Department of Medical Oncology, Medical School, University of Ioannina, Greece.
Anticancer Res. 2012 Apr;32(4):1273-81.
The epithelial to mesenchymal transition (EMT) has been associated with metastatic dissemination and poor outcome in several solid tumour types. Our aim was to study its incidence and its prognostic significance in cancer of unknown primary (CUP).
One hundred tumour samples of CUP were loaded in tissue microarrays and were studied for immunohistochemical (IHC) expression of E-cadherin, N-cadherin, vimentin, the EMT transcription factor (SNAIL) and the stem cell marker octamer-binding transcription marker 4(OCT4). An EMT phenotype was defined as low expression of E-cadherin, expression of N-cadherin with/without vimentin with concomitant expression of SNAIL, as assessed by percentage of tumour cell staining.
Among 100 CUP cases, the histological diagnosis was adenocarcinoma in 55, squamous carcinoma in 20 and undifferentiated carcinoma in 15, with a high grade seen in 46. Therapy consisted of palliative chemotherapy, mostly platinum based. The median progression-free survival and overall survival (OS) were 7 and 12 months respectively. Distributional studies resulted in selection of IHC cut-offs for E-cadherin (negative when expressed in <60% of tumour cells), N-cadherin, vimentin (positive when expressed in ≥40% of tumour cells), SNAIL (positive when stained in ≥80% of tumour cells). An EMT phenotype was observed in 8 cases (8.1%) and was strongly associated with poor OS (median OS EMT(-)=13 months vs. median OS EMT(+)=8 months, p=0.023). When we used staining intensity (H-Score), an EMT phenotype was observed in 16 patients and carried borderline adverse prognostic utility for outcome (median OS 9 vs. 14 months, p=0.07). The presence of the EMT phenotype correlated significantly with male gender, high grade and presence of visceral metastases (χ(2) p<0.05), while EMT mediator expression was correlated to high NOTCH 2/3 expression. Other factors, prognostic for poor survival, were male gender, PS≥2, non-platinum therapy (χ(2) p<0.05).
EMT is infrequently seen in tumours of CUP. However, an adverse prognostic significance for patient outcome has been identified and may warrant studies of therapeutic targeting.
上皮间质转化（EMT）与几种实体肿瘤的转移扩散和不良预后有关。我们的目的是研究 EMT 在不明原发灶肿瘤（CUP）中的发生率及其预后意义。
将 100 例 CUP 肿瘤样本加载于组织微阵列中，并通过免疫组织化学（IHC）检测 E-钙黏蛋白、N-钙黏蛋白、波形蛋白、EMT 转录因子（SNAIL）和干细胞标志物八聚体结合转录因子 4（OCT4）的表达。EMT 表型定义为 E-钙黏蛋白低表达，N-钙黏蛋白有/无波形蛋白表达，同时 SNAIL 表达阳性，通过肿瘤细胞染色的百分比来评估。
在 100 例 CUP 病例中，组织学诊断为腺癌 55 例，鳞癌 20 例，未分化癌 15 例，高级别 46 例。治疗方法为姑息性化疗，主要为铂类药物。中位无进展生存期和总生存期（OS）分别为 7 个月和 12 个月。分布研究导致选择 E-钙黏蛋白（肿瘤细胞中表达<60%时为阴性）、N-钙黏蛋白、波形蛋白（肿瘤细胞中表达≥40%时为阳性）、SNAIL（肿瘤细胞中染色≥80%时为阳性）的 IHC 截断值。8 例（8.1%）观察到 EMT 表型，与不良 OS 密切相关（EMT(-)组中位 OS=13 个月，EMT(+)组中位 OS=8 个月，p=0.023）。当我们使用染色强度（H 评分）时，16 例患者观察到 EMT 表型，对结局有边缘不良预后作用（中位 OS 9 个月 vs. 14 个月，p=0.07）。EMT 表型的存在与男性、高级别和内脏转移显著相关（χ(2) p<0.05），而 EMT 介质的表达与 NOTCH 2/3 表达相关。其他预后不良的因素包括男性、PS≥2、非铂类治疗（χ(2) p<0.05）。
CUP 肿瘤中 EMT 少见。然而，已确定 EMT 对患者预后有不良的预后意义，可能需要进行治疗靶点的研究。
