Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes
Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes
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DOI：
10.1038/modpathol.2014.100
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发表时间：
2015-02-01
期刊：
影响因子：
7.5
通讯作者：
Kloeppel, Guenter
中科院分区：
文献类型：
--
作者：
Agaimy, Abbas;Haller, Florian;Kloeppel, Guenter
胰腺未分化癌是一组异质性肿瘤，包括多形性巨细胞癌、肉瘤样癌、圆细胞癌和横纹肌样癌，其分子特征迄今尚不充分。我们研究了14个未分化癌突出横纹肌样细胞，发生在7名女性和7名男性年龄44-96岁（平均：65岁）的晚期肿瘤。组织学上，10例肿瘤为多形性巨细胞癌，4例为单形性未分化癌。14例肿瘤中有5例（10例多形性巨细胞型中有4例，4例单形间变性亚型中有1例）在原发灶或转移灶中可见腺体成分。破骨细胞样巨细胞缺失。免疫组化显示大多数病例中细胞角蛋白和波形蛋白共表达，膜β-catenin和E-cadherin染色缺失。14例病例中有4例（28%）的细胞核SMARCB 1（INN）表达缺失，代表了所有4种单形间变性亚型肿瘤。FISH和KRAS突变检测显示，13例成功分析病例中有5例（38%）KRAS扩增，11例成功分析病例中有6例（54%）外显子2突变。发现KRAS改变（突变和/或拷贝数变化）与完整SMARCB 1表达之间存在强相关性（8例中有7例; 87%）。另一方面，SMARCB 1表达的缺失与KRAS改变的缺失相关（3/5例; 60%）。结果表明，胰腺未分化横纹肌样癌的横纹肌样表型具有异质性的遗传背景。SMARCB 1丢失仅限于间变性单形亚型，与KRAS改变的缺乏相关，而多形性巨细胞亚型的特征是KRAS改变和完整的SMARCB 1表达。识别和适当的亚型，这些罕见的变异可能成为必要的未来的治疗策略。
Pancreatic undifferentiated carcinoma is a heterogeneous group of neoplasms, including pleomorphic giant cell, sarcomatoid, round cell, and rhabdoid carcinomas, the molecular profiles of which have so far been insufficiently characterized. We studied 14 undifferentiated carcinomas with prominent rhabdoid cells, occurring as advanced tumors in seven females and seven males aged 44-96 years (mean: 65 years). Histologically, 10 tumors qualified as pleomorphic giant cell and 4 as monomorphic anaplastic carcinomas. A glandular component, either in the primary or in the metastases, was seen in 5 out of 14 tumors (4 out of 10 pleomorphic giant cell and 1 out of 4 monomorphic anaplastic subtypes, respectively). Osteoclast-like giant cells were absent. lmmunohistochemistry revealed coexpression of cytokeratin and vimentin, and loss of membranous beta-catenin and E-cadherin staining in the majority of cases. Nuclear SMARCB1 (INN) expression was lost in 4 out of 14 cases (28%), representing all 4 tumors of the monomorphic anaplastic subtype. FISH and mutation testing of KRAS revealed KRAS amplification in 5 out of 13(38%) and exon 2 mutations in 6 out of 11 (54%) successfully analyzed cases. A strong correlation was found between KRAS alterations (mutation and/or copy number changes) and intact SMARCB1 expression (7 out of 8; 87%). On the other hand, loss of SMARCB1 expression correlated with the absence of KRAS alterations (3 out of 5 cases; 60%). The results suggest that rhabdoid phenotype in pancreatic undifferentiated rhabdoid carcinomas has a heterogeneous genetic background. SMARCB1 loss is restricted to the anaplastic monomorphic subtype and correlates with the absence of KRAS alterations, whereas the pleomorphic giant cell subtype is characterized by KRAS alterations and intact SMARCB1 expression. Recognition and appropriate subtyping of these rare variants might become necessary for future therapeutic strategies.