ORIGINAL ARTICLE
Expression of the E-cadherin–catenins complex in sentinel node is related to tumor morphology but not to spread to nonsentinel nodes

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Abstract

The sentinel node (SN) technique has gained a key role in breast cancer surgery, allowing for an accurate staging of the axillary status with a minimally invasive resection. In this study, we explored the implication of three proteins (E-cadherin, a- and b-catenins) that form the cadherin–catenin complex, a receptorial structure strictly involved in tumoral vascular invasion and embolization in this biologic event. We studied the immunohistochemical expression of the complex in patients with metastatic SN, matching the group with involved nonsentinel lymph nodes (NSNs) with that having free axillary NSNs. The simultaneous staining of the SN metastases for the three proteins has been considered an indicator of preserved function. Our data confirmed the lack of cadherin–catenin complex in tumors with lobular morphology even in SN metastasis, but statistical evaluation could not prove a significant relation between complex integrity and NSN involvement. Moreover, considering traditional histopathologic parameters, only vascular peritumoral embolization was related to an increased risk of metastatic spread to axillary NSNs.

Introduction

Axillary node resection in breast carcinoma has actually lost its therapeutic significance. However, it is still of outstanding importance in disease staging, since axillary nodes represent the most frequent way of the tumor's metastatic spread.

The sentinel node (SN) technique was introduced in breast surgery in the first half of the last decade [16]. The functional evidence underlying this technique is that the state of the first axillary lymph node draining an invasive carcinoma accurately predicts the condition of the whole axillary district [3], [34]. It consists of resection of the first lymph node possibly affected by carcinoma cells, detected by draining with blue dye and/or lymphoscintigraphy [4] and subsequent accurate examination of histologic specimens [33]. The benefit of this technique lies in an accurate axillary node staging with a minimally invasive procedure. Large-scale studies have demonstrated that the presence of metastases in SN is highly predictive of the status of axillary nodes in smaller tumors (<3 cm). Therefore, its examination could prevent N0 patients from undergoing axillary dissection. Follow-up studies on patients with negative SN proved the efficacy of the SN technique, since no metastasis could be detected in residual axillary lymph nodes [8], [37].

SN resection is now becoming a common practice in the surgical management of breast carcinoma. As a consequence, the management of patients with metastatic SN is becoming a frequent issue for surgeons and oncologists. Hence, it is becoming essential to individualize features associated with the risk of nonsentinel lymph node (NSN) involvement in patients with metastatic SN. A large-scale study [14] described the correlation between the size of primary tumor, the presence of peritumoral vascular invasion, and the presence of metastases in axillary NSNs, and another recent paper on micrometastatic SNs confirmed these data [26].

We believe that it could be of interest to explore the biologic setting of tumoral cells in SN metastases, especially the expression of molecules with a proved role in tissue invasion, embolization, and metastatic spread. Our aim was to establish relationships between protein expression in these elements and their metastatic potential.

Recent acquirements in cancer research have highlighted the role of membrane proteins with function of intercellular adhesion, contact, and signaling in neoplastic progression.

E-cadherin is a 120 kDa transmembrane glycoprotein encoded by CDH-1 gene (16q22.1), having the function of a Ca++ dependent adhesion receptor with an important role in cell recognition and migration signals. The extracellular domain of E-cadherins mediates the extracellular migration with omophylic interaction of omotypic (same tissue cells) or heterotypic (different tissue cells) kind. The cytoplasmic domain of the protein is connected to cytoskeleton proteins (actins and others) through linkage with catenins [7], [22], [30].

ThE-cadherin–catenin complex is constituted by E-cadherins and β-catenins, and interacts with proteins essential in carcinogenetic pathways, such as APC [29] and α-catenins, stabilizing the attachment between these two proteins.

The E-cadherin–catenin chain may loose its function in tumoral cells owing to the alteration of relative genes, posttranscriptional modifications, or the alteration of the functional status in the presence of a normal protein. Such an event leads to changes in tumoral tissue morphology, with acquisition of an infiltrative pattern and modification in metastatic potential [28], [36].

The role of E-cadherin–catenins complex in breast carcinomas has been widely studied over the recent years [11], [25]. An analysis of the E-cadherin gene status in breast carcinoma showed that lack of protein in tumoral cell membrane may be related to different damages, mainly LOH [23]. Decreased expression of E-cadherin has been described in in situ and infiltrating carcinomas: this phenomenon has been related to high-grade histology and lobular histotype [6], [17], [23], [27]. A recent study identifies a subtype of lobular in situ carcinoma with membrane expression of E-cadherin, with higher risk of subsequent carcinoma [10].

The relation between the absence of E-cadherin expression and the lobular morphology in breast carcinomas is so close that E-cadherin has been proposed as a diagnostic marker of lobular pattern in mixed tumors or tumors with ambiguous histology [1].

The aim of the present study was to evaluate E-cadherin–catenin expression in SN metastatic tissue, and with regard to this, we postulated the hypothesis that the loss of this complex could distinguish a subset of metastases with a more aggressive behavior and a higher risk of metastatic spread of NSNs.

Section snippets

Materials and methods

Sixty patients with metastatic SN were considered in this study, obtained from 320 SN lymphadenectomies performed in our center from March 2000 to September 2002. We selected 26 cases in which the sectioning standard protocol was not performed, as metastases were evident on frozen sections or at macroscopy, and for which at least three new histologic sections were available for IHC stainings. In all cases, subsequent axillary dissection was performed: 13 of them had metastatic NSN nodes, and 13

Results

The distribution of the components of the receptorial structure was evaluated in neoplastic cells of SN metastases. Coordinate membrane staining for E-cadherins and α- and β-catenins was considered a sign of an appropriate localization of these proteins and, therefore, of a normal functional state of the complex. Moreover, only focal or diffuse distribution of membrane staining was regarded as significant in determining tumor behavior. Data on membrane distribution of the three proteins are

Discussion

The role of the E-cadherin–catenin complex in the evolution of the neoplastic process is widely recognized, but the significance of the complex deficiency as a predictive factor in metastatic spread is still debated.

The relationship between E-cadherin expression and metastatic potential of breast tumor still needs to be clarified. However, most of the data are favor an increase in the metastatic potential in tumors with lack of E-cadherin [9], [12], [15], [19], [39], and E-cadherin-encoding

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