Graham Rondell P, Terracciano Luigi M, Meves Alexander, Vanderboom Patrick M, Dasari Surendra, Yeh Matthew M, Torbenson Michael S, Cruise Michael W
Division of Anatomic Pathology, Department of Pathology, Mayo Clinic, Rochester, MN, USA.
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Mod Pathol. 2016 Jun;29(6):607-15. doi: 10.1038/modpathol.2016.59. Epub 2016 Mar 25.
Rare hepatic adenomas are associated with synchronous or metachronous fibrolamellar carcinomas. The morphology of these adenomas has not been well described and they have not been subclassifed using the current molecular classification schema. We examined four hepatic adenomas co-occurring with or preceding a diagnosis of fibrolamellar carcinoma in three patients. On histological examination, three of the adenomas showed the typical morphology of HNF1-α inactivated adenomas, whereas one showed a myxoid adenoma morphology. All of the adenomas were negative for PRKACA rearrangements by Fluorescence in situ Hybridization (FISH) analysis. All four of the adenomas showed complete loss or significant reduction of liver fatty acid binding protein (LFABP) expression by immunohistochemistry. Interestingly, the fibrolamellar carcinomas in each case also showed loss of LFABP by immunohistochemistry. One of the fibrolamellar carcinomas was negative for PRKACA rearrangements by FISH, whereas the others were positive. To investigate if LFBAP loss is typical of fibrolamellar carcinomas in general, an additional cohort of tumors was studied (n=19). All 19 fibrolamellar carcinomas showed the expected PRKACA rearrangements and immunostains showed loss of LFABP in each case, consistent with HNF1-α inactivation. To validate this observation, mass spectrometry-based proteomics was performed on tumor-normal pairs of six fibrolamellar carcinomas and showed an average 10-fold reduction in LFABP protein levels, compared with matched normal liver tissue. In conclusion, hepatic adenomas co-occurring with fibrolamellar carcinomas show LFABP loss and are negative for PRKACA rearrangements, indicating they are genetically distinct lesions. These data also demonstrate that LFABP loss, which characterizes HNF1-α inactivation, is a consistent feature of fibrolamellar carcinoma, indicating HNF1-α inactivation is an important event in fibrolamellar carcinoma pathogenesis.
罕见的肝腺瘤与同时性或异时性纤维板层癌相关。这些腺瘤的形态尚未得到充分描述，并且尚未使用当前的分子分类模式进行亚分类。我们检查了三名患者中与纤维板层癌诊断同时出现或先于该诊断的四个肝腺瘤。组织学检查显示，其中三个腺瘤呈现HNF1-α失活腺瘤的典型形态，而另一个呈现黏液样腺瘤形态。通过荧光原位杂交（FISH）分析，所有腺瘤的PRKACA重排均为阴性。通过免疫组织化学，所有四个腺瘤均显示肝脂肪酸结合蛋白（LFABP）表达完全缺失或显著降低。有趣的是，每个病例中的纤维板层癌通过免疫组织化学也显示LFABP缺失。其中一个纤维板层癌通过FISH检测PRKACA重排为阴性，而其他纤维板层癌为阳性。为了研究LFABP缺失是否是纤维板层癌的普遍特征，我们研究了另外一组肿瘤（n = 19）。所有19个纤维板层癌均显示预期的PRKACA重排，免疫染色显示每个病例中LFABP缺失，这与HNF1-α失活一致。为了验证这一观察结果，我们对六个纤维板层癌的肿瘤-正常组织对进行了基于质谱的蛋白质组学分析，结果显示与匹配的正常肝组织相比，LFABP蛋白水平平均降低了10倍。总之，与纤维板层癌同时出现的肝腺瘤显示LFABP缺失且PRKACA重排为阴性，表明它们是基因上不同的病变。这些数据还表明，表征HNF1-α失活的LFABP缺失是纤维板层癌的一致特征，表明HNF1-α失活是纤维板层癌发病机制中的一个重要事件。
