功能解剖影像PET/CT在肿瘤诊断相关常见问题中的应用研究
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摘要
目的：结、直肠癌术后复发及转移灶监测,原发灶不明转移癌寻找原发灶以及18F-FDG PET/CT'‘假阳性”摄取、肿瘤放射治疗敏感性预测、放射治疗后肿瘤内FDG高摄取区的临床病理学意义等是肿瘤临床常见的有代表性的与诊断相关的问题,通过功能解剖影像PET/CT解决这些常见问题的研究,探讨其在肿瘤定位、定性诊断及放射治疗相关诊断中的应用价值。
方法：(1)66例结／直肠癌术后临床可疑复发或转移患者、120例原发灶不明转移癌患者的全身18FFDG PET/CT显像与同期增强CT为主的常规影像学检查结果对比研究,根据病理诊断和临床随访结果,探讨18F-FDG PET/CT在肿瘤诊断中的应用价值。
(2)18F-FDG PET/CT "假阳性”摄取的常见原因是由炎症造成的。解决18F-FDG PET/CT“假阳性”摄取的方法之一就是研发新的PET示踪剂。18-FLT是新近发展起来的反映细胞增殖的示踪剂。通过食管癌ECa109BALB/C裸鼠移植瘤模型探讨"F-FLT PET/CT在肿瘤诊断、肿瘤放射治疗敏感性预测中的应用价值以及放射治疗后肿瘤内FDG高摄取区的临床病理学意义。
①食管癌ECa109BALB/C裸鼠移植瘤模型和炎症小鼠模型各20只分别随机分为18F-FDG和18F-FLT组,每组10只,各行18F-FDG及18F-FLT PET/CT显像研究,对比研究F-FLT PET/CT在肿瘤诊断中的应用价值。
②40只食管癌ECa109BALB/C裸鼠移植瘤模型随机均分为18F-FDG组和18F-FLT组,IOGy6MV-X线单次照射右后肢移植瘤,分别于放射治疗后第1天、3天、5天、7天、10天行FLT及FDG PET/CT显像,每次显像每组随机抽取4只。测量肿瘤／非肿瘤组织放射性比值(T/N),各组每次取平均值绘制时间变化曲线；FLT PFT显像T/N值与相应移植瘤免疫组化所测的Ki-67指数作相关性分析；放射治疗后移植瘤FDG高摄取区细针穿刺行组织病理及免疫组化测增殖动力学参数Ki-67、乏氧标志物HIF-1α。对比分析放射治疗后FDG高摄取区的临床病理意义。
结果：(1)经病理或临床随访证实,18F-FDG PET/CT诊断结直肠癌术后复发的灵敏性和特异性分别为96.30%、94.87%,同期增强CT分别为70.37%、87.18%;诊断结直肠癌术后淋巴结或远处器官转移的灵敏性和特异性分别为95.35%、82.61%,同期增强CT分别为61.9%、75.00%。半定量法最大标准摄取值(SUVmax)复发灶(变化区间4.16-22.00,平均值±标准差8.06±4.30)明显高于良性病变(区间1.18-6.25,平均值±标准差2.82±1.02)差异具有统计学意义(P<0.01)。
(2)经病理或临床随访证实,120例原发灶不明转移癌患者18F-FDG PET/CT准确检测出原发灶54例,检出率42.5%。原发灶位于头颈部17例,肺19例,乳腺2例,食管1例,胃2例,胆管1例,胰腺3例,结肠3例,卵巢2例,前列腺1例,其他部位3例。18F-FD G PET/CT诊断出现假阳性9例(7.5%)：头颈部3例,肺1例,胃1例,结肠2例,卵巢1例,前列腺1例。18F-FDG PET/CT未检出原发灶的66例患者在平均32个月(12-45个月)的临床随访中,仅5例找到原发灶,具体为乳腺癌、胃癌、结肠癌、前列腺癌和输尿管癌各1例。18F-FDG PET/CT在原发灶不明转移癌患者中定位原发灶的灵敏性、特异性和准确性分别为91.5%,85.2%和88.3%。
(3)成功制作食管癌ECa109BALB/C裸鼠移植瘤模型和炎症小鼠模型,并成功合成18F-FLT。187F-FDG及18F-FLT PET组均表现为移植瘤放射性摄取增高,T/N的平均值±标准差分别为4.73±1.34和3.68±1.08,t检验示t=1.75,p>0.05,差异无统计学意义。而在炎性组织,18F-FDG PET组放射性摄取增高,T/N平均值±标准差为2.74±0.64,18F-FLT PET组则无放射性摄取增高,T/N平均值±标准差为1.15±0.14,t检验示t=6.79,p<0.O1。FLT PET T/N在移植瘤放射治疗后第1天即出现明显下降,第3天降到最低;而FDG PET则于移植瘤放射治疗后缓慢下降,3天后出现明显下降至放射治疗后第5天降至最低。T/N的下降程度FLT组与FDG组差别具有统计学意义(53.15±9.22%vs45.62±11.08%,t=2.34,p<0.05)。放射治疗后移植瘤Ki-67表达指数下降,FLT摄取与Ki-67表达指数有显著相关性(r=0.828)。放射治疗后移植瘤FDG高摄取区的Ki-67、HIF-1α等指标均高于瘤内其他区域。
结论：1.与以CT为代表的常规影像学相比,功能解剖融合影像PET/CT在结直肠癌术后复发及转移灶监测,原发灶不明转移癌寻找原发灶等肿瘤临床常见问题的定位、定性诊断中均表现出更高的灵敏性、特异性及准确性,在肿瘤诊断及分期、优化治疗方案等方面发挥着越来越重要的作用。
2.18F-FLT作为反映细胞增殖的PET示踪剂,在炎症组织中无放射性摄取,比FDG具有更高的肿瘤诊断特异性。
3.18F-FLT和F-FDG PET均可用于食管癌放射治疗敏感性预测,18F-FLT更为灵敏,放射治疗后肿瘤放射性摄取较早出现下降,与Ki-67表达指数有显著相关性。放射治疗后肿瘤内FDG高摄取区的增殖和乏氧指标均高于肿瘤内其他区域,可能对放射治疗剂量生物调强、个体化放射治疗提供帮助,有待于进一步临床研究证实。
Purpose:Recurrence and metastases monitoring of postoperative patients with c olorectal cancer, detecting the primary tumor in patients with carcinoma of unk nown primary,"false positive" uptake in F-FDG PET/CT, predicting of tumor radiosensitivity and the clinicopathological significance of high metabolic area i n tumor after radiation therapy are common and urgent issues needed to resolv e.The purpose of this research is to evaluate the application value of function al anatomy imaging PET/CT in these tumor diagnosis related common problem s.
Methods:(1)66postoperative patients with colorectal cancer,suspicious of recu rrence/metastases and120cases of unknown primary tumor with confirmed met astase(s)were recruited in the research. The final histopathological and formal cl inical follow-up findings were used as gold standard to determine the sensitivit y and specificity of FDG PET/CT and enhanced CT of the same periods.
(2) More than half of the false positive(FP) interpretations by FDG PET were of uptake by inflammatory infiltrates. The development of F-FLT, as a new P ET tracer, has enabled demonstration of cell proliferation. BALB/c nude mice bearing human esophageal cancer Eca109. BALB/c nude mice bearing human e sophageal cancer Eca109.The study in vivo model of BALB/c nude mice beari ng human esophageal cancer Eca109was to investigate the value of F-FLT PET/CT for diagnosis、predicting of tumor radiosensitivity and the clinicopathol ogical significance of high FDG uptake area in tumor after radiation therapy.
①Twenty BALB/c nude mice bearing human esophageal cancer Eca109and twenty inflammation BALB/c mice models were randomly divided into two gr oups according to the different tracers:18F-FLT and18F-FDG(each group:n=10, r espectively). Value of18F-FLT PET/CT for diagnosis of tumor was investigated, compared to18F-FDG PET/CT.
②orty BALB/c nude mice bearing human esophageal cancer Eca109were randomly divided into two groups according to the different tracers:18F-FLT and18F-FDG(each group:n=20, respectively). PET/CT imaging was performed for f our mice every time each group at60min after tracer injection from tail vein s. After imaging,instantly sacrificed the four mice respectively and took out tra nsplanted tumor completely to perform pathological and immunohistochemistry examination. The whole process mentioned above was repeated on lstday、3rdday.5thday、7thday、10thday after the xenograft was irradiated with a single dose10Gy6MV-X ray for each group.Based on PET imaging of18F-FLT and18F-FDG, Tumor and tumor-to-nontumor ratios(T/N) were measured.Maximum decline in tumor-to-nontumor ratios(T/N) for18F-FLT and18F-FDG were determined. Aft er irridiation,position the district with high FDG uptake and perform needle asp iration biopsy to investigate the clinicopathological value by pathological and i mmunohistochemical examination:Ki-67label index and HIF-1α.
Results:The sensitivity and specificity of FDG PET/CT in detecting recurrence are96.30%,94.87%(while enhanced CT are70.37%and87.18%,respectively).The sensitivity and specificity in detecting metastasis are95.35%,82.61%(enhanced CT are61.90%,75.00%).SUVmax was significantly higher in malignant lesions (x±s,8.06±4.30) than in benign ones (x±s,2.82±1.02) and P<0.01.
FDG PET/CT was able to detect the primary tumor in54/120patients(42.5%).The primary tumors were confirmed by histopathologic and formal clinical follow-up findings,and located in the head and neck(n=17),the lung(n=19),the breast(n=2),the esophagus(n=1),the stomach(n=2),the bile ducts(n=1).the pancreas (n=3).the colon(n=3),the ovary(n=2).the prostate(n=1),others(n=3).FDG PET resul ts were proved false positive in9patients(7.5%),which were located in the hea d and neck(n=3),the lung(n=1),the stomach(n=1),the colon(n=2),the ovary(n=1),th e prostate(n=1).During the clinical follow-up of median32months (range,12-45months),primary tumor was found in only5patients of66cases unidentified by PET/CT(breast cancer,gastric cancer,colon cancer.prostate cancer and urinary tumors,respectively).The sensitivity,specificity, and accuracy of18F-FDG PET/C T in the detection of the primary tumor site were91.5%,85.2%,and88.3%,resp ectively.18F-FLT and18F-FDG PET/CT both showed clear tumor images. F LT uptake was higher than that of FDG,but the T/N of18F-FDG and18F-FLT in Eca109tumors was different without significantly (3.68±1.08vs4.73±1.34, t=1.75, p>0.05). While the T/N of18F-FDG and18F-FLT in inflammatory tissu e was different with significantly(2.74±0.64vs1.15±0.14,t=6.79,p<0.01).Decline in tumor-to-nontumor ratios (T/N) was observed after irridiation. For FDG, mo st significant decline was observed on5th day; whereas, for FLT,this was alread y noted on1st day. Maximum decline in T/N for FDG and FLT was different with significantly(45.62±11.08%vs53.15±9.22%,t=2.34,p<0.05).Expression of Ki-67declined in irradiated tumors compared to that of control,and statistical signif icant correlations were found for Ki-67with FLT uptake(r=0.828).Tumor cells i n irradiation group manifested a significant appearance of apoptosis.After irridia tion,Ki-67,HIF-la in the district with high FDG uptake were expressed higher t han the other regions of the tumor.
Conclusion:1.Compared to CT, PET/CT showed higher sensitivity, spec ificity and accuracy, and plays an increasingly important role in tumor diagnosi s and staging, optimize treatment regimens.
2.18F-FLT and18F-FDG uptake can be used to monitor the biologic resp onse of esophageal SCC and normal tissue to radiation therapy. F-FLT PET/C T may have an advantage over F-FDG PET/CT in differentiating inflammation tissue from tumor. After irridiation,Ki-67.HIF-la in the district with high FDG uptake were expressed higher than in the other regions of the tumor, which may be helpful for dose painting of IMRT.and additional investigation is nee ded to validate these findings.
方法：(1)66例结／直肠癌术后临床可疑复发或转移患者、120例原发灶不明转移癌患者的全身18FFDG PET/CT显像与同期增强CT为主的常规影像学检查结果对比研究,根据病理诊断和临床随访结果,探讨18F-FDG PET/CT在肿瘤诊断中的应用价值。
(2)18F-FDG PET/CT "假阳性”摄取的常见原因是由炎症造成的。解决18F-FDG PET/CT“假阳性”摄取的方法之一就是研发新的PET示踪剂。18-FLT是新近发展起来的反映细胞增殖的示踪剂。通过食管癌ECa109BALB/C裸鼠移植瘤模型探讨"F-FLT PET/CT在肿瘤诊断、肿瘤放射治疗敏感性预测中的应用价值以及放射治疗后肿瘤内FDG高摄取区的临床病理学意义。
①食管癌ECa109BALB/C裸鼠移植瘤模型和炎症小鼠模型各20只分别随机分为18F-FDG和18F-FLT组,每组10只,各行18F-FDG及18F-FLT PET/CT显像研究,对比研究F-FLT PET/CT在肿瘤诊断中的应用价值。
②40只食管癌ECa109BALB/C裸鼠移植瘤模型随机均分为18F-FDG组和18F-FLT组,IOGy6MV-X线单次照射右后肢移植瘤,分别于放射治疗后第1天、3天、5天、7天、10天行FLT及FDG PET/CT显像,每次显像每组随机抽取4只。测量肿瘤／非肿瘤组织放射性比值(T/N),各组每次取平均值绘制时间变化曲线；FLT PFT显像T/N值与相应移植瘤免疫组化所测的Ki-67指数作相关性分析；放射治疗后移植瘤FDG高摄取区细针穿刺行组织病理及免疫组化测增殖动力学参数Ki-67、乏氧标志物HIF-1α。对比分析放射治疗后FDG高摄取区的临床病理意义。
结果：(1)经病理或临床随访证实,18F-FDG PET/CT诊断结直肠癌术后复发的灵敏性和特异性分别为96.30%、94.87%,同期增强CT分别为70.37%、87.18%;诊断结直肠癌术后淋巴结或远处器官转移的灵敏性和特异性分别为95.35%、82.61%,同期增强CT分别为61.9%、75.00%。半定量法最大标准摄取值(SUVmax)复发灶(变化区间4.16-22.00,平均值±标准差8.06±4.30)明显高于良性病变(区间1.18-6.25,平均值±标准差2.82±1.02)差异具有统计学意义(P<0.01)。
(2)经病理或临床随访证实,120例原发灶不明转移癌患者18F-FDG PET/CT准确检测出原发灶54例,检出率42.5%。原发灶位于头颈部17例,肺19例,乳腺2例,食管1例,胃2例,胆管1例,胰腺3例,结肠3例,卵巢2例,前列腺1例,其他部位3例。18F-FD G PET/CT诊断出现假阳性9例(7.5%)：头颈部3例,肺1例,胃1例,结肠2例,卵巢1例,前列腺1例。18F-FDG PET/CT未检出原发灶的66例患者在平均32个月(12-45个月)的临床随访中,仅5例找到原发灶,具体为乳腺癌、胃癌、结肠癌、前列腺癌和输尿管癌各1例。18F-FDG PET/CT在原发灶不明转移癌患者中定位原发灶的灵敏性、特异性和准确性分别为91.5%,85.2%和88.3%。
(3)成功制作食管癌ECa109BALB/C裸鼠移植瘤模型和炎症小鼠模型,并成功合成18F-FLT。187F-FDG及18F-FLT PET组均表现为移植瘤放射性摄取增高,T/N的平均值±标准差分别为4.73±1.34和3.68±1.08,t检验示t=1.75,p>0.05,差异无统计学意义。而在炎性组织,18F-FDG PET组放射性摄取增高,T/N平均值±标准差为2.74±0.64,18F-FLT PET组则无放射性摄取增高,T/N平均值±标准差为1.15±0.14,t检验示t=6.79,p<0.O1。FLT PET T/N在移植瘤放射治疗后第1天即出现明显下降,第3天降到最低;而FDG PET则于移植瘤放射治疗后缓慢下降,3天后出现明显下降至放射治疗后第5天降至最低。T/N的下降程度FLT组与FDG组差别具有统计学意义(53.15±9.22%vs45.62±11.08%,t=2.34,p<0.05)。放射治疗后移植瘤Ki-67表达指数下降,FLT摄取与Ki-67表达指数有显著相关性(r=0.828)。放射治疗后移植瘤FDG高摄取区的Ki-67、HIF-1α等指标均高于瘤内其他区域。
结论：1.与以CT为代表的常规影像学相比,功能解剖融合影像PET/CT在结直肠癌术后复发及转移灶监测,原发灶不明转移癌寻找原发灶等肿瘤临床常见问题的定位、定性诊断中均表现出更高的灵敏性、特异性及准确性,在肿瘤诊断及分期、优化治疗方案等方面发挥着越来越重要的作用。
2.18F-FLT作为反映细胞增殖的PET示踪剂,在炎症组织中无放射性摄取,比FDG具有更高的肿瘤诊断特异性。
3.18F-FLT和F-FDG PET均可用于食管癌放射治疗敏感性预测,18F-FLT更为灵敏,放射治疗后肿瘤放射性摄取较早出现下降,与Ki-67表达指数有显著相关性。放射治疗后肿瘤内FDG高摄取区的增殖和乏氧指标均高于肿瘤内其他区域,可能对放射治疗剂量生物调强、个体化放射治疗提供帮助,有待于进一步临床研究证实。
Purpose:Recurrence and metastases monitoring of postoperative patients with c olorectal cancer, detecting the primary tumor in patients with carcinoma of unk nown primary,"false positive" uptake in F-FDG PET/CT, predicting of tumor radiosensitivity and the clinicopathological significance of high metabolic area i n tumor after radiation therapy are common and urgent issues needed to resolv e.The purpose of this research is to evaluate the application value of function al anatomy imaging PET/CT in these tumor diagnosis related common problem s.
Methods:(1)66postoperative patients with colorectal cancer,suspicious of recu rrence/metastases and120cases of unknown primary tumor with confirmed met astase(s)were recruited in the research. The final histopathological and formal cl inical follow-up findings were used as gold standard to determine the sensitivit y and specificity of FDG PET/CT and enhanced CT of the same periods.
(2) More than half of the false positive(FP) interpretations by FDG PET were of uptake by inflammatory infiltrates. The development of F-FLT, as a new P ET tracer, has enabled demonstration of cell proliferation. BALB/c nude mice bearing human esophageal cancer Eca109. BALB/c nude mice bearing human e sophageal cancer Eca109.The study in vivo model of BALB/c nude mice beari ng human esophageal cancer Eca109was to investigate the value of F-FLT PET/CT for diagnosis、predicting of tumor radiosensitivity and the clinicopathol ogical significance of high FDG uptake area in tumor after radiation therapy.
①Twenty BALB/c nude mice bearing human esophageal cancer Eca109and twenty inflammation BALB/c mice models were randomly divided into two gr oups according to the different tracers:18F-FLT and18F-FDG(each group:n=10, r espectively). Value of18F-FLT PET/CT for diagnosis of tumor was investigated, compared to18F-FDG PET/CT.
②orty BALB/c nude mice bearing human esophageal cancer Eca109were randomly divided into two groups according to the different tracers:18F-FLT and18F-FDG(each group:n=20, respectively). PET/CT imaging was performed for f our mice every time each group at60min after tracer injection from tail vein s. After imaging,instantly sacrificed the four mice respectively and took out tra nsplanted tumor completely to perform pathological and immunohistochemistry examination. The whole process mentioned above was repeated on lstday、3rdday.5thday、7thday、10thday after the xenograft was irradiated with a single dose10Gy6MV-X ray for each group.Based on PET imaging of18F-FLT and18F-FDG, Tumor and tumor-to-nontumor ratios(T/N) were measured.Maximum decline in tumor-to-nontumor ratios(T/N) for18F-FLT and18F-FDG were determined. Aft er irridiation,position the district with high FDG uptake and perform needle asp iration biopsy to investigate the clinicopathological value by pathological and i mmunohistochemical examination:Ki-67label index and HIF-1α.
Results:The sensitivity and specificity of FDG PET/CT in detecting recurrence are96.30%,94.87%(while enhanced CT are70.37%and87.18%,respectively).The sensitivity and specificity in detecting metastasis are95.35%,82.61%(enhanced CT are61.90%,75.00%).SUVmax was significantly higher in malignant lesions (x±s,8.06±4.30) than in benign ones (x±s,2.82±1.02) and P<0.01.
FDG PET/CT was able to detect the primary tumor in54/120patients(42.5%).The primary tumors were confirmed by histopathologic and formal clinical follow-up findings,and located in the head and neck(n=17),the lung(n=19),the breast(n=2),the esophagus(n=1),the stomach(n=2),the bile ducts(n=1).the pancreas (n=3).the colon(n=3),the ovary(n=2).the prostate(n=1),others(n=3).FDG PET resul ts were proved false positive in9patients(7.5%),which were located in the hea d and neck(n=3),the lung(n=1),the stomach(n=1),the colon(n=2),the ovary(n=1),th e prostate(n=1).During the clinical follow-up of median32months (range,12-45months),primary tumor was found in only5patients of66cases unidentified by PET/CT(breast cancer,gastric cancer,colon cancer.prostate cancer and urinary tumors,respectively).The sensitivity,specificity, and accuracy of18F-FDG PET/C T in the detection of the primary tumor site were91.5%,85.2%,and88.3%,resp ectively.18F-FLT and18F-FDG PET/CT both showed clear tumor images. F LT uptake was higher than that of FDG,but the T/N of18F-FDG and18F-FLT in Eca109tumors was different without significantly (3.68±1.08vs4.73±1.34, t=1.75, p>0.05). While the T/N of18F-FDG and18F-FLT in inflammatory tissu e was different with significantly(2.74±0.64vs1.15±0.14,t=6.79,p<0.01).Decline in tumor-to-nontumor ratios (T/N) was observed after irridiation. For FDG, mo st significant decline was observed on5th day; whereas, for FLT,this was alread y noted on1st day. Maximum decline in T/N for FDG and FLT was different with significantly(45.62±11.08%vs53.15±9.22%,t=2.34,p<0.05).Expression of Ki-67declined in irradiated tumors compared to that of control,and statistical signif icant correlations were found for Ki-67with FLT uptake(r=0.828).Tumor cells i n irradiation group manifested a significant appearance of apoptosis.After irridia tion,Ki-67,HIF-la in the district with high FDG uptake were expressed higher t han the other regions of the tumor.
Conclusion:1.Compared to CT, PET/CT showed higher sensitivity, spec ificity and accuracy, and plays an increasingly important role in tumor diagnosi s and staging, optimize treatment regimens.
2.18F-FLT and18F-FDG uptake can be used to monitor the biologic resp onse of esophageal SCC and normal tissue to radiation therapy. F-FLT PET/C T may have an advantage over F-FDG PET/CT in differentiating inflammation tissue from tumor. After irridiation,Ki-67.HIF-la in the district with high FDG uptake were expressed higher than in the other regions of the tumor, which may be helpful for dose painting of IMRT.and additional investigation is nee ded to validate these findings.
引文
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[1]Hu M, Han A, Xing L, et al. Value of dual-time-point FDG PET/CT for mediastinal nodal staging innon-small-cell lung cancer patients with lung comorbidity. Clin Nucl Med.2011.36(6):429-33.
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