超声内镜与高分辨熔解曲线分析技术对胃肠间质瘤的诊断作用
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摘要
目的：
胃肠间质瘤(GISTs)是一种有潜在恶性的黏膜下肿瘤,很难做到术前确诊。组织学表现和免疫组化结果仍然是GISTs诊断的金标准。基因突变检测对于GISTs的治疗有指导性意义。超声内镜(EUS)是诊断胃肠道间质瘤的最常用的工具。高分辨熔解曲线分析技术(HRM)是在实时荧光PCR基础上发展起来的一种新的突变扫描和基因分型的遗传分析技术,具有高通量、简单、快速、低成本、高灵敏度的优点。本研究旨在探讨EUS在术前诊断GISTs的作用,以及HRM在检测GISTs基因突变中的作用。
方法：
入选超声内镜诊断为胃黏膜下病变,且最终取得病理确诊的患者,根据超声内镜结果和病理结果比较超声内镜对GISTs的诊断的敏感性、特异性和准确性。对小于2cm无EUS危险特征的胃GISTs患者进行EUS随访,了解小GISTs的发展特征,探讨EUS对小GISTs的随访价值。对部分术后GISTs再行组织学和免疫组化的检测,了解GISTs的危险分级和生物学特征。再用HRM检测GISTs的基因突变情况,并与DNA测序相比较,分析HRM在检测GISTs基因突变中的作用。
结果：
本研究中共63位胃黏膜下病变的患者参与评估,39例患者经病理确诊GISTs,平均年龄为：54.4±11.1岁,中位年龄54岁。超声内镜诊断胃间质瘤的敏感性为100%,特异性为45.8%,阳性预测值为75%,阴性预测值为100%。参与EUS随访的29例GIST患者首发平均年龄为51.8±10.7岁,中位年龄52岁。29例GISTs经过平均22±16.0月的随访,未发现肿瘤有明显增大。11例胃GISTs再次用新标准进行了病理评估,CD117和DOG-1均为阳性,其中极低危1例,低危5例,中危3例,高危2例。有3例Ki-67在5-10%的患者均为中高危GISTs。12例GISTs的新鲜冰冻组织参与了基因突变的检测,其中有10例存在突变,9例胃GISTs突变发生在KIT基因第11外显子的突变热点区,1例小肠GIST的突变发生在KIT基因第9外显子。HRM对GISTs的KIT基因和PDGFRA基因外显子突变检测的敏感性、特异性和准确性达到100%。基因突变的类型与GISTs的危险程度无关。
结论：
(1)超声内镜可以分辨胃壁各层次和胃壁占位的内部性质,诊断胃间质瘤敏感性高,具有易操作,无放射性的优点,是诊断胃间质瘤的首选方法。
(2)最大直径<2cm且无高危EUS特征的胃间质瘤可以用超声内镜进行随访,间隔时间推荐为1-1.5年。
(3)Ki-67阳性程度与GISTs的危险程度相关,或许能成为预后检测指标。
(4)HRM对GISTs基因突变检测的敏感性、特异性和准确性均较高。是一种适合临床诊断的基因突变检测方法。
Objiective:
Gastrointestinal stromal tumors (GISTs) are submucosal lesions with overlying normal mucosal tissue. All GISTs have malignant potential. The preoperative diagnosis of GISTs is difficult. Morphologic examination and immunohistochemical staining for KIT or DOG-1, corroborated with the gastrointestinal anatomic location of the tumor, are essential for confirming GIST diagnosis. The pathogenesis of GIST are the exclusive mutations of the KIT and PDGFRA gene, which serve as crucial diagnostic and therapeutic targets. Endoscopic ultrasound (EUS) is the prime imaging modality when evaluating GISTs in stomach. High Resolution Melting Analysis (HRM or HRMA) is a recently developed technique for fast, high-throughput post-PCR analysis of genetic mutations. In this study, we examined whether EUS was useful in diagnosing GISTs. And we used a high-resolution melting (HRM) curve analysis approach to scan for mutations in the KIT and PDGFRA gene.
Patients and methods:
Gastric submucosal tumors were diagnosed from the immunohistochemical staining of specimens by excision at our hospital. All lesions underwent EUS preoperatively. Patients with small tumor (<2cm) and benign EUS features werw offered regular EUS surveillance. Hematoxylin and eosin-stained and immunohistochemistry was performed again in some GISTs. Stratifies risk of these tumors was established. HRM was used to detect mutations in the KIT and PDGFRA gene with postoperative freshly frozen tissue samples.
Results:
Among63gastric submucosal tumors,39GISTs were identified. The sensitivity, specificity, positive predictive value and negative predictive value of EUS for diagnosis of GISTs in stomach was100%,45.8%,75%and100%respectively. The median age of39GISTs patients was54years (range:34-77). Twenty-nine patients elected to undergo regular EUS surveillance for a mean periond of22±16.0months. Their median age was52years (range:31-71). None of patients showed internal increase in tumor size and change in EUS features.11gastric GISTs were established risk. All cases were positive for CD117, DOG-1and CD34. one case was regarded as very low risk,5cases were in the low risk,3case were in the intermediate risk and2cases were in the high-risk category. Three cases with5%-10%Ki-67staining positive cells were intermediate-high risk. Finally, we validated the HRM assay on12freshly frozen tissue samples. All mutated samples were correctly identified by HRM.10samples mutated in exon11of KIT gene could clearly be distinguished from the two wild-type samples. Among the ten mutated samples,9cases were from stomach and1cases was from intestine.
Conclusion:
(1) EUS has an advantage in evaluating the layer of origin of tumors and their internal architecture and is sensitive to diagnosis of GISTs in stomach.
(2) For patients with small gastric GISTs (<2cm) with no high risk EUS features, EUS surveillance at12-to18-month intervals may be considered。
(3) Elevated Ki-67scores were associated to high risk category and may be used as a putative prognostic marker.
(4) HRM analysis is a powerful diagnostic tool for detection of KIT and PDGFRA gene mutation with a high sensitivity.
胃肠间质瘤(GISTs)是一种有潜在恶性的黏膜下肿瘤,很难做到术前确诊。组织学表现和免疫组化结果仍然是GISTs诊断的金标准。基因突变检测对于GISTs的治疗有指导性意义。超声内镜(EUS)是诊断胃肠道间质瘤的最常用的工具。高分辨熔解曲线分析技术(HRM)是在实时荧光PCR基础上发展起来的一种新的突变扫描和基因分型的遗传分析技术,具有高通量、简单、快速、低成本、高灵敏度的优点。本研究旨在探讨EUS在术前诊断GISTs的作用,以及HRM在检测GISTs基因突变中的作用。
方法：
入选超声内镜诊断为胃黏膜下病变,且最终取得病理确诊的患者,根据超声内镜结果和病理结果比较超声内镜对GISTs的诊断的敏感性、特异性和准确性。对小于2cm无EUS危险特征的胃GISTs患者进行EUS随访,了解小GISTs的发展特征,探讨EUS对小GISTs的随访价值。对部分术后GISTs再行组织学和免疫组化的检测,了解GISTs的危险分级和生物学特征。再用HRM检测GISTs的基因突变情况,并与DNA测序相比较,分析HRM在检测GISTs基因突变中的作用。
结果：
本研究中共63位胃黏膜下病变的患者参与评估,39例患者经病理确诊GISTs,平均年龄为：54.4±11.1岁,中位年龄54岁。超声内镜诊断胃间质瘤的敏感性为100%,特异性为45.8%,阳性预测值为75%,阴性预测值为100%。参与EUS随访的29例GIST患者首发平均年龄为51.8±10.7岁,中位年龄52岁。29例GISTs经过平均22±16.0月的随访,未发现肿瘤有明显增大。11例胃GISTs再次用新标准进行了病理评估,CD117和DOG-1均为阳性,其中极低危1例,低危5例,中危3例,高危2例。有3例Ki-67在5-10%的患者均为中高危GISTs。12例GISTs的新鲜冰冻组织参与了基因突变的检测,其中有10例存在突变,9例胃GISTs突变发生在KIT基因第11外显子的突变热点区,1例小肠GIST的突变发生在KIT基因第9外显子。HRM对GISTs的KIT基因和PDGFRA基因外显子突变检测的敏感性、特异性和准确性达到100%。基因突变的类型与GISTs的危险程度无关。
结论：
(1)超声内镜可以分辨胃壁各层次和胃壁占位的内部性质,诊断胃间质瘤敏感性高,具有易操作,无放射性的优点,是诊断胃间质瘤的首选方法。
(2)最大直径<2cm且无高危EUS特征的胃间质瘤可以用超声内镜进行随访,间隔时间推荐为1-1.5年。
(3)Ki-67阳性程度与GISTs的危险程度相关,或许能成为预后检测指标。
(4)HRM对GISTs基因突变检测的敏感性、特异性和准确性均较高。是一种适合临床诊断的基因突变检测方法。
Objiective:
Gastrointestinal stromal tumors (GISTs) are submucosal lesions with overlying normal mucosal tissue. All GISTs have malignant potential. The preoperative diagnosis of GISTs is difficult. Morphologic examination and immunohistochemical staining for KIT or DOG-1, corroborated with the gastrointestinal anatomic location of the tumor, are essential for confirming GIST diagnosis. The pathogenesis of GIST are the exclusive mutations of the KIT and PDGFRA gene, which serve as crucial diagnostic and therapeutic targets. Endoscopic ultrasound (EUS) is the prime imaging modality when evaluating GISTs in stomach. High Resolution Melting Analysis (HRM or HRMA) is a recently developed technique for fast, high-throughput post-PCR analysis of genetic mutations. In this study, we examined whether EUS was useful in diagnosing GISTs. And we used a high-resolution melting (HRM) curve analysis approach to scan for mutations in the KIT and PDGFRA gene.
Patients and methods:
Gastric submucosal tumors were diagnosed from the immunohistochemical staining of specimens by excision at our hospital. All lesions underwent EUS preoperatively. Patients with small tumor (<2cm) and benign EUS features werw offered regular EUS surveillance. Hematoxylin and eosin-stained and immunohistochemistry was performed again in some GISTs. Stratifies risk of these tumors was established. HRM was used to detect mutations in the KIT and PDGFRA gene with postoperative freshly frozen tissue samples.
Results:
Among63gastric submucosal tumors,39GISTs were identified. The sensitivity, specificity, positive predictive value and negative predictive value of EUS for diagnosis of GISTs in stomach was100%,45.8%,75%and100%respectively. The median age of39GISTs patients was54years (range:34-77). Twenty-nine patients elected to undergo regular EUS surveillance for a mean periond of22±16.0months. Their median age was52years (range:31-71). None of patients showed internal increase in tumor size and change in EUS features.11gastric GISTs were established risk. All cases were positive for CD117, DOG-1and CD34. one case was regarded as very low risk,5cases were in the low risk,3case were in the intermediate risk and2cases were in the high-risk category. Three cases with5%-10%Ki-67staining positive cells were intermediate-high risk. Finally, we validated the HRM assay on12freshly frozen tissue samples. All mutated samples were correctly identified by HRM.10samples mutated in exon11of KIT gene could clearly be distinguished from the two wild-type samples. Among the ten mutated samples,9cases were from stomach and1cases was from intestine.
Conclusion:
(1) EUS has an advantage in evaluating the layer of origin of tumors and their internal architecture and is sensitive to diagnosis of GISTs in stomach.
(2) For patients with small gastric GISTs (<2cm) with no high risk EUS features, EUS surveillance at12-to18-month intervals may be considered。
(3) Elevated Ki-67scores were associated to high risk category and may be used as a putative prognostic marker.
(4) HRM analysis is a powerful diagnostic tool for detection of KIT and PDGFRA gene mutation with a high sensitivity.
引文
[1]Agaimy A, Wunsch PH, Hofstaedter F, Blaszyk H, Rummele P, Gaumann A, Dietmaier W, Hartmann A. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol.2007;31:113-20.
[2]Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors:an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 2005; 100:162-8.
[3]Lok KH, Lai L, Yiu HL, Szeto ML, Leung SK. Endosonographic surveillance of small gastrointestinal tumors originating from muscularis propria.J Gastrointestin Liver Dis.2009 Jun; 18(2):177-80.
[4]Sepe PS, Brugge WR. A guide for the diagnosis and management of gastrointestinal stromal cell tumors. Nat Rev Gastroenterol Hepatol 2009;6:363-371.
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[8]West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R, Goldblum JR, Brown PO, Heinrich MC, van de Rijn M. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004; 165:107-13.
[9]Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors:a study of 1840 cases. Am J Surg Pathol. 2009;33:1401-8.
[10]CSCO胃肠间质瘤专家委员会。中国胃肠间质瘤诊断治疗专家共识(2011年版)。临床肿瘤学杂志,2011；16：836-44.
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[1]Agaimy A, Wunsch PH, Hofstaedter F, Blaszyk H, Rummele P, Gaumann A, Dietmaier W, Hartmann A. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol.2007;31:113-20.
[2]金震东,消化超声内镜学。科学出版社,2006：1
[3]Joensuu H.Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol.2008;39:1411-9.
[4]Miettinen M, Sobin LH, Lasota J.Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol.2005;29:52-68.
[5]M. Al-Kalaawy, Mohamed A. El-Zohairy, Ahmed Mostafa*, A. Al-Kalaawy,H. El-Sebae. Gastrointestinal stromal tumors (GISTs),10-year experience:Patterns of failure and prognostic factors for survival of 127 patients Journal of the Egyptian National Cancer Institute 2012; 24,31-9.
[6]A Polkowski M. Endoscopic ultrasound and endoscopic ultrasoundguided fine-needle biopsy for the diagnosis of malignant submucosal tumors. Endoscopy.2005;37:635-45.
[7]B Polkowski M, Butruk E. Submucosal lesions. Gastrointest Endosc Clin N Am. 2005;15:33-54.
[8]Miettinen M, Lasota J.Gastrointestinal stromal tumors:review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466-78.
[9]Jeon SW, Park YD, Chung YJ, Tak WY, Kweon YO, Kim SK, Choi YH.Gastrointestinal stromal tumors of the stomach:endosonographic differentiation in relation to histological risk. J Gastroenterol Hepatol. 2007;22:2069-75.
[10]Lok KH, Lai L, Yiu HL, Szeto ML, Leung SK. Endosonographic surveillance of small gastrointestinal tumors originating from muscularis propria. Gastrointestin Liver Dis.2009; 18:177-80.
[11]Akahoshi K, Sumida Y, Matsui N, Oya M, Akinaga R, Kubokawa M, Motomura Y, Honda K, Watanabe M, Nagaie T. Preoperative diagnosis of gastrointestinal stromal tumor by endoscopic ultrasound-guided fine needle aspiration. World J Gastroenterol.2007; 13:2077-82.
[12]Sepe PS, Brugge WR.A guide for the diagnosis and management of gastrointestinal stromal cell tumors. Nat Rev Gastroenterol Hepatol. 2009;6:363-71.
[1]Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors:an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 2005; 100:162-8.
[2]Miettinen M, Lasota J. Gastrointestinal stromal tumors:pathology and prognosis at different sites. Semin Diagn Pathol.2006;23:70-83.
[3]Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PW, Raut CP, Riedel RF, Schuetze S, Sundar HM, Trent JC, Wayne JD. NCCN Task Force report:update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Cane Netw.2010;8 Suppl 2:S1-41; quiz S42-4.
[4]CSCO胃肠间质瘤专家委员会,中国胃肠间质瘤诊断治疗专家共识(2011年版)。临床肿瘤学杂志；2011,16,836-844.
[5]Emory TS, Sobin LH, Lukes L, Lee DH, O'Leary TJ.Prognosis of gastrointestinal smooth-muscle (stromal) tumors:dependence on anatomic site. Am J Surg Pathol. 1999;23:82-7.
[6]田忠,勾健,赵海鹰,杨福,全乔麟,刘源,孙思予,王孟春,刘金钢。腹腔镜微创外科治疗胃间质瘤17例报告。中国实用外科杂志,2006,2,
[7]顾国利,王石林,任力,魏学明,李德昌,周晓武,黄蓉蓉。胃肠道间质瘤的临场病理分析和免疫组化特点。世界华人消化杂志,2006；14：2241-46.
[8]Joensuu H.Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol.2008 Oct;39(10):1411-9.
[9]Miettinen M, Lasota J. Gastrointestinal stromal tumors:review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006; 130:1466-78.
[10]Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y.Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.Science.1998;279:577-80.
[11]West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, Zhu S, Ball CA, Nielsen TO, Patel R, Goldblum JR, Brown PO, Heinrich MC, van de Rijn M. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004;165:107-13.
[12]Miettinen M, Wang ZF, Lasota J. DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors:a study of 1840 cases. Am J Surg Pathol. 2009;33:1401-8.
[13]Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW. Diagnosis of gastrointestinal stromal tumors:A consensus approach. Hum Pathol. 2002;33:459-65.
[14]Franquemont DW.Differentiation and risk assessment of gastrointestinal stromal tumors. Am J Clin Pathol.1995; 103:41-7. Review.
[15]Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW.Diagnosis of gastrointestinal stromal tumors:A consensus approach. Hum Pathol.2002;33:459-65.
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