Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, SE-205 02 Malmö, Sweden.
Hum Pathol. 2012 May;43(5):708-19. doi: 10.1016/j.humpath.2011.06.019. Epub 2011 Oct 10.
Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma.
大约 8%的透明细胞肾细胞癌病例中存在形态学截然不同的区域，其组织学表现为类似于肉瘤的间充质外观。这些双相性肿瘤被称为肉瘤样透明细胞肾细胞癌。由于转移的倾向增加，诊断为肉瘤样透明细胞肾细胞癌的患者预后明显较差。在本研究中，我们研究了透明细胞肾细胞癌的肉瘤样转化是否可以解释为与上皮-间充质转化过程相关。使用 6 例双相透明细胞肾细胞癌病例，我们表明肉瘤样透明细胞肾细胞癌与常规透明细胞肾细胞癌共享与 von Hippel-Lindau 肿瘤抑制基因丢失相关的特征性标志物，并且还表现出明显更高的增殖指数。此外，与透明细胞肾细胞癌相比，肉瘤样成分表现出增强的上皮-间充质转化相关的间充质标志物表达。我们进一步选择了一个具有代表性的病例，临床上表现为肉瘤样成分直接向肝脏和结肠生长，进行了扩展的免疫组织化学特征分析，得出了另一组阳性和阴性上皮-间充质转化标志物以及明显的转化生长因子β阳性，表明肉瘤样透明细胞肾细胞癌可能与上皮-间充质转化相关。转化生长因子β 1 暴露于体外培养的原代透明细胞肾细胞癌细胞中，导致细胞采用类似于肉瘤样透明细胞肾细胞癌的间充质形态。关键上皮-间充质转化标志物的 RNA 水平也发生相应变化。因此，我们认为肉瘤样透明细胞肾细胞癌在形态学和免疫组织化学上可能代表已完成的上皮-间充质转化，转化生长因子β 1 可能是透明细胞肾细胞癌肉瘤样转化过程中的重要驱动力。
