Vieira André Filipe, Dionísio Maria Rita, Gomes Madalena, Cameselle-Teijeiro Jorge F, Lacerda Manuela, Amendoeira Isabel, Schmitt Fernando, Paredes Joana
Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal.
Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.
Mod Pathol. 2017 May;30(5):698-709. doi: 10.1038/modpathol.2016.232. Epub 2017 Jan 13.
Axillary lymph node metastases represent the most powerful breast cancer prognostic factor, dictating disease staging and clinical therapeutic decisions. Nonetheless, breast cancer patients with positive lymph nodes still exhibit a heterogeneous behavior regarding disease progression. Stem-like subpopulations of cancer cells show high migratory and metastatic capacity, thus we hypothesize that breast cancer stem cell markers evaluation in metastasized lymph nodes could provide a more accurate prediction of patient's prognosis. Therefore, the expression profile of P-cadherin, CD44, and CD49f, which have been already associated to stem cell properties in breast cancer, has been evaluated by immunohistochemistry in a series of 135 primary tumors and matched axillary lymph node metastases from 135 breast cancer patients. Taking in consideration the expression of the stem cell markers only in axillary nodes, P-cadherin was the only biomarker significantly associated with poor disease-free and overall patient's survival. Moreover, although a concordant expression between primary tumors and matched lymph nodes has been found in the majority of the cases, a small but significant percentage displayed divergent expression (18.2-26.2%). Remarkably, although CD44 and CD49f changes between primary tumors and lymph node metastasis did not impact survival, the cases that were positive for P-cadherin in lymph node metastases being negative in the primary tumor, presented the worst disease-free and overall survival of the whole series. Accordingly, negative cases for this marker in the lymph nodes with positive expression in the matched breast carcinoma demonstrated a better prognosis, which overlapped with tumors that were negative in both sites. P-cadherin and CD49f gain of expression was mainly found in triple-negative carcinomas. Our results indicate for the first time that the evaluation of P-cadherin expression in lymph node metastases is an important predictor of disease outcome, being a putative valuable marker for axillary-based breast cancer decisions in the clinical practice.
腋窝淋巴结转移是乳腺癌最有力的预后因素，决定着疾病分期和临床治疗决策。尽管如此，有阳性淋巴结的乳腺癌患者在疾病进展方面仍表现出异质性。癌细胞的干细胞样亚群具有高迁移和转移能力，因此我们推测，对转移淋巴结中的乳腺癌干细胞标志物进行评估可以更准确地预测患者预后。因此，通过免疫组织化学对135例原发性肿瘤及与之匹配的135例乳腺癌患者的腋窝淋巴结转移灶中已与乳腺癌干细胞特性相关的P-钙黏蛋白、CD44和CD49f的表达谱进行了评估。仅考虑干细胞标志物在腋窝淋巴结中的表达，P-钙黏蛋白是唯一与无病生存期差和患者总生存期显著相关的生物标志物。此外，虽然在大多数病例中发现原发性肿瘤与匹配淋巴结之间存在一致的表达，但仍有一小部分但显著比例的病例表现出不同的表达（18.2%-26.2%）。值得注意的是，尽管原发性肿瘤与淋巴结转移之间CD44和CD49f的变化不影响生存期，但在淋巴结转移中P-钙黏蛋白呈阳性而在原发性肿瘤中呈阴性的病例，其无病生存期和总生存期在整个系列中最差。因此，在匹配的乳腺癌中呈阳性表达的淋巴结中该标志物呈阴性的病例预后较好，这与在两个部位均呈阴性的肿瘤情况重叠。P-钙黏蛋白和CD49f表达增加主要见于三阴性癌。我们的结果首次表明，评估淋巴结转移中P-钙黏蛋白的表达是疾病预后的重要预测指标，在临床实践中是基于腋窝的乳腺癌决策的一个潜在有价值的标志物。
