滑膜肉瘤SYT-SSX融合基因检测和Her-2/neu基因及其蛋白表达的研究
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摘要
滑膜肉瘤是相对常见的软组织恶性肿瘤之一,患者多为中青年,由于肿瘤复发和转移率较高,对其明确诊断和治疗成为外科和病理科共同关注的问题。
研究目的
诊断方面:从临床病理学、免疫组织化学和分子遗传学角度逐层分析滑膜肉瘤的特征,为明确诊断提供实验依据。包括:
1)总结滑膜肉瘤的临床病理学特征;
2)探寻相对特异的免疫标记物,用于滑膜肉瘤的病理诊断;
3)探索荧光原位杂交(Fluorescence in Situ Hybridization,FISH)方法检测SYT-SSX基因的意义和可行性;
治疗方面:通过观察Her-2基因及其蛋白在滑膜肉瘤中的表达,初步探讨针对Her-2受体的治疗应用于滑膜肉瘤的可行性。
方法
1)收集71例滑膜肉瘤的临床和病理学资料,分析其临床病理特点。
2)运用免疫组织化学EnVision~+两步法检测Calponin(59例)、TLE1(55例)、Her-2(51例)、Ki-67(41例)等蛋白的表达;以MPNST、PNET、SFT等肿瘤作为对照组,calponin对照组为64例,TLE1对照组为112例。
3)运用FISH方法检测66例存档石蜡包埋组织中SYT基因分离状态,对照组为9例形态近似的其它软组织肉瘤;
4)逆转录聚合酶链反应(reverse transcript polymerase chain reaction,RT-PCR)法检测53例存档石蜡包埋组织中SYT-SSX融合基因;
5)运用FISH方法检测Her-2基因扩增状态;
6)运用实时定量PCR(Quantitative Real-Time RT-PCR,Q-PCR)检测Her-2mRNA的水平。
结果
1) 71例滑膜肉瘤中特殊部位滑膜肉瘤34例(47.8%),低分化滑膜肉瘤30例(42.3%),比例均较高;单相纤维细胞型滑膜肉瘤47例(66.2%),单相上皮细胞型2例(2.8%),双相型22例(31.0%)。许多形态变异的肿瘤位于特殊部位。肿瘤的组织学类型和分化程度无关。
2) AE1/AE3和EMA联合使用的阳性率为97.7%。选择性表达其中一种的占34.1%。Bcl-2和CD99的阳性率分别为:88.0%和77.8%。近1/3的病例表达S-100蛋白。
89.8%(53/59)滑膜肉瘤表达Calponin,其中中等以上阳性者26例,弱阳性表达27例。与分化相对好的滑膜肉瘤相比,低分化滑膜肉瘤Calponin表达明显较弱。对照组Calponin在肌源性和肌纤维母细胞源性肿瘤中的表达较高,其余肿瘤表达的频率和强度明显低于滑膜肉瘤。
98.2%(54/55)的滑膜肉瘤表达TLE1抗体,其中50例显示较强或弥漫的染色(2+～3+),4例染色较弱,阴性1例。大多数非滑膜肉瘤不表达TLE1或仅以弱表达为主,但部分肿瘤如恶性黑色素瘤,间皮瘤等也有较高的阳性率。
3) 66例滑膜肉瘤中,62例(93.9%)FISH检测成功,其中56例显示SYT基因易位,6例显示无SYT基因易位。对照组均显示无SYT基因易位。观察FISH检测结果,仅1例阳性细胞数为30%,该例肿瘤细胞的比例较低而间质比例高,其余均在80%以上。3例滑膜肉瘤的FISH信号较为特殊,这3例均为低分化,预后差,RT-PCR证实其中2例有SYT-SSX融合基因存在,1例未能获取组织。
86.8%(46/53)的滑膜肉瘤获得满意的mRNA。41例显示SYT-SSX融合基因,5例未检测到融合基因。融合基因类型和组织学分型无关。同时得到FISH及RT-PCR检测结果的滑膜肉瘤病例为44例,42例结果相同,两者结果显著相关。
4) 35.3%(18/51)的滑膜肉瘤表达Her-2。其中多数为弱阳性表达,3+者仅有1例(2.0%)。阳性定位包括胞质和胞膜,胞质内以弱阳性表达为主,胞膜染色较强。低分化滑膜肉瘤组中,Her-2蛋白表达较高。Her-2蛋白表达较强的病例中,DNA未见明显扩增。滑膜肉瘤中Her-2 mRNA水平较低;在蛋白表达较高的病例中,mRNA水平未见明显升高。
结论
1)滑膜肉瘤可以广泛发生于四肢以外的全身各部位,许多少见部位的肿瘤都有各自临床病理学特征,也常常伴有形态学的变异。
2) AE1/AE3和EMA的联合应用做为滑膜肉瘤上皮性标记敏感性高,阳性范围覆盖其它种类的上皮性标记。TLE1抗体敏感性很高,但特异性略差。Calponin在诊断滑膜肉瘤中的敏感性较高,排除肌源性和肌纤维母细胞来源的肿瘤后,阳性表达有较高的特异性。我们推荐在常规工作中联合采用AE1/AE3,EMA,Calponin,TLE1,作为滑膜肉瘤的免疫组化标记物,以提高其诊断率。
3) RT-PCR和FISH技术对于滑膜肉瘤融合基因的检出率均较高,两种方法所得结果明显相关,均可以做为确诊依据。FISH技术操作简便,不易污染,结果直观,改进实验方法后可以大大减少成本。因而这一技术可以在滑膜肉瘤的诊断中切实地开展,尤其适用于与其它类型软组织肉瘤在免疫表型上有重叠的或发生于特殊部位的滑膜肉瘤,并可以推广应用于其它软组织肿瘤中。
4) FISH信号的异常反映了染色体的部分缺失和扩增,这种改变很可能提示患者预后差。
5)在观察和分析的基础上,首次提出我们对FISH结果的判断标准及原则。
6)滑膜肉瘤中Her-2的表达方式以及在滑膜肉瘤中的作用很可能不同于乳腺癌,因而针对Her-2受体的治疗在滑膜肉瘤中宜慎重。
[Objectives]Synovial sarcoma is a relatively common high grade soft tissue sarcoma,which arises mostly in young adults with high risk of metastasis and recurrence.Diagnoses of synovial sarcoma of morphological variants and unexpected location are usually challenging.As a result,aiming to distinguish synovial sarcoma from other lesions,we analyzed the distinctive features of synovial sarcoma from clinicopathologic,immunohistochemic and genetic aspects.
For long period of time,researchers have been craving for the effective therapy against synovial sarcoma.The recently developed against the receptor tyrosine kinases(RTK) such as Her-2/neu may be an alternate candidate.
[Methods]We firstly observed the clinicopathological datas of 71 cases of synovial sarcoma including those developed at unexpected location and those with variant mophlogy.To assesse the frequency of expression and potential diagnostic utility of a series of antibodies especially calponin and TLE1,immunohistochemistry was undertaken in paraffin sections from 59 and 55 synovial sarcoma respectively, comparing with 64 and 112 cases of morphologically similar tumors such as MPNST, PNET and SFT et al.Molecular genetically,interphase FISH was utilized in 67 cases of SS and 9 of non-synovial sarcoma with a LSI SYT(18q11.2) dual color, break apart probe.In 53 of the cases,the resultant gene fusion SYT-SSX and its subtype were also analyzed by RT-PCR.51 cases of synovial sarcoma were assesed for Her-2 protein expression by immunohistochemical techniques and 44 of which for quantitative real-time polymerase chain reaction assay.
[Results]Of the 71 synovial sarcoma,34(47.8%) arose at unexpected site including pleura,lung,kidney,heart,tibia and etc;30 cases(42.3%) were undifferentiated type;47(66.2%) were monophasic fibrous type,2(2.8%) were monophasic epithelial type and 22(31.0%) were biphasic type.Many cases of unusual sites exhibited unusual morphology.Histologic type had no relationship with the malignancy grade.
34.1%synovial sarcoma exhibited immunostain with single antibody of AE1/AE3 or EMA,but 97.7%with both combined.88.0%,77.8%,33.3%cases were positive for Bcl-2,CD99 and S-100 respectively.
For calponin antibody,89.8%(53/59) synovial sarcoma cases showed at least focal reactivity,with 26 cases of 2+/3+ and 27 cases of 1+.The immunostain was rather weak in the group of poorly differentiated tumors.It is highly expressed in control tumors derived with relation to smooth muscle or myofirboblastoma,and is seldom expressed in other else.
For TLE1 antibody,98.2%(54/55) cases are positive,with 50 cases of 2+/3+,4 cases of 1+ and only 1 case of negative.Despite limited expression of the control group,some kinds of tumors,such as melanoma,mesothelioma,fibromatosis, exhibited high rate of expression.
In 66 cases of synovial sarcoma,we obtained definite results in 62(93.9%) by FISH,56 are positive and 6 are negative.More than 80%cells of most positive cases exhibited translocation signal.In the exceptional 1 case,such translocation cells accounted to 30%.Microscopically,tumor cells of this case were limited due to large amount of fibrovascular components among them.2 of unequal signals and 1 of multiple signals(2 orange and 1 green or 3 orange and 2 green) were identified. All of the 3 cases were poorly differentiated with unfavorable outcome,2 of which with available paraffin blocks were proved to be synovial sarcoma by RT-PCR.No SYT aberration was identified in the control group.
Detectable mRNA were gained from 86.8%(46/53) synovial sarcoma,41 of which bore SYT-SSX,and 5 negative.The type of transcripts(SYT-SSX1 or SYT-SSX2) had no relationship with histologic type.A total of 44 cases were detected by both FISH and RT-PCR,42 of which got same results.Results from both methods were nearly identical.
Her-2 protein expression was detected in 35.3%(18/51) synovial sarcoma, mainly very weak,and strong positive in only 1 case.Higher intensity was present in poorly differentiated synovial sarcoma.
Q-PCR demonstrated the presence of mRNA for Her-2 in 23 of 44 specimens. Her-2 mRNA of synovial sarcoma was low level compared with that of breast cancer with DNA amplification.Concentration of the protein did not change with intensity of the mRNA.No evidence of gene amplification was observed.
[Conclusions]Synovial sarcoma may occur in any part of the body.Some of the unusual site tumors have overlapping clinicopathological features as well as variant morphology.
Combined use of AE1/AE3 and EMA can be very sensitive,rather than other kinds of epithelia markers.TLE1 is high sensitive but not very specific. Comparatively,calponin is also sensitive,and may be used in differential diagnosis if that is not with tumors derived from smooth muscle or myofibroblast.A panel of antibodies including AE1/AE3,EMA,Calponin,TLE1 are recommended as valuable tool in diagnosis of synovial sarcoma.
FISH may act as diagnostic aid in problematic cases of SS.Comparing with RT-PCR,FISH takes the advantage of sensitivity,reliability and rapidity of result. As the laboratory and labor costs can be decreased to a great extent,we conclude that FISH is a robust approach and may be more broadly applicable in soft tissue molecular oncology.On the ground of the current research data,we proposed the principles in explanation to FISH results.
Abnormalities of FISH signals indicate chromosomal deletion or amplification, which may imply a poor prognosis.
As the way Her-2 expressed in synovial sarcoma is greatly different from that in breast cancer,the therapeutic modal against the receptor tyrosine kinases(RTK) such as Her-2/neu may not fit synovial sarcoma well.
研究目的
诊断方面:从临床病理学、免疫组织化学和分子遗传学角度逐层分析滑膜肉瘤的特征,为明确诊断提供实验依据。包括:
1)总结滑膜肉瘤的临床病理学特征;
2)探寻相对特异的免疫标记物,用于滑膜肉瘤的病理诊断;
3)探索荧光原位杂交(Fluorescence in Situ Hybridization,FISH)方法检测SYT-SSX基因的意义和可行性;
治疗方面:通过观察Her-2基因及其蛋白在滑膜肉瘤中的表达,初步探讨针对Her-2受体的治疗应用于滑膜肉瘤的可行性。
方法
1)收集71例滑膜肉瘤的临床和病理学资料,分析其临床病理特点。
2)运用免疫组织化学EnVision~+两步法检测Calponin(59例)、TLE1(55例)、Her-2(51例)、Ki-67(41例)等蛋白的表达;以MPNST、PNET、SFT等肿瘤作为对照组,calponin对照组为64例,TLE1对照组为112例。
3)运用FISH方法检测66例存档石蜡包埋组织中SYT基因分离状态,对照组为9例形态近似的其它软组织肉瘤;
4)逆转录聚合酶链反应(reverse transcript polymerase chain reaction,RT-PCR)法检测53例存档石蜡包埋组织中SYT-SSX融合基因;
5)运用FISH方法检测Her-2基因扩增状态;
6)运用实时定量PCR(Quantitative Real-Time RT-PCR,Q-PCR)检测Her-2mRNA的水平。
结果
1) 71例滑膜肉瘤中特殊部位滑膜肉瘤34例(47.8%),低分化滑膜肉瘤30例(42.3%),比例均较高;单相纤维细胞型滑膜肉瘤47例(66.2%),单相上皮细胞型2例(2.8%),双相型22例(31.0%)。许多形态变异的肿瘤位于特殊部位。肿瘤的组织学类型和分化程度无关。
2) AE1/AE3和EMA联合使用的阳性率为97.7%。选择性表达其中一种的占34.1%。Bcl-2和CD99的阳性率分别为:88.0%和77.8%。近1/3的病例表达S-100蛋白。
89.8%(53/59)滑膜肉瘤表达Calponin,其中中等以上阳性者26例,弱阳性表达27例。与分化相对好的滑膜肉瘤相比,低分化滑膜肉瘤Calponin表达明显较弱。对照组Calponin在肌源性和肌纤维母细胞源性肿瘤中的表达较高,其余肿瘤表达的频率和强度明显低于滑膜肉瘤。
98.2%(54/55)的滑膜肉瘤表达TLE1抗体,其中50例显示较强或弥漫的染色(2+～3+),4例染色较弱,阴性1例。大多数非滑膜肉瘤不表达TLE1或仅以弱表达为主,但部分肿瘤如恶性黑色素瘤,间皮瘤等也有较高的阳性率。
3) 66例滑膜肉瘤中,62例(93.9%)FISH检测成功,其中56例显示SYT基因易位,6例显示无SYT基因易位。对照组均显示无SYT基因易位。观察FISH检测结果,仅1例阳性细胞数为30%,该例肿瘤细胞的比例较低而间质比例高,其余均在80%以上。3例滑膜肉瘤的FISH信号较为特殊,这3例均为低分化,预后差,RT-PCR证实其中2例有SYT-SSX融合基因存在,1例未能获取组织。
86.8%(46/53)的滑膜肉瘤获得满意的mRNA。41例显示SYT-SSX融合基因,5例未检测到融合基因。融合基因类型和组织学分型无关。同时得到FISH及RT-PCR检测结果的滑膜肉瘤病例为44例,42例结果相同,两者结果显著相关。
4) 35.3%(18/51)的滑膜肉瘤表达Her-2。其中多数为弱阳性表达,3+者仅有1例(2.0%)。阳性定位包括胞质和胞膜,胞质内以弱阳性表达为主,胞膜染色较强。低分化滑膜肉瘤组中,Her-2蛋白表达较高。Her-2蛋白表达较强的病例中,DNA未见明显扩增。滑膜肉瘤中Her-2 mRNA水平较低;在蛋白表达较高的病例中,mRNA水平未见明显升高。
结论
1)滑膜肉瘤可以广泛发生于四肢以外的全身各部位,许多少见部位的肿瘤都有各自临床病理学特征,也常常伴有形态学的变异。
2) AE1/AE3和EMA的联合应用做为滑膜肉瘤上皮性标记敏感性高,阳性范围覆盖其它种类的上皮性标记。TLE1抗体敏感性很高,但特异性略差。Calponin在诊断滑膜肉瘤中的敏感性较高,排除肌源性和肌纤维母细胞来源的肿瘤后,阳性表达有较高的特异性。我们推荐在常规工作中联合采用AE1/AE3,EMA,Calponin,TLE1,作为滑膜肉瘤的免疫组化标记物,以提高其诊断率。
3) RT-PCR和FISH技术对于滑膜肉瘤融合基因的检出率均较高,两种方法所得结果明显相关,均可以做为确诊依据。FISH技术操作简便,不易污染,结果直观,改进实验方法后可以大大减少成本。因而这一技术可以在滑膜肉瘤的诊断中切实地开展,尤其适用于与其它类型软组织肉瘤在免疫表型上有重叠的或发生于特殊部位的滑膜肉瘤,并可以推广应用于其它软组织肿瘤中。
4) FISH信号的异常反映了染色体的部分缺失和扩增,这种改变很可能提示患者预后差。
5)在观察和分析的基础上,首次提出我们对FISH结果的判断标准及原则。
6)滑膜肉瘤中Her-2的表达方式以及在滑膜肉瘤中的作用很可能不同于乳腺癌,因而针对Her-2受体的治疗在滑膜肉瘤中宜慎重。
[Objectives]Synovial sarcoma is a relatively common high grade soft tissue sarcoma,which arises mostly in young adults with high risk of metastasis and recurrence.Diagnoses of synovial sarcoma of morphological variants and unexpected location are usually challenging.As a result,aiming to distinguish synovial sarcoma from other lesions,we analyzed the distinctive features of synovial sarcoma from clinicopathologic,immunohistochemic and genetic aspects.
For long period of time,researchers have been craving for the effective therapy against synovial sarcoma.The recently developed against the receptor tyrosine kinases(RTK) such as Her-2/neu may be an alternate candidate.
[Methods]We firstly observed the clinicopathological datas of 71 cases of synovial sarcoma including those developed at unexpected location and those with variant mophlogy.To assesse the frequency of expression and potential diagnostic utility of a series of antibodies especially calponin and TLE1,immunohistochemistry was undertaken in paraffin sections from 59 and 55 synovial sarcoma respectively, comparing with 64 and 112 cases of morphologically similar tumors such as MPNST, PNET and SFT et al.Molecular genetically,interphase FISH was utilized in 67 cases of SS and 9 of non-synovial sarcoma with a LSI SYT(18q11.2) dual color, break apart probe.In 53 of the cases,the resultant gene fusion SYT-SSX and its subtype were also analyzed by RT-PCR.51 cases of synovial sarcoma were assesed for Her-2 protein expression by immunohistochemical techniques and 44 of which for quantitative real-time polymerase chain reaction assay.
[Results]Of the 71 synovial sarcoma,34(47.8%) arose at unexpected site including pleura,lung,kidney,heart,tibia and etc;30 cases(42.3%) were undifferentiated type;47(66.2%) were monophasic fibrous type,2(2.8%) were monophasic epithelial type and 22(31.0%) were biphasic type.Many cases of unusual sites exhibited unusual morphology.Histologic type had no relationship with the malignancy grade.
34.1%synovial sarcoma exhibited immunostain with single antibody of AE1/AE3 or EMA,but 97.7%with both combined.88.0%,77.8%,33.3%cases were positive for Bcl-2,CD99 and S-100 respectively.
For calponin antibody,89.8%(53/59) synovial sarcoma cases showed at least focal reactivity,with 26 cases of 2+/3+ and 27 cases of 1+.The immunostain was rather weak in the group of poorly differentiated tumors.It is highly expressed in control tumors derived with relation to smooth muscle or myofirboblastoma,and is seldom expressed in other else.
For TLE1 antibody,98.2%(54/55) cases are positive,with 50 cases of 2+/3+,4 cases of 1+ and only 1 case of negative.Despite limited expression of the control group,some kinds of tumors,such as melanoma,mesothelioma,fibromatosis, exhibited high rate of expression.
In 66 cases of synovial sarcoma,we obtained definite results in 62(93.9%) by FISH,56 are positive and 6 are negative.More than 80%cells of most positive cases exhibited translocation signal.In the exceptional 1 case,such translocation cells accounted to 30%.Microscopically,tumor cells of this case were limited due to large amount of fibrovascular components among them.2 of unequal signals and 1 of multiple signals(2 orange and 1 green or 3 orange and 2 green) were identified. All of the 3 cases were poorly differentiated with unfavorable outcome,2 of which with available paraffin blocks were proved to be synovial sarcoma by RT-PCR.No SYT aberration was identified in the control group.
Detectable mRNA were gained from 86.8%(46/53) synovial sarcoma,41 of which bore SYT-SSX,and 5 negative.The type of transcripts(SYT-SSX1 or SYT-SSX2) had no relationship with histologic type.A total of 44 cases were detected by both FISH and RT-PCR,42 of which got same results.Results from both methods were nearly identical.
Her-2 protein expression was detected in 35.3%(18/51) synovial sarcoma, mainly very weak,and strong positive in only 1 case.Higher intensity was present in poorly differentiated synovial sarcoma.
Q-PCR demonstrated the presence of mRNA for Her-2 in 23 of 44 specimens. Her-2 mRNA of synovial sarcoma was low level compared with that of breast cancer with DNA amplification.Concentration of the protein did not change with intensity of the mRNA.No evidence of gene amplification was observed.
[Conclusions]Synovial sarcoma may occur in any part of the body.Some of the unusual site tumors have overlapping clinicopathological features as well as variant morphology.
Combined use of AE1/AE3 and EMA can be very sensitive,rather than other kinds of epithelia markers.TLE1 is high sensitive but not very specific. Comparatively,calponin is also sensitive,and may be used in differential diagnosis if that is not with tumors derived from smooth muscle or myofibroblast.A panel of antibodies including AE1/AE3,EMA,Calponin,TLE1 are recommended as valuable tool in diagnosis of synovial sarcoma.
FISH may act as diagnostic aid in problematic cases of SS.Comparing with RT-PCR,FISH takes the advantage of sensitivity,reliability and rapidity of result. As the laboratory and labor costs can be decreased to a great extent,we conclude that FISH is a robust approach and may be more broadly applicable in soft tissue molecular oncology.On the ground of the current research data,we proposed the principles in explanation to FISH results.
Abnormalities of FISH signals indicate chromosomal deletion or amplification, which may imply a poor prognosis.
As the way Her-2 expressed in synovial sarcoma is greatly different from that in breast cancer,the therapeutic modal against the receptor tyrosine kinases(RTK) such as Her-2/neu may not fit synovial sarcoma well.
引文
1.Miettinen M,Virtanen I.Synovial sarcoma—a misnomer[J].Am J Pathol,1984,117(1):18-25.
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