凝集素相关分子和细胞凋亡调控分子在甲状腺疾病中的表达
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摘要
第一部分凝集素相关分子的表达在甲状腺癌定性诊断中的意义
背景：甲状腺癌的组织学类型众多，恶性程度各异，临床上缺乏特异性的术前诊断手段。细针穿刺抽吸细胞学检查虽可明确诊断未分化癌和髓样癌，但对滤泡状病变的定性诊断有一定的局限性。Galectin-3和CD44v6是两种凝集素相关分子，已知细胞增殖、恶性转化和肿瘤浸润时其表达发生改变。目前国内文献中未见到有关Galectin-3在甲状腺癌中表达情况的研究，国外的同类研究中也未见到Galectin-3和CD44v6二者结合在甲状腺癌定性诊断和预后评估方面的参考价值的报道。本研究的目的是了解这两种物质在甲状腺良、恶性病变组织中表达的情况，分析二者的异常表达与甲状腺癌鉴别诊断及评估预后的关系，探讨其作为甲状腺恶性肿瘤标志物的临床应用价值。
方法：研究对象为60例手术切除的甲状腺组织标本，包括：37例甲状腺癌(20例乳头状癌、14例滤泡状癌、2例未分化癌和1例髓样癌)、23例
硕士研究生论文
良性病变（15例腺瘤和8例结节性甲状腺肿）和10例从病变旁或对侧叶取
得的正常甲状腺组织。所有标本经 10％中性福尔马林固定、石蜡包埋制成蜡
块后切片，用免疫组化法对每例标本都分别做增殖细胞核抗原中roliferating
cell nuclear antigen，PCNA）、Galectin－3和 CD44v6的染色，然后对染色结果
进行定性和半定量分析，其中 PCNA的表达水平用增殖指数（Proliferation
Index，PI），即计数 1000个细胞中的阳性细胞百分率来表示。
结果：
1．甲状腺良、恶性病变组织的PI值无明显差异（P＞0．05）。但在甲状腺
癌中，分化癌的PI值为38土15，而未分化癌的PI值为78土20，后者明显高
于前者（P＜0．05）。
2．Galectin－3在恶性病变表达的阳性率（86．49％，32／37）显著高于良
性病变J．3叱，1亿3）u．005＼正常甲状腺组织未见其表达。乳头状癌
表达Galectin－3的阳性率为100％（20／20），而且均表现为弥漫分布的细胞
浆强阳性表达；Galectin－3在滤泡状癌中的表达变异较大，14例中有10例
呈阳性表达，其中6例为强阳性表达；2例未分化癌均呈强阳性表达；1例髓
样癌为阴性表达。Galectin－3对甲状腺乳头状癌和滤泡状癌与良性病变鉴别
诊断的准确率分别为97．67％和86．49％。
3．CD44V6在甲状腺癌中表达的阳性率为89．19％（33／37），而在良牲病
变中的阳性率为 ZI．74％（5／23），前者明显高于后者（P＜0．005）。正常甲状
腺组织未见其表达。阳性部位主要在细胞膜，5例标本可见到细胞浆也呈阳
性染色的细胞。比较不同发展阶段的甲状腺癌表达CD44V6的阳性率发现，伴
有淋巴结转移的组织学标本中CD44V6的阳性率为96．43％（27／28），而不伴
淋巴结转移转移的标本中 CD44V6的阳性率为 66．67％（6／9），二者相比有显
著性差异（P二0．0375）。
结论：
2
硕士研究生论文
1．肿瘤细胞的增殖活性与分化程度有关。增殖活性越强，则分化越差，
恶性度也越高。
2．Galectin－3在甲状腺癌表达的阳性率显著高于良性病变和正常甲状
腺组织，提示Galectin－3可作为甲状腺癌尤其是乳头状癌可靠的肿瘤标志物
之一。
3．CD44V6在甲状腺癌中的表达明显高于良性病变，而且伴有淋巴结转移
的标本中表达CD44V6的阳性率高于不伴淋巴结转移者，提示CD44V6的高表
达与甲状腺癌的定性诊断以及不良的临床预后有关。
4．总之，Galectin－3和CD44v6与甲状腺癌的转化和转移有关，二者的
协同表达可作为甲状腺癌可靠的肿瘤标志物。应用免疫组化法检测这两种物
质在甲状腺肿瘤组织或细胞学标本中的表达，可提高甲状腺结节患者的鉴别
诊断准确率，并可预测患者预后，为临床医师制定适宜的治疗方案提供参考。
Chapter 1 The expression of lection-related molecules correlates
with the qualitative diagnosis of thyroid carcinomas
Background: Up to now, no special method has been established to identify the group of malignant tumors in a presurgical phase because of different histological and behavior patterns. FNAC (fine-needle aspiration cytology) boasts excellent diagnostic accuracy for anaplastic and medullary carcinomas, but the main limitation is the lack of sensitivity in the evaluation of follicular lesions. Galectin-3 and CD44v6 are two groups of lectin-related molecules, the expression of which is altered during cell proliferation, malignant transformation and tumor progression. At present, the study of galectin-3 expression in thyroid carcinomas has not been found in native literatures, moreover, we have not found foreign
reports about the significance of galectin-3 and CD44v6 expression in qualitative diagnosis together with prognostic assessment of thyroid tumors. Therefore, in this study we examined their expression hi a spectrum of surgically excised benign and malignant thyroid lesions and analyzed the relationship between their abnormal expression and differential diagnosis as well as prognostic assessment of thyroid carcinomas in order to explore the clinical significance of the specific tumor marker.
Methods: 60 tissue samples were examined in this study. They were taken from patients who had undergone thyroidectomy, including 37 thyroid carcinomas (20 papillary carcinomas, 14 follicular carcinomas, 2 anaplastic carcinomas and 1 medullary carcinoma), 23 benign thyroid lesions (15 adenomas and 8 nodular goiters) and 10 normal thyroid tissues obtained from histologically normal areas adjacent to the lesions or the other lobe. All the specimens were fixed in 10% neutral formalin, embedded in paraffin, and cut into sections. Immunostaining was performed on these sections using monoclonal antibodies against PCNA (proliferaing cell nuclear antigen), galectin-3 and CD44v6, and the results were analyzed qualitatively and half-quantitatively. The levels of PCNA expression were evaluated by PI (Proliferation Index), namely a percentage of positive cells in a total of 1000 counted cells.
Results:
1. The PI of differentiated thyroid carcinomas was 38 + 15, while that of undifferentiated carcinomas was 78 ?0. Undifferentiated carcinomas showed significantly higher PI than undifferentiated carcinomas (P<0.05), although the PI of malignant lesions was not predominantly different from benign lesions.
2. The incidence of galectin-3 positive expression in thyroid carcinomas
(86.49%, 32/37) was significantly higher than that in benign lesions (4.3f %, 1/23) (P<0.005). The normal thyroids were negative for galectin-3. An intense and diffuse cytoplasmic staining was observed in all 20 papillary carcinomas and 6 of 14 follicular carcinomas. Galectin-3 immunostaining in follicular carcinomas showed great variability. The two cases of anaplastic carcinoma were all positive staining and 1 medullary carcinoma was negative. The diagnostic accuracy of galectin-3 evaluation was 97.67% in papillary carcinomas and 86.49% in follicular carcinomas respectively, compared to its expression in benign lesions.
3. The incidence of CD44v6 positive expression in thyroid carcinomas (89.19%, 33/37) was significantly higher than that in benign lesions (21.74%, 5/23) (P< 0.005). The normal thyroids were also negative for CD44v6. The pattern of staining for CD44v6 was mainly membranous but cytoplasmic, as well. The frequency of CD44v6 positive expression in NI lesions (96.43%, 27/28) was higher than that in NO lesions (66.67%, 6/9), thus it could be seen that the levels of CD44v6 expression was different in different pathologic stages of thyroid rumors.
Conclusion:
1. The proliferating activity of tumor cells is associated with the differentiation degree. The higher the proliferating activity is, the lower the differentiation degree is.
2. Galectin-3 expression in thyroid carcinomas is higher than tha
背景：甲状腺癌的组织学类型众多，恶性程度各异，临床上缺乏特异性的术前诊断手段。细针穿刺抽吸细胞学检查虽可明确诊断未分化癌和髓样癌，但对滤泡状病变的定性诊断有一定的局限性。Galectin-3和CD44v6是两种凝集素相关分子，已知细胞增殖、恶性转化和肿瘤浸润时其表达发生改变。目前国内文献中未见到有关Galectin-3在甲状腺癌中表达情况的研究，国外的同类研究中也未见到Galectin-3和CD44v6二者结合在甲状腺癌定性诊断和预后评估方面的参考价值的报道。本研究的目的是了解这两种物质在甲状腺良、恶性病变组织中表达的情况，分析二者的异常表达与甲状腺癌鉴别诊断及评估预后的关系，探讨其作为甲状腺恶性肿瘤标志物的临床应用价值。
方法：研究对象为60例手术切除的甲状腺组织标本，包括：37例甲状腺癌(20例乳头状癌、14例滤泡状癌、2例未分化癌和1例髓样癌)、23例
硕士研究生论文
良性病变（15例腺瘤和8例结节性甲状腺肿）和10例从病变旁或对侧叶取
得的正常甲状腺组织。所有标本经 10％中性福尔马林固定、石蜡包埋制成蜡
块后切片，用免疫组化法对每例标本都分别做增殖细胞核抗原中roliferating
cell nuclear antigen，PCNA）、Galectin－3和 CD44v6的染色，然后对染色结果
进行定性和半定量分析，其中 PCNA的表达水平用增殖指数（Proliferation
Index，PI），即计数 1000个细胞中的阳性细胞百分率来表示。
结果：
1．甲状腺良、恶性病变组织的PI值无明显差异（P＞0．05）。但在甲状腺
癌中，分化癌的PI值为38土15，而未分化癌的PI值为78土20，后者明显高
于前者（P＜0．05）。
2．Galectin－3在恶性病变表达的阳性率（86．49％，32／37）显著高于良
性病变J．3叱，1亿3）u．005＼正常甲状腺组织未见其表达。乳头状癌
表达Galectin－3的阳性率为100％（20／20），而且均表现为弥漫分布的细胞
浆强阳性表达；Galectin－3在滤泡状癌中的表达变异较大，14例中有10例
呈阳性表达，其中6例为强阳性表达；2例未分化癌均呈强阳性表达；1例髓
样癌为阴性表达。Galectin－3对甲状腺乳头状癌和滤泡状癌与良性病变鉴别
诊断的准确率分别为97．67％和86．49％。
3．CD44V6在甲状腺癌中表达的阳性率为89．19％（33／37），而在良牲病
变中的阳性率为 ZI．74％（5／23），前者明显高于后者（P＜0．005）。正常甲状
腺组织未见其表达。阳性部位主要在细胞膜，5例标本可见到细胞浆也呈阳
性染色的细胞。比较不同发展阶段的甲状腺癌表达CD44V6的阳性率发现，伴
有淋巴结转移的组织学标本中CD44V6的阳性率为96．43％（27／28），而不伴
淋巴结转移转移的标本中 CD44V6的阳性率为 66．67％（6／9），二者相比有显
著性差异（P二0．0375）。
结论：
2
硕士研究生论文
1．肿瘤细胞的增殖活性与分化程度有关。增殖活性越强，则分化越差，
恶性度也越高。
2．Galectin－3在甲状腺癌表达的阳性率显著高于良性病变和正常甲状
腺组织，提示Galectin－3可作为甲状腺癌尤其是乳头状癌可靠的肿瘤标志物
之一。
3．CD44V6在甲状腺癌中的表达明显高于良性病变，而且伴有淋巴结转移
的标本中表达CD44V6的阳性率高于不伴淋巴结转移者，提示CD44V6的高表
达与甲状腺癌的定性诊断以及不良的临床预后有关。
4．总之，Galectin－3和CD44v6与甲状腺癌的转化和转移有关，二者的
协同表达可作为甲状腺癌可靠的肿瘤标志物。应用免疫组化法检测这两种物
质在甲状腺肿瘤组织或细胞学标本中的表达，可提高甲状腺结节患者的鉴别
诊断准确率，并可预测患者预后，为临床医师制定适宜的治疗方案提供参考。
Chapter 1 The expression of lection-related molecules correlates
with the qualitative diagnosis of thyroid carcinomas
Background: Up to now, no special method has been established to identify the group of malignant tumors in a presurgical phase because of different histological and behavior patterns. FNAC (fine-needle aspiration cytology) boasts excellent diagnostic accuracy for anaplastic and medullary carcinomas, but the main limitation is the lack of sensitivity in the evaluation of follicular lesions. Galectin-3 and CD44v6 are two groups of lectin-related molecules, the expression of which is altered during cell proliferation, malignant transformation and tumor progression. At present, the study of galectin-3 expression in thyroid carcinomas has not been found in native literatures, moreover, we have not found foreign
reports about the significance of galectin-3 and CD44v6 expression in qualitative diagnosis together with prognostic assessment of thyroid tumors. Therefore, in this study we examined their expression hi a spectrum of surgically excised benign and malignant thyroid lesions and analyzed the relationship between their abnormal expression and differential diagnosis as well as prognostic assessment of thyroid carcinomas in order to explore the clinical significance of the specific tumor marker.
Methods: 60 tissue samples were examined in this study. They were taken from patients who had undergone thyroidectomy, including 37 thyroid carcinomas (20 papillary carcinomas, 14 follicular carcinomas, 2 anaplastic carcinomas and 1 medullary carcinoma), 23 benign thyroid lesions (15 adenomas and 8 nodular goiters) and 10 normal thyroid tissues obtained from histologically normal areas adjacent to the lesions or the other lobe. All the specimens were fixed in 10% neutral formalin, embedded in paraffin, and cut into sections. Immunostaining was performed on these sections using monoclonal antibodies against PCNA (proliferaing cell nuclear antigen), galectin-3 and CD44v6, and the results were analyzed qualitatively and half-quantitatively. The levels of PCNA expression were evaluated by PI (Proliferation Index), namely a percentage of positive cells in a total of 1000 counted cells.
Results:
1. The PI of differentiated thyroid carcinomas was 38 + 15, while that of undifferentiated carcinomas was 78 ?0. Undifferentiated carcinomas showed significantly higher PI than undifferentiated carcinomas (P<0.05), although the PI of malignant lesions was not predominantly different from benign lesions.
2. The incidence of galectin-3 positive expression in thyroid carcinomas
(86.49%, 32/37) was significantly higher than that in benign lesions (4.3f %, 1/23) (P<0.005). The normal thyroids were negative for galectin-3. An intense and diffuse cytoplasmic staining was observed in all 20 papillary carcinomas and 6 of 14 follicular carcinomas. Galectin-3 immunostaining in follicular carcinomas showed great variability. The two cases of anaplastic carcinoma were all positive staining and 1 medullary carcinoma was negative. The diagnostic accuracy of galectin-3 evaluation was 97.67% in papillary carcinomas and 86.49% in follicular carcinomas respectively, compared to its expression in benign lesions.
3. The incidence of CD44v6 positive expression in thyroid carcinomas (89.19%, 33/37) was significantly higher than that in benign lesions (21.74%, 5/23) (P< 0.005). The normal thyroids were also negative for CD44v6. The pattern of staining for CD44v6 was mainly membranous but cytoplasmic, as well. The frequency of CD44v6 positive expression in NI lesions (96.43%, 27/28) was higher than that in NO lesions (66.67%, 6/9), thus it could be seen that the levels of CD44v6 expression was different in different pathologic stages of thyroid rumors.
Conclusion:
1. The proliferating activity of tumor cells is associated with the differentiation degree. The higher the proliferating activity is, the lower the differentiation degree is.
2. Galectin-3 expression in thyroid carcinomas is higher than tha
引文
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44． Pollina L, Pacini F, Fontanini G, et al. Bcl-2, p53 and proliferating cell nuclear antigen expression is related to the degree of differentiation in thyroid carcinoma. Br J Cancer 1996; 73:139-143．
45． Niedobitek C, Niedobitek F, Linddenberg G, et al. Expression of galectin-3 in thyroid gland and follicular cell tumors of the thyroid. A critical study of its possible role in preoperative differential diagnosis. Pathologe 2001; 22: 205-213
46． Lloyd RV. Distinguishing benign from malignant thyroid lesions: galectin 3 as the latest candidate. 2001; 12: 255-257
47． Coli A, Bigotti G, Zucchetti F, et al. Galectin-3, a marker of well-differentiated thyroid carcinoma, is expressed in thyroid nodules with cytological atypia. Histopathology 2002; 40: 80-87
48． Wang JL, Werner EA, Laing JG, et al. Nuclear and cytoplasmic localization of a lectin-ribonucleoprotein complex. Biochem Soc Transact 1992; 20:269-274．
49． Wang L, Inohara H, Pienta KJ, et al. Galectin-3 is a nuclear matrix protein which binds RNA. Biochem Biophys Res Commun 1995; 217:292-303．
50． Lee EC, Woo HJ, Korzelius CA, et al. Carbohydrate-binding protein 35 is the major cell surface laminin-binding protein in colon carcinoma. Arch Surg 1991; 126:1496-1502．
51． Ohannesian DW, Lotan D, Thomas P, et al. Carcinoembryonic antigen
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52． Cvejic D, Savin S, Paunovic I, et al. Immunohistochemical localization of galectin-3 in malignant and benign human thyroid tassue. Anticancer Res 1998; 18:2637-2642．
53． Saito H, Tsujitani S, Katano K, et al. Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma. Cancer 1998; 83:1094-1101
54． 梁雨荣，何尔斯泰．转移相关基因CD44v6在胃癌中的表达意义．中国肿 瘤临床1999：26：33-35．