甲状腺滤泡性增生结节的良恶性鉴别诊断研究
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摘要
目的:检测DDIT3 mRNA和DDIT3蛋白、Galectin-3、CK19和Ki-67蛋白在良恶性甲状腺滤泡性增生结节中的表达情况,为甲状腺滤泡性增生结节的诊断及鉴别诊断提供依据。
方法:本研究收集新疆石河子大学医学院第一附属医院病理科和新疆维吾尔自治区人民医院1983～2007年甲状腺滤泡性增生结节石蜡包埋组织99例,其中包括46例滤泡癌、14例滤泡亚型乳头状癌、25例滤泡性腺瘤和14例腺瘤样甲状腺肿。收集2006年12月～2007年11月的甲状腺病变手术新鲜标本23例,包括4例乳头状癌(滤泡亚型1例),2例滤泡癌,8例滤泡性腺瘤和9例结节性甲状腺肿。所有病例均经HE染色并由两名高年资病理学教授按照2004年WHO最新分类标准进行形态学观察。免疫组织化学方法检测DDIT3、Galectin-3、CK19和Ki-67蛋白在良恶性甲状腺滤泡性增生结节中的表达。逆转录聚合酶链反应(RT-PCR)技术检测良恶性甲状腺结节中DDIT3基因mRNA水平的表达,并结合临床病理资料采用SPSS13.0统计分析软件对实验结果进行分析。
结果: 99例甲状腺滤泡性增生结节免疫组化染色结果显示,DDIT3、Galectin-3和CK19蛋白在甲状腺滤泡性增生结节良性组和恶性组的阳性率分别为23.1%、10.1%、23.1%和91.7%、76.7%、60%,良性组与恶性组相比差异有统计学意义(P < 0.001)。其中Galectin-3和CK19蛋白在滤泡亚型乳头状癌组与滤泡癌组中的阳性率分别为100%、92.9%和69.6%、50%,滤泡亚型乳头状癌组与滤泡癌组比较差异有统计学意义(P < 0.01)。Ki-67在甲状腺滤泡性增生结节良性组与恶性组中的表达指数分别为2.49±1.98和8.98±9.24,两组比较差异有统计学意义(P < 0.001)。应用逆转录聚合酶链反应技术(RT-PCR)检测40例甲状腺结节DDIT3 mRNA的表达,结果显示DDIT3 mRNA在9例结节性甲状腺肿、8例滤泡性腺瘤和23例甲状腺癌中表达指数分别为0.13±0.19、0.55±0.35和1.05±0.36,检测的5例甲状腺癌癌旁组织,DDIT3 mRNA均不表达。
结论: (1)结合形态学特点的基础上,DDIT3、Galectin-3、CK19和Ki-67蛋白的高表达有助于甲状腺癌的诊断和鉴别诊断。(2)Galectin-3和CK19蛋白对甲状腺滤泡亚型乳头状癌的敏感性更高。良性病变中出现Galectin-3阳性表达,应视为具有恶变潜能的高危病变,临床应加强随访观察。(3)DDIT3 mRNA在甲状腺癌中表达明显增强,可作为甲状腺癌早期诊断的分子指标,但是否参与甲状腺癌的发生发展有待于进一步研究证实。
Objective: In order to provide marker of diagnosis and differentiated diagnosis of benign and malignant thyroid follicular hyperplastic nodules, the expression of DDIT3 mRNA and DDIT3 protein, Galectin-3, CK19 and Ki-67 protein was detected in benign and malignant thyroid follicular hyperplastic nodules.
Methods: 99 cases of paraffin-embedded tissue of thyroid follicular hyperplastic nodules were collected from archives of Department of Pathology in Shihezi University School of Medicine and People's Hospital of Xinjiang Uygur Autonomous Region from 1983 to 2007, including 46 cases of follicular carcinoma (FTC), 14 cases of follicular variant of papillary carcinoma (FVPTC), 25 cases of follicular adenoma (FTA) and 14 cases of adenomatous goiter. 23 cases of surgery fresh specimens of thyroid nodules were collected from December 2006 to November 2007, including 4 cases of papillary carcinoma, 2 cases of FTC, 8 cases of FTA and 9 cases of nodular goiter. All cases were stained by HE staining and diagnosed by two senior pathological professors referring to the 2004 WHO classification standards. The expression of DDIT3, Galectin-3, CK19 and Ki-67 protein was detected in benign and malignant thyroid follicular hyperplastic nodules by immunohistochemical staining and the expression of DDIT3 gene mRNA was detected in 40 cases of benign and malignant thyroid nodules by reverse transcriptase polymerase chain reaction (RT-PCR). All dates were analysis by software SPSS13.0 and combining with clinical and pathological data to analysis it.
Results: The positive rates of DDIT3, Galectin-3 and CK19 protein expression in benign and malignant thyroid follicular hyperplastic nodule were 23.1%, 10.1%, 23.1% and 91.7%, 76.7%, 60%, respectively. There was a significant difference of the three markers expression between benign and malignant group (P < 0.001). While Galectin-3 and CK19 protein expression was significant difference between FVPTC and FTC group (P < 0.01). The expression indexes of Ki-67 in benign and malignant group were 2.49±1.98 and 8.98±9.24, respectively and there was also a significant difference between benign and malignant group (P < 0.001). DDIT3 mRNA expression of 40 cases of thyroid nodules by RT-PCR showed that DDIT3 mRNA expression in 9 cases of nodular goiter, 8 cases of FTA, 23 cases of thyroid carcinoma was 0.13±0.19, 0.55±0.35 and 1.05±0.36, respectively, but five cases of adjacent thyroid carcinoma tissues had negative expression of DDIT3 mRNA.
Conclusion: (1) DDIT3, Galectin-3, CK19 and Ki-67 protein expression was helpful for the diagnosis and differential diagnosis of thyroid carcinoma based on the morphological characteristics. (2) The expression of Galectin-3 and CK19 protein had high sensitivity for diagnosis of FVPTC. If the expression of Galectin-3 was positive in benign lesions, we regarded it as a potential higher-risk of malignant lesions and it is needed to further study by clinical follow-up. (3) DDIT3 mRNA expression in thyroid carcinoma had noticeably increased. It can be used as molecular target in early diagnosis of thyroid cancer. Whether it will participate in the development of thyroid carcinoma or not, we should further study with more cases.
方法:本研究收集新疆石河子大学医学院第一附属医院病理科和新疆维吾尔自治区人民医院1983～2007年甲状腺滤泡性增生结节石蜡包埋组织99例,其中包括46例滤泡癌、14例滤泡亚型乳头状癌、25例滤泡性腺瘤和14例腺瘤样甲状腺肿。收集2006年12月～2007年11月的甲状腺病变手术新鲜标本23例,包括4例乳头状癌(滤泡亚型1例),2例滤泡癌,8例滤泡性腺瘤和9例结节性甲状腺肿。所有病例均经HE染色并由两名高年资病理学教授按照2004年WHO最新分类标准进行形态学观察。免疫组织化学方法检测DDIT3、Galectin-3、CK19和Ki-67蛋白在良恶性甲状腺滤泡性增生结节中的表达。逆转录聚合酶链反应(RT-PCR)技术检测良恶性甲状腺结节中DDIT3基因mRNA水平的表达,并结合临床病理资料采用SPSS13.0统计分析软件对实验结果进行分析。
结果: 99例甲状腺滤泡性增生结节免疫组化染色结果显示,DDIT3、Galectin-3和CK19蛋白在甲状腺滤泡性增生结节良性组和恶性组的阳性率分别为23.1%、10.1%、23.1%和91.7%、76.7%、60%,良性组与恶性组相比差异有统计学意义(P < 0.001)。其中Galectin-3和CK19蛋白在滤泡亚型乳头状癌组与滤泡癌组中的阳性率分别为100%、92.9%和69.6%、50%,滤泡亚型乳头状癌组与滤泡癌组比较差异有统计学意义(P < 0.01)。Ki-67在甲状腺滤泡性增生结节良性组与恶性组中的表达指数分别为2.49±1.98和8.98±9.24,两组比较差异有统计学意义(P < 0.001)。应用逆转录聚合酶链反应技术(RT-PCR)检测40例甲状腺结节DDIT3 mRNA的表达,结果显示DDIT3 mRNA在9例结节性甲状腺肿、8例滤泡性腺瘤和23例甲状腺癌中表达指数分别为0.13±0.19、0.55±0.35和1.05±0.36,检测的5例甲状腺癌癌旁组织,DDIT3 mRNA均不表达。
结论: (1)结合形态学特点的基础上,DDIT3、Galectin-3、CK19和Ki-67蛋白的高表达有助于甲状腺癌的诊断和鉴别诊断。(2)Galectin-3和CK19蛋白对甲状腺滤泡亚型乳头状癌的敏感性更高。良性病变中出现Galectin-3阳性表达,应视为具有恶变潜能的高危病变,临床应加强随访观察。(3)DDIT3 mRNA在甲状腺癌中表达明显增强,可作为甲状腺癌早期诊断的分子指标,但是否参与甲状腺癌的发生发展有待于进一步研究证实。
Objective: In order to provide marker of diagnosis and differentiated diagnosis of benign and malignant thyroid follicular hyperplastic nodules, the expression of DDIT3 mRNA and DDIT3 protein, Galectin-3, CK19 and Ki-67 protein was detected in benign and malignant thyroid follicular hyperplastic nodules.
Methods: 99 cases of paraffin-embedded tissue of thyroid follicular hyperplastic nodules were collected from archives of Department of Pathology in Shihezi University School of Medicine and People's Hospital of Xinjiang Uygur Autonomous Region from 1983 to 2007, including 46 cases of follicular carcinoma (FTC), 14 cases of follicular variant of papillary carcinoma (FVPTC), 25 cases of follicular adenoma (FTA) and 14 cases of adenomatous goiter. 23 cases of surgery fresh specimens of thyroid nodules were collected from December 2006 to November 2007, including 4 cases of papillary carcinoma, 2 cases of FTC, 8 cases of FTA and 9 cases of nodular goiter. All cases were stained by HE staining and diagnosed by two senior pathological professors referring to the 2004 WHO classification standards. The expression of DDIT3, Galectin-3, CK19 and Ki-67 protein was detected in benign and malignant thyroid follicular hyperplastic nodules by immunohistochemical staining and the expression of DDIT3 gene mRNA was detected in 40 cases of benign and malignant thyroid nodules by reverse transcriptase polymerase chain reaction (RT-PCR). All dates were analysis by software SPSS13.0 and combining with clinical and pathological data to analysis it.
Results: The positive rates of DDIT3, Galectin-3 and CK19 protein expression in benign and malignant thyroid follicular hyperplastic nodule were 23.1%, 10.1%, 23.1% and 91.7%, 76.7%, 60%, respectively. There was a significant difference of the three markers expression between benign and malignant group (P < 0.001). While Galectin-3 and CK19 protein expression was significant difference between FVPTC and FTC group (P < 0.01). The expression indexes of Ki-67 in benign and malignant group were 2.49±1.98 and 8.98±9.24, respectively and there was also a significant difference between benign and malignant group (P < 0.001). DDIT3 mRNA expression of 40 cases of thyroid nodules by RT-PCR showed that DDIT3 mRNA expression in 9 cases of nodular goiter, 8 cases of FTA, 23 cases of thyroid carcinoma was 0.13±0.19, 0.55±0.35 and 1.05±0.36, respectively, but five cases of adjacent thyroid carcinoma tissues had negative expression of DDIT3 mRNA.
Conclusion: (1) DDIT3, Galectin-3, CK19 and Ki-67 protein expression was helpful for the diagnosis and differential diagnosis of thyroid carcinoma based on the morphological characteristics. (2) The expression of Galectin-3 and CK19 protein had high sensitivity for diagnosis of FVPTC. If the expression of Galectin-3 was positive in benign lesions, we regarded it as a potential higher-risk of malignant lesions and it is needed to further study by clinical follow-up. (3) DDIT3 mRNA expression in thyroid carcinoma had noticeably increased. It can be used as molecular target in early diagnosis of thyroid cancer. Whether it will participate in the development of thyroid carcinoma or not, we should further study with more cases.
引文
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