Small sentinel node metastases in breast cancer : displaced epithelium or malignant cells

Sentinel node biopsy limits axillary lymph node resection to breast cancer (BC) patients with metastases in the sentinel node (SN). The reduced number of nodes allows detailed histopathologic assessment, followed by detection of foci <2 mm size (micrometastases) or isolated tumor cells (ITC) ≤ 0.2 mm in size, with contradictory metastatic nature and prognostic significance. The aim was to investigate the malignant nature of smaller metastases by comparison analyses of altogether 1074 BC primary tumors (PT) and corresponding SN metastases, including macrometastases (≥ 2 mm in size), micrometastases and ITCs. This was performed by morphometry on 95 PTs and corresponding metastases and an analysis of MTA-1. Preoperative diagnostic needling as a possible cause for ITCs was investigated. HER-2 amplification analyzed by in situ hybridization was evaluated in 29 HER-2 amplified and 36 HER-2 non-amplified PTs and metastases, including ER and PR. Fifty-two BCs separated by Ki-67 ≤ 14% into luminal A and B subtypes for immunohistochemic CXCR4-, CCR7-, and Maspin-, and FOXP3-expression, all linked to more aggressive tumor behavior. Prevalence and risk factors for nonsentinel node (NSN) metastases in 484 patients with SN micrometastases and ITC were analysed. Statistical analyses were mostly descriptive. Factors between PTs and metastases were analysed by Chi square- and Mann-Whitney U -test and logistic regression analysis for NSN metastasis- associated factors as a nomogram. Morphometric analysis of ITCs showed similar atypia with the PTs. ITC prevalence was unrelated to PT biopsy methods. Concordance between PTs and ITCs in ER, PR, and HER-2 expression was high. HER-2 remained amplified in the metastases including the 3 cases with ITC. MTA-1, Maspin and CXCR4 expression pointed to more benign disease, no differences appeared between ITC and larger metastases. CCR7 expression and FOXP3-positive tumors showed some tendency toward more aggressive features; and combined CXCR4 and CCR7 seemed to suggest more aggressive disease. Factors associated with NSN metastases in patients with SN micrometastases an ITC were larger tumor size and multifocality. Only 7.2% had additional NSN metastases pointing to a low risk group. In the light of these studies, ITCs seem to represent malignant cells like micro- and macrometases, but their invasive character cannot be confirmed by these investigations. The expression of factors associated with invasion, metastasis, and poorer survival were expressed in ITCs as in their larger counterparts equally and seem to show connections with factors that may be associated with circulating tumor cells or tumor dormancy.