胃肠道间质瘤NIH方案的应用与评价及Dog1、WISP-1表达与意义
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摘要
目的：通过检测Dogl和WISP-1在胃肠道间质瘤(GIST)中的表达情况,探讨Dogl和WISP-1在胃肠道间质瘤中的诊断及预后意义；通过分析临床病理特征和美国国立卫生研究院(NIH)推荐的风险分级对于GIST患者生存率的影响,探讨GIST的生物学行为和NIH方案对原发性局限性GIST风险分级的评估效能。
方法：收集川北医学院附属医院病理科124例有完整临床病理资料的GIST,应用免疫组织化学方法Envision二步法检测了Dog1和WISP-1蛋白在124例GIST中的表达情况,并与非胃肠道间质瘤进行对照研究；总结临床病理特征包括年龄、核分裂计数、肿瘤直径等,应用新版NIH分级方案对本组病例进行风险分级,并进行统计学分析。
结果：124例GIST中Dogl的阳性表达率为96%(119/124),CD117的阳性变表达率为91.0%(111/124),二者在GIST中的表达水平差异无统计学意义(P>0.05)；胃肠道间质瘤与非胃肠道间质瘤Dog1的表达水平差异有统计学意义(P<0.001)；本组病例中WISP-1阳性率80.6%(100/124),其中极低风险性,低风险性,中度风险性,高风险性的阳性表达率分别为44.4%(4/9),66.7%(26/39),86.9%(17/20),95.0%(38/40),其阳性表达例数与NIH风险分级呈正相关关系(P<0.001)；胃肠道间质瘤与非胃肠道间质瘤WISP-1的表达水平差异无统计学意义(P>0.05)。124例GIST有13例为进展性(恶性)GIST,111例为原发性局限性GIST,平均年龄57岁；82例获得随访,其中进展性GIST9例,原发性局限性GIST73例。73例有随访资料的原发性局限性GIST患者中,肿瘤直径大于5 cm(P=0.009),核分裂计数多于5个/50HPF (P<0.001)提示生存率低；肿瘤大小相同(在5.1~10.0 cm区间),非胃GIST比胃GIST的无病生存率低(P=0.011)；发病年龄和性别与生存率无关；该组资料按新版NIH分级方案进行评估,高危组的总生存率和无病生存率显著低于极低、低、和中度风险组(P<0.05),但极低、低、中度风险三组之间的总生存率和无病生存率差异无统计学意义。
结论：Dogl是胃肠道间质瘤中一个敏感又特异的标记物,与CD117联用能提高GIST的诊断准确率,可作为鉴别消化道间叶源性肿瘤的一线抗体应用于临床；WISP-1的表达可能和GIST恶性进程有关,有可能作为评估GIST生物学行为的指标；按肿瘤最大径、核分裂计数及发病部位评估GIST危险程度的NIH分级方案能更准确地认识原发性局限性GIST的生物学行为；在GIST的病理诊断中,注明NIH分级有利于判断GIST的预后以及指导对GIST的临床治疗。
Objective To investigate the expression and clinical significance of Dogl and WISP-1 in gastrointestinal stromal tumors(GISTs), and to evaluate the prognostic significance of various clinicopathologic parameters and the implication of NIH(National Institutes of Health) grading criteria in gastrointestinal stromal tumors.
Methods One hundred and twenty-four GISTs with complete clinicopathologic data were retrieved from the archival files of the Department of Pathology, Affiliated Hospital of North Sichuan Medical College. The clincal features, site of occurrence, tumour diameter, mitotic index were studied and analyzed statistically. The biologic potential by new-edited NIH grading criteria were evaluated. The expression levels of Dogl and WISP-1 were detected by immunohistochemistry in 124 cases of GIST tissues, and specimens from non-GISTs were used as controls.
Results Of 124 GISTs,119(96%) were positive for Dog1 and 111 (91.0%) for CD 117. Dogl protein expression rate was significantly different between GISTs and non-GISTs (P< 0.001), but there were no significant differences between Dog1 and CD117 expression in GISTs. As for WISP-1, this antibody yielded positive staining in 100 of 124 (80.6%) GISTs. The expression rate of WISP-1 protein in very low risk, low risk, intermediate risk, and high risk cases was 44.4%(4/9),66.7%(26/39),86.9%(17/20),95.0% (38/40), and there was a significant correlation between WISP-1 protein expression and the risk score proposed by NIH(2008). Of all caes,13 were advanced (malignancy) GISTs and 111 were localized primary GISTs. The mean age of patients was 57 years. Follow-up information was available in 82 cases, of which 9 cases were advanced GISTs and 73 were localized primary GIST in which survival analyses were carried out. For the 73 localized primary GISTs, large tumour size(P=0.009), high mitotic index(P<0.001) was associated with lower survival. Statistical analysis showed that, with the largest tumour diameter of 5.1 to 10.0 cm, the nongastric GIST had lower disease-free survial(DFS) rate than gastric GIST (P=0.011). Survival rate had no correlation with age and sex. Evaluated by the new NIH(2008) grading criteria, the overall and disease-free survival rate of high risk GISTs was lower than that of very low risk, low risk, intermediate risk(P<0.05), whereas the overall and disease-free survival rate of very low risk, low risk, intermediate risk GISTs had no statistical differences.
Conclusions Dogl was a sensitivity and specificity marker for GIST and should be used as "the first line" antibody as CD117 protein in routine diagnosis. The expression of WISP-1 maybe associated with GIST progression and could be used as a prognosis marker in GIST. Tumour size, location and mitotic index are the most important prognostic parameters in GISTs. The risk criteria for assessing the natural course of primary GISTs proposed by NIH(2008) were validated and indication of the NIH classification in the pathological diagnosis of GIST was beneficial to prognosis assessment of GIST as well as guidance on the clinical treatment of GIST.
方法：收集川北医学院附属医院病理科124例有完整临床病理资料的GIST,应用免疫组织化学方法Envision二步法检测了Dog1和WISP-1蛋白在124例GIST中的表达情况,并与非胃肠道间质瘤进行对照研究；总结临床病理特征包括年龄、核分裂计数、肿瘤直径等,应用新版NIH分级方案对本组病例进行风险分级,并进行统计学分析。
结果：124例GIST中Dogl的阳性表达率为96%(119/124),CD117的阳性变表达率为91.0%(111/124),二者在GIST中的表达水平差异无统计学意义(P>0.05)；胃肠道间质瘤与非胃肠道间质瘤Dog1的表达水平差异有统计学意义(P<0.001)；本组病例中WISP-1阳性率80.6%(100/124),其中极低风险性,低风险性,中度风险性,高风险性的阳性表达率分别为44.4%(4/9),66.7%(26/39),86.9%(17/20),95.0%(38/40),其阳性表达例数与NIH风险分级呈正相关关系(P<0.001)；胃肠道间质瘤与非胃肠道间质瘤WISP-1的表达水平差异无统计学意义(P>0.05)。124例GIST有13例为进展性(恶性)GIST,111例为原发性局限性GIST,平均年龄57岁；82例获得随访,其中进展性GIST9例,原发性局限性GIST73例。73例有随访资料的原发性局限性GIST患者中,肿瘤直径大于5 cm(P=0.009),核分裂计数多于5个/50HPF (P<0.001)提示生存率低；肿瘤大小相同(在5.1~10.0 cm区间),非胃GIST比胃GIST的无病生存率低(P=0.011)；发病年龄和性别与生存率无关；该组资料按新版NIH分级方案进行评估,高危组的总生存率和无病生存率显著低于极低、低、和中度风险组(P<0.05),但极低、低、中度风险三组之间的总生存率和无病生存率差异无统计学意义。
结论：Dogl是胃肠道间质瘤中一个敏感又特异的标记物,与CD117联用能提高GIST的诊断准确率,可作为鉴别消化道间叶源性肿瘤的一线抗体应用于临床；WISP-1的表达可能和GIST恶性进程有关,有可能作为评估GIST生物学行为的指标；按肿瘤最大径、核分裂计数及发病部位评估GIST危险程度的NIH分级方案能更准确地认识原发性局限性GIST的生物学行为；在GIST的病理诊断中,注明NIH分级有利于判断GIST的预后以及指导对GIST的临床治疗。
Objective To investigate the expression and clinical significance of Dogl and WISP-1 in gastrointestinal stromal tumors(GISTs), and to evaluate the prognostic significance of various clinicopathologic parameters and the implication of NIH(National Institutes of Health) grading criteria in gastrointestinal stromal tumors.
Methods One hundred and twenty-four GISTs with complete clinicopathologic data were retrieved from the archival files of the Department of Pathology, Affiliated Hospital of North Sichuan Medical College. The clincal features, site of occurrence, tumour diameter, mitotic index were studied and analyzed statistically. The biologic potential by new-edited NIH grading criteria were evaluated. The expression levels of Dogl and WISP-1 were detected by immunohistochemistry in 124 cases of GIST tissues, and specimens from non-GISTs were used as controls.
Results Of 124 GISTs,119(96%) were positive for Dog1 and 111 (91.0%) for CD 117. Dogl protein expression rate was significantly different between GISTs and non-GISTs (P< 0.001), but there were no significant differences between Dog1 and CD117 expression in GISTs. As for WISP-1, this antibody yielded positive staining in 100 of 124 (80.6%) GISTs. The expression rate of WISP-1 protein in very low risk, low risk, intermediate risk, and high risk cases was 44.4%(4/9),66.7%(26/39),86.9%(17/20),95.0% (38/40), and there was a significant correlation between WISP-1 protein expression and the risk score proposed by NIH(2008). Of all caes,13 were advanced (malignancy) GISTs and 111 were localized primary GISTs. The mean age of patients was 57 years. Follow-up information was available in 82 cases, of which 9 cases were advanced GISTs and 73 were localized primary GIST in which survival analyses were carried out. For the 73 localized primary GISTs, large tumour size(P=0.009), high mitotic index(P<0.001) was associated with lower survival. Statistical analysis showed that, with the largest tumour diameter of 5.1 to 10.0 cm, the nongastric GIST had lower disease-free survial(DFS) rate than gastric GIST (P=0.011). Survival rate had no correlation with age and sex. Evaluated by the new NIH(2008) grading criteria, the overall and disease-free survival rate of high risk GISTs was lower than that of very low risk, low risk, intermediate risk(P<0.05), whereas the overall and disease-free survival rate of very low risk, low risk, intermediate risk GISTs had no statistical differences.
Conclusions Dogl was a sensitivity and specificity marker for GIST and should be used as "the first line" antibody as CD117 protein in routine diagnosis. The expression of WISP-1 maybe associated with GIST progression and could be used as a prognosis marker in GIST. Tumour size, location and mitotic index are the most important prognostic parameters in GISTs. The risk criteria for assessing the natural course of primary GISTs proposed by NIH(2008) were validated and indication of the NIH classification in the pathological diagnosis of GIST was beneficial to prognosis assessment of GIST as well as guidance on the clinical treatment of GIST.
引文
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[2]Hashimoto Y, Shindo-Okada N, Tani M, el al. Identification of genes differentially expressed in association with metastatic potential of K-1735 murine melanoma by messenger RNA differential display [J]. Cancer Res,1996,56(22):5266-5271.
[3]中国胃肠道间质瘤病理专家组.中国胃肠道间质瘤病理共识意见[J].中华病理学杂志,2007,36(10)：704-707.
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