Carbonic anhydrase 4 and crystallin α-B immunoreactivity may distinguish benign from malignant thyroid nodules in patients with indeterminate thyroid cytology.
Carbonic anhydrase 4 and crystallin α-B immunoreactivity may distinguish benign from malignant thyroid nodules in patients with indeterminate thyroid cytology.
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DOI：
10.1016/j.jss.2014.03.042
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Trooskin S
中科院分区：
文献类型：
--
作者：
Davidov T;Nagar M;Kierson M;Chekmareva M;Chen C;Lu SE;Lin Y;Chernyavsky V;Potdevin L;Arumugam D;Barnard N;Trooskin S
甲状腺结节存在于19%-67%的人群中，并具有5%-10%的恶性风险。不幸的是，细针穿刺活检在20%-30%的患者中是不确定的，通常需要甲状腺手术进行诊断。许多DNA微阵列研究，包括最近商业化的分子分类器，有助于更好地区分良性和恶性甲状腺结节。不幸的是，这些测定通常需要用于>100个基因的探针，是昂贵的，并且仅在少数实验室可用。我们试图在蛋白质水平上验证这些DNA微阵列检测，并确定是否简单和广泛使用的免疫组织化学生物标志物单独可以区分良性和恶性甲状腺结节。一个组织微阵列（TMA）组成的26个滤泡性甲状腺癌（FTC）和53个滤泡性腺瘤（FA）的患者不确定的甲状腺结节染色与17个免疫组化生物标志物的基础上选择先前的DNA微阵列研究。使用的抗体包括半乳糖凝集素3、生长和分化因子15、蛋白质转化酶2、分化簇44（CD 44）、谷草转氨酶1（GOT 1）、三叶因子3（TFF 3）、弗里德赖希共济失调基因（X123）、成纤维细胞生长因子13（FGF 13）、碳酸酐酶4（CA 4）、晶状体蛋白α-B（CRYSTAB）、肽基脯氨酰异构酶F（PPIF）、天冬酰胺合酶（ASNS）、钠通道、非电压门控、1 α亚基（SCNN 1A）、卷曲同源物1（FZD 1）、酪氨酸相关蛋白1（TYRP 1）、E钙粘蛋白1型（ECAD）和甲状腺激素受体相关蛋白220（TRAP 220）。值得注意的是，这些生物标志物中的两种（GOT 1和CD 44）现在用于Afirma分类器测定。我们选择特异性比较FTC与FA，而不是包括所有组织学分类，以建立更统一的免疫组化比较。此外，我们发现，大多数甲状腺乳头状癌往往可以合理地区分从良性疾病的形态细胞学发现单独。在不确定的甲状腺标本中，CA 4AB免疫反应性增加与甲状腺恶性肿瘤相关（c-统计量，0.644;阴性预测值[NPV]，0.90），CA 4免疫反应性丧失也与恶性肿瘤相关（c-统计量，0.715; NPV，0.90）。CA 4和CANAB的组合用于区分FTC和FA导致更好的c-统计量为0.75，灵敏度为0.76，特异性为0.59，阳性预测值（PPV）为0.32，NPV为0.91。当比较广泛血管侵入性FTC与FA时，所得c统计量提高至0.84，灵敏度为0.75，特异性为0.76，PPV为0.11，NPV为0.99。CA 4的丢失和CA 2AB免疫反应性的增加在NPV为91%的甲状腺TMA上的不确定甲状腺结节中区分FTC和FA。需要对术前患者细针穿刺（FNAs）进行进一步研究以验证这些结果。
Thyroid nodules are present in 19%–67% of the population and carry a 5%–10% risk of malignancy. Unfortunately, fine-needle aspiration biopsies are indeterminate in 20%–30% of patients, often necessitating thyroid surgery for diagnosis. Numerous DNA microarray studies including a recently commercialized molecular classifier have helped to better distinguish benign from malignant thyroid nodules. Unfortunately, these assays often require probes for >100 genes, are expensive, and only available at a few laboratories. We sought to validate these DNA microarray assays at the protein level and determine whether simple and widely available immunohistochemical biomarkers alone could distinguish benign from malignant thyroid nodules. A tissue microarray (TMA) composed of 26 follicular thyroid carcinomas (FTCs) and 53 follicular adenomas (FAs) from patients with indeterminate thyroid nodules was stained with 17 immunohistochemical biomarkers selected based on prior DNA microarray studies. Antibodies used included galectin 3, growth and differentiation factor 15, protein convertase 2, cluster of differentiation 44 (CD44), glutamic oxaloacetic transaminase 1 (GOT1), trefoil factor 3 (TFF3), Friedreich Ataxia gene (X123), fibroblast growth factor 13 (FGF13), carbonic anhydrase 4 (CA4), crystallin alpha-B (CRYAB), peptidylprolyl isomerase F (PPIF), asparagine synthase (ASNS), sodium channel, non-voltage gated, 1 alpha subunit (SCNN1A), frizzled homolog 1 (FZD1), tyrosine related protein 1 (TYRP1), E cadherin, type 1 (ECAD), and thyroid hormone receptor associated protein 220 (TRAP220). Of note, two of these biomarkers (GOT1 and CD44) are now used in the Afirma classifier assay. We chose to compare specifically FTC versus FA rather than include all histologic categories to create a more uniform immunohistochemical comparison. In addition, we have found that most papillary thyroid carcinoma could often be reasonably distinguished from benign disease by morphological cytology findings alone. Increased immunoreactivity of CRYAB was associated with thyroid malignancy (c-statistic, 0.644; negative predictive value [NPV], 0.90) and loss of immunoreactivity of CA4 was also associated with malignancy (c-statistic, 0.715; NPV, 0.90) in indeterminate thyroid specimens. The combination of CA4 and CRYAB for discriminating FTC from FA resulted in a better c-statistic of 0.75, sensitivity of 0.76, specificity of 0.59, positive predictive value (PPV) of 0.32, and NPV of 0.91. When comparing widely angioinvasive FTC from FA, the resultant c-statistic improved to 0.84, sensitivity of 0.75, specificity of 0.76, PPV of 0.11, and NPV of 0.99. Loss of CA4 and increase in CRYAB immunoreactivity distinguish FTC from FA in indeterminate thyroid nodules on a thyroid TMA with an NPV of 91%. Further studies in preoperative patient fine needle aspiration (FNAs) are needed to validate these results.
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