Clinicopathological characteristics of anaplastic carcinoma of the pancreas with rhabdoid features
Clinicopathological characteristics of anaplastic carcinoma of the pancreas with rhabdoid features
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DOI：
10.1007/s00428-014-1631-5
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发表时间：
2014-11-01
期刊：
影响因子：
3.5
通讯作者：
Nemoto, Norimichi
中科院分区：
文献类型：
--
作者：
Sano, Makoto;Homma, Taku;Nemoto, Norimichi
具有横纹肌样特征的未分化癌是胰腺癌的一种罕见的侵袭性亚型。在这里，我们报告的临床，组织学和免疫组化表型在6例尸检的间变性癌横纹肌样功能。患者年龄范围为44 - 76岁（中位数61岁），包括4名男性和2名女性。除1例患者外，所有患者均在诊断后3个月内死亡，因为这些肿瘤是在晚期发现的，并且具有化疗耐药性。尸检时，最大直径为4-22 cm的肿瘤肿块主要位于胰腺体部和尾部。显微镜下，所有病例均表现为间变性癌，具有横纹肌样特征，具有圆形至多边形嗜酸性细胞质，偶见包涵体，细胞核呈囊状，核仁突出。免疫组化显示横纹肌样细胞，特别是包涵体，泛细胞角蛋白（AE 1/AE 3）和波形蛋白呈强阳性。同时，在横纹肌样细胞中经常观察到E-cadherin、beta-catenin和EMA的下调或异常胞质定位与局灶性聚集。此外，胞浆内包涵体标记有选择性的自噬相关分子，包括p62/SQSTM 1，泛素和kelch样ECH相关蛋白1（KEAP 1）。此外，核因子红细胞2相关因子2（NRF 2）及其靶分子多药耐药相关蛋白1（MRP 1）的过表达通常在横纹肌样细胞中观察到。因此，这些结果表明，p62介导的泛素化的中间丝和膜蛋白的聚集是一个重要的现象，在横纹肌样表型。事实上，p62和KEAP 1的泛素化聚集体将诱导NRF 2的活化和MRP 1的上调，导致具有横纹肌样特征的间变性癌的潜在化疗耐药性。
Undifferentiated (anaplastic) carcinoma with rhabdoid features is a rare and aggressive subtype of pancreatic carcinoma. Here, we report the clinical, histological, and immunohistochemical phenotypes in six autopsy cases of anaplastic carcinoma with rhabdoid features. The patients ranged between 44 and 76 years of age (median, 61 years) and consisted of four males and two females. All patients except one case died within 3 months of diagnosis, as these tumors were found at an advanced stage and were chemoresistant. At autopsy, tumor masses measuring 4-22 cm in maximum diameter were mainly located in the pancreatic body and tail. Microscopically, all cases showed anaplastic carcinoma with rhabdoid features that were discohesive with round to polygonal eosinophilic cytoplasm with occasional inclusions, and that had vesicular nuclei, and prominent nucleoli. Immunohistochemistry showed that the rhabdoid cells, particularly the inclusions, were strongly positive for pan-cytokeratin (AE1/AE3) and vimentin. Meanwhile, downregulation or aberrant cytoplasmic localization with focal aggregation of E-cadherin, beta-catenin, and EMA were frequently observed in the rhabdoid cells. Moreover, the intracytoplasmic inclusions were labeled with selective autophagy-related molecules including p62/SQSTM1, ubiquitin, and kelch-like ECH-associated protein 1 (KEAP1). In addition, nuclear factor erythroid 2-related factor 2 (NRF2) and overexpression of its target molecule multidrug resistance-associated protein 1 (MRP1) were commonly observed in the rhabdoid cells. Therefore, these results suggest that p62-mediated aggregation of ubiquitinated intermediate filaments and membranous proteins is an important phenomenon in the rhabdoid phenotype. Indeed, the ubiquitinated aggregates of p62 and KEAP1 would induce activation of NRF2 and upregulation of MRP1, leading to potential chemoresistance of anaplastic carcinoma with rhabdoid features.