70例骨肉瘤临床病理分析及其Notch亚型表达的预后意义
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摘要
目的探讨骨肉瘤的临床病理特征、Notch受体配体表达及其对预后的影响。方法收集2008-2015年陆军军医大学(第三军医大学)第二附属医院、陆军特色医学中心病理科70例骨肉瘤进行临床资料总结和组织学观察,并行Notch通路4个受体Notch 1～4和3个配体Jagged1、Jagged2、DLL4免疫组织化学染色。对54例病例行预后因素分析。结果 70例患者平均年龄25. 1岁,男女比例3∶2。95. 7%(67/70例)的患者就诊时处于临床Ⅱ～Ⅲ期。影像学表现显示:61例(87. 1%)存在骨质破坏,8例(11. 4%)髓腔累及,29例(41. 4%)骨皮质累及,28例(40%)有骨膜反应。组织病理学可见,40例(57. 1%)浸润性生长,70例肉瘤细胞和肿瘤性骨样组织。免疫组化结果显示:受体Notch4表达率最高,为91. 4%(64/70),其次分别为Notch1(87. 1%)、Notch3(68. 6%)、Notch2(33. 9%)。配体Jagged1、Jagged2、DLL4表达率分别为87. 1%(61/70)、84. 3%(59/70)、88. 6%(62/70)。42例患者(60%)接受了化疗,67例患者(95. 7%)进行了手术。54例有随访资料的患者平均生存时间41. 68个月。1、2年和5年生存率分别为87%、66%和30%。生存曲线比较示Enneking分期、术前化疗、Notch3表达与预后相关(P=0. 017),Cox比例风险回归模型分析Enneking分期、术前化疗、Notch3表达是独立预后因素。结论骨肉瘤5年生存率低,Enneking分期晚、未行术前化疗、Notch3表达的患者生存时间短。
Objective To investigate the clinicopathological features of osteosarcoma and the prognostic significance of the expression of Notch receptors and ligands. Methods We retrospectively analyzed the clinical and histopathological data of 70 patients with osteosarcoma treated in the Second and Third Affiliated Hospitals of Army Medical University from 2008 to 2015. Immunohistochemical staining was used to examine the expressin levels of 4 Notch receptors( Notch1-4) and 3 Notch ligands( Jagged1,Jagged2 and DLL4) in the surgical specimens. The risk factors that affected the outcomes of the patients were analyzed in 54 cases. Results The patients had a mean age of 25. 1 years with a male to female ratio of 3∶ 2,and 95. 7% of the patients were in stage Ⅱ-Ⅲ. Imaging examinations revealed bone destruction in 61 cases( 87. 1%),medullary cavity involvement in 8 cases( 11. 4%) and bone cortex involvement in 29 cases( 41. 4%); periosteal reaction was detected in 28 cases( 40%). Histopathologically,57. 1% of patients( 40 cases) showed invasive growth of osteosarcoma,and all the patients had sarcoma cells and neoplastic osteoid tissues. Immunohistochemical analysis showed positive Notch1, Notch2, Notch3 and Notch4 expression in 87. 1%( 61/70),33. 9%( 23/70),68. 6%( 48/70) and 91. 4%( 64/70) of the patients,respectively with the last one of the highest; positive expression of Jagged1,Jagged2 and DLL4 were detected in 87. 1%( 61/70),84. 3%( 59/70) and 88. 6%( 62/70) of the patients. Sixty percent of the patients( 42 cases) received chemotherapy,and 95. 7% of the patients( 67 cases) underwent surgeries. The mean survival time of the 54 patients with full follow-up data was 41. 68 months and their 1-,2-and 5-year survival rates were 87%,66% and 30%, respectively. Survival curre analysis showed thed Enneking stage,oreoperative chemotherapy and Notch 3 experssion were related with prognosis( P = 0. 017). Cox regression analysis showed that Enneking stage,preoperative chemotherapy and Notch3 expression were independent prognostic factors in these patients. Conclusion Patients with osteosarcoma have a rather low 5-year survival rate. Advanced Enneking stage, positive Notch3 expression and no preoperative chemotherapy are all predictive of a short survival time of the patients.
Objective To investigate the clinicopathological features of osteosarcoma and the prognostic significance of the expression of Notch receptors and ligands. Methods We retrospectively analyzed the clinical and histopathological data of 70 patients with osteosarcoma treated in the Second and Third Affiliated Hospitals of Army Medical University from 2008 to 2015. Immunohistochemical staining was used to examine the expressin levels of 4 Notch receptors( Notch1-4) and 3 Notch ligands( Jagged1,Jagged2 and DLL4) in the surgical specimens. The risk factors that affected the outcomes of the patients were analyzed in 54 cases. Results The patients had a mean age of 25. 1 years with a male to female ratio of 3∶ 2,and 95. 7% of the patients were in stage Ⅱ-Ⅲ. Imaging examinations revealed bone destruction in 61 cases( 87. 1%),medullary cavity involvement in 8 cases( 11. 4%) and bone cortex involvement in 29 cases( 41. 4%); periosteal reaction was detected in 28 cases( 40%). Histopathologically,57. 1% of patients( 40 cases) showed invasive growth of osteosarcoma,and all the patients had sarcoma cells and neoplastic osteoid tissues. Immunohistochemical analysis showed positive Notch1, Notch2, Notch3 and Notch4 expression in 87. 1%( 61/70),33. 9%( 23/70),68. 6%( 48/70) and 91. 4%( 64/70) of the patients,respectively with the last one of the highest; positive expression of Jagged1,Jagged2 and DLL4 were detected in 87. 1%( 61/70),84. 3%( 59/70) and 88. 6%( 62/70) of the patients. Sixty percent of the patients( 42 cases) received chemotherapy,and 95. 7% of the patients( 67 cases) underwent surgeries. The mean survival time of the 54 patients with full follow-up data was 41. 68 months and their 1-,2-and 5-year survival rates were 87%,66% and 30%, respectively. Survival curre analysis showed thed Enneking stage,oreoperative chemotherapy and Notch 3 experssion were related with prognosis( P = 0. 017). Cox regression analysis showed that Enneking stage,preoperative chemotherapy and Notch3 expression were independent prognostic factors in these patients. Conclusion Patients with osteosarcoma have a rather low 5-year survival rate. Advanced Enneking stage, positive Notch3 expression and no preoperative chemotherapy are all predictive of a short survival time of the patients.
引文
[1]蒋智铭,张惠箴,陈洁晴,等.骨肉瘤的组织学类型[J].临床与实验病理学杂志,2004,20(2):127-130.JIANG Z M,ZHANG H Z,CHEN J Q,et al. Histological types of osteosarcoma[J]. Chin J Clin Exp Pathol,2004,20(2):127-130.
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[3] KOHN A,DONG Y,MIRANDO A J,et al. Cartilagespecific RBPjκ-dependent and-independent Notch signals regulate cartilage and bone development[J]. Development,2012,139(6):1198-1212. DOI:10. 1242/dev. 070649.
[4] ESPINOZA I,MIELE L. Deadly crosstalk:Notch signaling at the intersection of EMT and cancer stem cells[J]. Cancer Lett,2013,341(1):41-45. DOI:10. 1016/j. canlet.2013. 08. 027.
[5] TAO J,JIANG M M,JIANG L,et al. Notch activation as a driver of osteogenic sarcoma[J]. Cancer Cell,2014,26(3):390-401. DOI:10. 1016/j. ccr. 2014. 07. 023.
[6] ZAMBO I,VESELY K. WHO classification of tumours of soft tissue and bone 2013:the main changes compared to the 3rd edition[J]. Cesk Patol,2014,50(2):64-70.
[7] KOZAKEWICH H,PEREZ-ATAYDE A R,GOORIN A M,et al. Osteosarcoma in young children[J]. Cancer,1991,67(3):638-642.
[8]谭平先,沈靖南,王晋,等.膝关节周围骨肉瘤保肢手术疗效及预后分析[J].实用骨科杂志,2018,24(1):15-18. DOI:10. 13795/j. cnki. sgkz. 2018. 01. 004.TAN P X,SHEN J N,WANG J,et al. Survival analysis of patients with osteosarcoma around the knee treated by limbsalvage surgery[J]. J Prac Orthopaed,2018,24(1):15-18. DOI:10. 13795/j. cnki. sgkz. 2018. 01. 004.
[9]韩加,于沂阳,吴苏稼,等.影响肢体骨肉瘤临床预后的多中心回顾性研究[J].中国骨与关节杂志,2018,7(1):7-13. DOI:10. 3969/j. issn. 2095-252X. 2018. 01. 003.HAN J,YU Y Y,WU S J,et al. A multi-center retrospective study on the clinical prognosis of limb osteosarcoma[J].Chin J Bone Joint,2018,7(1):7-13. DOI:10. 3969/j.issn. 2095-252X. 2018. 01. 003.
[10]黄振华,张甫婷,邓琼,等.非经典型高级别骨肉瘤60例临床分析[J].广东医学,2017,38(16):2506-2510. DOI:10. 13820/j. cnki. gdyx. 2017. 16. 016.HUANG Z H,ZHANG F T,DENG Q,et al. Clinical analysis of 60 cases of non-classical high-grade osteosarcoma[J]. Guangdong Med J,2017,38(16):2506-2510.DOI:10. 13820/j. cnki. gdyx. 2017. 16. 016.
[11]上官建伟,梁俊芳,肖新广,等.骨肉瘤X线与CT和MRI影像特点及诊断价值[J].医药论坛杂志,2015,36(11):17-19.SHANGGUAN J W,LIANG J F,XIAO X G,et al. Analysis of imaging characteristics of X-ray,CT and MRI for osteosarcoma and diagnostic value[J]. J Med Forum,2015,36(11):17-19.
[12]龚印华.新辅助化疗结合保肢手术治疗骨肉瘤的临床观察[J].肿瘤基础与临床,2012,25(3):221-223.GONG Y H. The clinical observation of neoadjuvant chemotherapy and limb-salvage surgery in the treatment of osteosarcoma[J]. J Basic Clin Oncol,2012,25(3):221-223.
[13] CHOEYPRASERT W,PAKAKASAMA S,SIRACHAINAN N,et al. Comparative outcome of Thai pediatric osteosarcoma treated with two protocols:the role of high-dose methotrexate(HDMTX)in a single institute experience[J]. Asian Pac J Cancer Prev,2014,15(22):9823-9829.
[14] HEYMANN M F,BROWN H K,HEYMANN D. Drugs in early clinical development for the treatment of osteosarcoma[J]. Expert Opin Investig Drugs,2016,25(11):1265-1280. DOI:10. 1080/13543784. 2016. 1237503.
[15] KAMAL A F,WIDYAWARMAN H,HUSODO K,et al.Clinical outcome and survival of osteosarcoma patients in Cipto mangunkusumo hospital:limb salvage surgery versus amputation[J]. Acta Med Indones,2016,48(3):175-183.
[16] YIN K,LIAO Q,ZHONG D,et al. Meta-analysis of limb salvage versus amputation for treating high-grade and localized osteosarcoma in patients with pathological fracture[J].Exp Ther Med,2012,4(5):889-894. DOI:10. 3892/etm. 2012. 685.
[17]祁伟祥,何爱娜,汤丽娜,等.成人骨肉瘤52例预后因素的COX比例风险模型分析[J].肿瘤,2011,31(9):846-850.QI W X,HE A N,TANG L N,et al. COX proportionalhazard regression analysis of prognostic factors in 52 adult patients with osteosarcoma[J]. Tumor,2011,31(9):846-850.
[18] ASTER J C. In brief:Notch signalling in health and disease[J]. J Pathol,2014,232(1):1-3. DOI:10. 1002/path. 4291.
[19] GURUHARSHA K G,KANKEL M W,ARTAVANIS-TSAKONAS S. The Notch signalling system:recent insights into the complexity of a conserved pathway[J]. Nat Rev Genet,2012,13(9):654-666. DOI:10. 1038/nrg3272.
[20] MCMANUS M M,WEISS K R,HUGHES D P. Understanding the role of Notch in osteosarcoma[J]. Adv Exp Med Biol,2014,804:67-92. DOI:10. 1007/978-3-319-04843-7_4.
[21] ANGULO P,KAUSHIK G,SUBRAMANIAM D,et al.Natural compounds targeting major cell signaling pathways:a novel paradigm for osteosarcoma therapy[J]. J Hematol Oncol,2017,10(1):10.
[22] MU X,AGARWAL R,MARCH D,et al. Notch signaling mediates skeletal muscle atrophy in cancer cachexia caused by osteosarcoma[J]. Sarcoma,2016,2016:1-12. DOI:10. 1155/2016/3758162.
[23] LIU P,MAN Y,WANG Y,et al. Mechanism of BMP9 promotes growth of osteosarcoma mediated by the Notch signaling pathway[J]. Oncol Lett,2016,11(2):1367-1370.DOI:10. 3892/ol. 2015. 4067.
[24] PUNZO F,TORTORA C,DI PINTO D,et al. Anti-proliferative,pro-apoptotic and anti-invasive effect of EC/EV system in human osteosarcoma[J]. Oncotarget,2017,8(33):54459-54471. DOI:10. 18632/oncotarget. 17089.
[25] CAO Y,YU L,DAI G,et al. Cinobufagin induces apoptosis of osteosarcoma cells through inactivation of Notch signaling[J]. Eur J Pharmacol,2017,794:77-84. DOI:10.1016/j. ejphar. 2016. 11. 016.
[26] LI C,GUO D,TANG B,et al. Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression[J]. Neoplasma,2016,63(5):734-742. DOI:10. 4149/neo_2016_510.
[27] YU L,FAN Z,FANG S,et al. Cisplatin selects for stemlike cells in osteosarcoma by activating Notch signaling[J].Oncotarget,2016,7(22):33055-33068. DOI:10.18632/oncotarget. 8849.
[28] ZHOU S,YU L,XIONG M,et al. Lnc RNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging mi R-195-5p[J]. Biochem Biophys Res Commun,2018,495(2):1822-1832. DOI:10. 1016/j. bbrc. 2017. 12. 047.
[29]许自力,邓展生,许宇霞. Notch1、Dll4蛋白在骨肉瘤的表达及临床意义[J].中国骨肿瘤骨病,2009,8(1):28-31.XU Z L,DENG Z S,XU Y X. The clinical significance of the expression of Notch1 and Dll4 in osteosarcoma[J]. Chin J Bone Tumor Bone Dis,2009,8(1):28-31.
[30]张建平. Notch配体Jagged1在骨肉瘤中的作用研究[D].西安:第四军医大学,2014.ZHANG J P. The role of Notch ligand Jagged1 in osteosarcoma[D]. Xi’an:Fourth Military Medical University,2014.
[31] LI H,HE Y,HAO P,et al. Identification of characteristic gene modules of osteosarcoma using bioinformatics analysis indicates the possible molecular pathogenesis[J]. Mol Med Rep,2017,15(4):2113-2119. DOI:10. 3892/mmr.2017. 6245.
[2] CHEN S,LEE B H,BAE Y. Notch signaling in skeletal stem cells[J]. Calcif Tissue Int,2014,94(1):68-77. DOI:10. 1007/s00223-013-9773-z.
[3] KOHN A,DONG Y,MIRANDO A J,et al. Cartilagespecific RBPjκ-dependent and-independent Notch signals regulate cartilage and bone development[J]. Development,2012,139(6):1198-1212. DOI:10. 1242/dev. 070649.
[4] ESPINOZA I,MIELE L. Deadly crosstalk:Notch signaling at the intersection of EMT and cancer stem cells[J]. Cancer Lett,2013,341(1):41-45. DOI:10. 1016/j. canlet.2013. 08. 027.
[5] TAO J,JIANG M M,JIANG L,et al. Notch activation as a driver of osteogenic sarcoma[J]. Cancer Cell,2014,26(3):390-401. DOI:10. 1016/j. ccr. 2014. 07. 023.
[6] ZAMBO I,VESELY K. WHO classification of tumours of soft tissue and bone 2013:the main changes compared to the 3rd edition[J]. Cesk Patol,2014,50(2):64-70.
[7] KOZAKEWICH H,PEREZ-ATAYDE A R,GOORIN A M,et al. Osteosarcoma in young children[J]. Cancer,1991,67(3):638-642.
[8]谭平先,沈靖南,王晋,等.膝关节周围骨肉瘤保肢手术疗效及预后分析[J].实用骨科杂志,2018,24(1):15-18. DOI:10. 13795/j. cnki. sgkz. 2018. 01. 004.TAN P X,SHEN J N,WANG J,et al. Survival analysis of patients with osteosarcoma around the knee treated by limbsalvage surgery[J]. J Prac Orthopaed,2018,24(1):15-18. DOI:10. 13795/j. cnki. sgkz. 2018. 01. 004.
[9]韩加,于沂阳,吴苏稼,等.影响肢体骨肉瘤临床预后的多中心回顾性研究[J].中国骨与关节杂志,2018,7(1):7-13. DOI:10. 3969/j. issn. 2095-252X. 2018. 01. 003.HAN J,YU Y Y,WU S J,et al. A multi-center retrospective study on the clinical prognosis of limb osteosarcoma[J].Chin J Bone Joint,2018,7(1):7-13. DOI:10. 3969/j.issn. 2095-252X. 2018. 01. 003.
[10]黄振华,张甫婷,邓琼,等.非经典型高级别骨肉瘤60例临床分析[J].广东医学,2017,38(16):2506-2510. DOI:10. 13820/j. cnki. gdyx. 2017. 16. 016.HUANG Z H,ZHANG F T,DENG Q,et al. Clinical analysis of 60 cases of non-classical high-grade osteosarcoma[J]. Guangdong Med J,2017,38(16):2506-2510.DOI:10. 13820/j. cnki. gdyx. 2017. 16. 016.
[11]上官建伟,梁俊芳,肖新广,等.骨肉瘤X线与CT和MRI影像特点及诊断价值[J].医药论坛杂志,2015,36(11):17-19.SHANGGUAN J W,LIANG J F,XIAO X G,et al. Analysis of imaging characteristics of X-ray,CT and MRI for osteosarcoma and diagnostic value[J]. J Med Forum,2015,36(11):17-19.
[12]龚印华.新辅助化疗结合保肢手术治疗骨肉瘤的临床观察[J].肿瘤基础与临床,2012,25(3):221-223.GONG Y H. The clinical observation of neoadjuvant chemotherapy and limb-salvage surgery in the treatment of osteosarcoma[J]. J Basic Clin Oncol,2012,25(3):221-223.
[13] CHOEYPRASERT W,PAKAKASAMA S,SIRACHAINAN N,et al. Comparative outcome of Thai pediatric osteosarcoma treated with two protocols:the role of high-dose methotrexate(HDMTX)in a single institute experience[J]. Asian Pac J Cancer Prev,2014,15(22):9823-9829.
[14] HEYMANN M F,BROWN H K,HEYMANN D. Drugs in early clinical development for the treatment of osteosarcoma[J]. Expert Opin Investig Drugs,2016,25(11):1265-1280. DOI:10. 1080/13543784. 2016. 1237503.
[15] KAMAL A F,WIDYAWARMAN H,HUSODO K,et al.Clinical outcome and survival of osteosarcoma patients in Cipto mangunkusumo hospital:limb salvage surgery versus amputation[J]. Acta Med Indones,2016,48(3):175-183.
[16] YIN K,LIAO Q,ZHONG D,et al. Meta-analysis of limb salvage versus amputation for treating high-grade and localized osteosarcoma in patients with pathological fracture[J].Exp Ther Med,2012,4(5):889-894. DOI:10. 3892/etm. 2012. 685.
[17]祁伟祥,何爱娜,汤丽娜,等.成人骨肉瘤52例预后因素的COX比例风险模型分析[J].肿瘤,2011,31(9):846-850.QI W X,HE A N,TANG L N,et al. COX proportionalhazard regression analysis of prognostic factors in 52 adult patients with osteosarcoma[J]. Tumor,2011,31(9):846-850.
[18] ASTER J C. In brief:Notch signalling in health and disease[J]. J Pathol,2014,232(1):1-3. DOI:10. 1002/path. 4291.
[19] GURUHARSHA K G,KANKEL M W,ARTAVANIS-TSAKONAS S. The Notch signalling system:recent insights into the complexity of a conserved pathway[J]. Nat Rev Genet,2012,13(9):654-666. DOI:10. 1038/nrg3272.
[20] MCMANUS M M,WEISS K R,HUGHES D P. Understanding the role of Notch in osteosarcoma[J]. Adv Exp Med Biol,2014,804:67-92. DOI:10. 1007/978-3-319-04843-7_4.
[21] ANGULO P,KAUSHIK G,SUBRAMANIAM D,et al.Natural compounds targeting major cell signaling pathways:a novel paradigm for osteosarcoma therapy[J]. J Hematol Oncol,2017,10(1):10.
[22] MU X,AGARWAL R,MARCH D,et al. Notch signaling mediates skeletal muscle atrophy in cancer cachexia caused by osteosarcoma[J]. Sarcoma,2016,2016:1-12. DOI:10. 1155/2016/3758162.
[23] LIU P,MAN Y,WANG Y,et al. Mechanism of BMP9 promotes growth of osteosarcoma mediated by the Notch signaling pathway[J]. Oncol Lett,2016,11(2):1367-1370.DOI:10. 3892/ol. 2015. 4067.
[24] PUNZO F,TORTORA C,DI PINTO D,et al. Anti-proliferative,pro-apoptotic and anti-invasive effect of EC/EV system in human osteosarcoma[J]. Oncotarget,2017,8(33):54459-54471. DOI:10. 18632/oncotarget. 17089.
[25] CAO Y,YU L,DAI G,et al. Cinobufagin induces apoptosis of osteosarcoma cells through inactivation of Notch signaling[J]. Eur J Pharmacol,2017,794:77-84. DOI:10.1016/j. ejphar. 2016. 11. 016.
[26] LI C,GUO D,TANG B,et al. Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression[J]. Neoplasma,2016,63(5):734-742. DOI:10. 4149/neo_2016_510.
[27] YU L,FAN Z,FANG S,et al. Cisplatin selects for stemlike cells in osteosarcoma by activating Notch signaling[J].Oncotarget,2016,7(22):33055-33068. DOI:10.18632/oncotarget. 8849.
[28] ZHOU S,YU L,XIONG M,et al. Lnc RNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging mi R-195-5p[J]. Biochem Biophys Res Commun,2018,495(2):1822-1832. DOI:10. 1016/j. bbrc. 2017. 12. 047.
[29]许自力,邓展生,许宇霞. Notch1、Dll4蛋白在骨肉瘤的表达及临床意义[J].中国骨肿瘤骨病,2009,8(1):28-31.XU Z L,DENG Z S,XU Y X. The clinical significance of the expression of Notch1 and Dll4 in osteosarcoma[J]. Chin J Bone Tumor Bone Dis,2009,8(1):28-31.
[30]张建平. Notch配体Jagged1在骨肉瘤中的作用研究[D].西安:第四军医大学,2014.ZHANG J P. The role of Notch ligand Jagged1 in osteosarcoma[D]. Xi’an:Fourth Military Medical University,2014.
[31] LI H,HE Y,HAO P,et al. Identification of characteristic gene modules of osteosarcoma using bioinformatics analysis indicates the possible molecular pathogenesis[J]. Mol Med Rep,2017,15(4):2113-2119. DOI:10. 3892/mmr.2017. 6245.