of expression of the basal cytokeratins, EGFR, and basal-like immunoprofile. There was a trend to higher expression of ALDH1 by stromal intratumoral cells. The expression of all other markers were similar in the two groups.

Conclusions

Lymphocyte-predominant TNBC in premenopausal patients are mostly of non-basal phenotype.

Introduction

Triple-negative breast carcinomas (TNBCs) are defined by lack of estrogen and progesterone receptor expression, and the absence of overexpression and/or amplification of the erb-b2 receptor tyrosine kinase 2 (HER2). Although they are often associated with a basal-like genetic phenotype, 21.4% of them correspond to other molecular types, such as HER2-enriched (7.8%), normal (7.0%), luminal B (4.4%), and luminal A (2.2%) [1]. The basal-like phenotype of TNBCs was first defined by the immunohistochemical expression of basal cytokeratin 5/6 and/or epidermal growth factor receptor (EGFR) [2], [3]. TNBCs are more prevalent in young patients and they usually have a clinically aggressive behavior [4], [5].

Tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) are the main actors of the immune response and have been recognized as an important prognostic and predictive factor, particularly among estrogen receptor-negative carcinomas [6], [7], [8]. A meta-analysis study with 2987 patients with TNBCs and early stage showed that tumors rich in TILs have a 30% reduction in recurrence, 22% in distant recurrence, and 34% in death [9]. Lymphocyte-predominant breast cancers (LPBC) correspond to tumors with at least 50–60% of stromal TILs [10]. The International TILs Working Group provided a standardized methodology for evaluating TILs in BC [10]. The criteria were applied in a cohort of 897 TNBCs from the European Institute of Oncology [11]. The authors reported that patients with LPBC had better disease-free survival, distant disease-free survival and overall survival. In addition, they observed that each 10% increase in TILs strongly predicted better survival independent of other prognostic variables.

The heterogeneous morphologic, gene-expression profiles and genomic changes of TNBCs have been a challenge in finding of targets for therapy. It is clear that potential targets will work only in subsets of TNBCs. Candidates of these subsets are BRCA-1 mutant, BRCA1-like tumors with underlying defects in homologous recombination-mediated DNA repair and androgen-receptor positive tumors [12]. Successful subgroups based on immunohistochemical profile are lacking. The luminal androgen receptor subtype is characterized by the expression of this receptor [12], [13]. However, the prognostic value of androgen receptor is controversial [14], [15]. Other attempts on the classification of TNBC based on the immunohistochemical profile included p16, e-cadherin, claudins, and Ki-67 [16], [17]. Some immunohistochemical markers have been related to prognosis, for example, vimentin [18] and aldehyde dehydrogenase 1A1 (ALDH-1A1) [19].

In this study, our aim was to compare triple-negative LPBC with non-LPBC according to immunohistochemical profile.