食管癌临床分期的影像学研究与肿瘤分子标志物的价值
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摘要
食管癌是人类常见恶性肿瘤之一,全世界每年约30万人死于食管癌。我国是食管癌的高发地区,每年因食管癌死亡者约16万人,占全部恶性肿瘤死亡近四分之一。其发病率和死亡率均很高,但临床就诊时绝大部分已属中晚期,大多失去手术治疗机会,放射治疗(放疗)成为其主要治疗方法。临床分期早晚是影响食管癌放疗预后的重要因素,目前食管癌非手术治疗尚无统一的分期标准。如何根据治疗前食管癌患者的期别早晚选择并制定合理化治疗方案,提高综合治疗疗效并准确地评估预后和生存,已成为当今肿瘤学界研究的热点和难题。
众所周知,食管癌手术病理TNM分期标准能准确指导预后,但多数患者就诊时已为中晚期,失去手术治疗机会,因此不能准确地进行TNM分期。目前已有学者提出根据CT和食管钡餐造影为基础的分期标准,对指导食管癌预后有较好的参考价值,但分期标准比较复杂,临床应用不够方便,为此拟根据CT扫描和钡餐造影显示的肿瘤体积大小作为T分期的标准,为非手术治疗食管癌提供更简便、更理想的临床分期方法。
目前国内外已有根据食管癌CT或CT结合EUS、PET的临床分期,但尚未检索到食管癌影像学分期与肿瘤分子标志物结合的分期系统,因此该分期的提出既考虑了传统影像学指标,又结合了代表食管癌生物学行为的分子指标,争取为食管癌疗前准确地选择治疗方案提供坚实的理论基础,在个体化治疗方面提供循证医学的证据,以此来改善食管癌患者的长期生存及生存质量,为攻克食管癌这一世界难题迈上新的台阶!
第一部分:18F-FDG PET/CT和CT对食管癌临床分期的价值
目的:评价18F-FDG PET/CT和CT判定食管癌T、N分期的敏感性、特异性及准确性,确定PET/CT在食管癌术前分期中的价值,并探讨SUV值与食管癌预后的相关性。
方法:29例食管癌患者术前均行PET/CT和CT扫描,分别进行T、N分期,并与术后病理分期进行对照分析。同时将重建图像传输至三维治疗计划系统,参照不同标准分别勾画靶区,比较不同标准下靶区勾画的差异及对正常组织受量的影响。
结果:(1)不同检测方法所得病变长度依次为CT>PET/CTsuv2.5>食管钡餐造影>PET/CT40%suvmax>电子胃镜;与食管钡餐造影长度最为接近的是PET/CTsuv2.5长度。(2)与术后病理证实的T、N分期结果比较,PET/CT扫描对食管癌术前T、N分期诊断准确率分别为44.8%和93.1%,CT扫描对食管癌术前T、N分期诊断的准确率分别为69.0%和79.3%。CT扫描对判断T分期的准确率明显高于PET/CT,PET/CT扫描对判断N分期的准确率虽高于CT,但未显示出统计学差异。(3)术前PET/CT扫描检测的T、N分期与术后病理T、N分期的一致性系数Kappa值分别为0.254和0.948;术前CT扫描检测的T、N分期与术后病理T、N分期的一致性系数Kappa值分别为0.568和0.704;仅术前PET/CT扫描检测T分期的一致性较差(Kappa值<0.4);术前PET/CT扫描检测N分期、术前CT扫描检测T、N分期一致性均较好(Kappa值>0.4)。(4) SUV值与PCT/CTsuv2.5显示病变长度及体积呈正相关,r值分别为0.803及0.726;SUV值<9.0患者预后好于SUV值≥9.0患者。(5)采用PET/CTsuv2.5图像勾画靶区,较CT图像勾画靶区后制定的放疗计划,在降低周围正常组织受量方面具有一定优势。
结论:(1) CT勾画的GTV长度最长,PET/CT40%suvmax最短,PET/CTsuv2.5与食管钡餐造影显示的长度最为接近。(2)CT在判断食管癌临床T分期方面较PCT/CT具有一定优势,PET/CT扫描对判断N分期的准确率虽高于CT,但未显示出统计学差异。(3) SUV值与食管癌病变长度、体积及分期成正相关;SUV临界值9.0可以作为一项实用的判断预后指标。(4)依据PET/CTsuv2.5勾画靶区,有望提高GTV勾画的准确性和精确性。
第二部分:超声内镜结合CT扫描在食管癌临床分期中的应用
目的:比较超声内镜(EUS)、CT扫描及两者联合应用在判定胸段食管癌术前T、N分期中的应用价值。
方法: 48例手术治疗食管癌患者术前均行EUS检查和CT扫描,同时分别进行T、N分期,并与术后病理分期进行对照分析。
结果: (1)食管癌术前EUS检查T、N分期的诊断准确率分别为77.1%(37/48)、75.0%(36/48),其中T1、T2、T3、T4期诊断准确率分别为87.5%、57.1%、94.1%、100% ,N0、N1期诊断准确率分别为78.6%、70.0%。(2)食管癌术前CT检查T、N分期的诊断准确率分别为52.1%(25/48)和77.1%(37/48),其中T1、T2、T3、T4期诊断准确率分别为37.5%、33.3%、81.2%、100% ,N0、N1期诊断准确率分别为78.6%、75.0%。(3) EUS对判断T1-2期的准确率明显高于CT(χ2=5.586,P=0.018),而对于T3-4期及N分期的判断两者则无明显差别(P>0.05)。(4)EUS联合CT检查T、N分期的诊断准确率分别为79.2%(38/48)和77.1%(37/48),其中T1、T2、T3、T4期诊断准确率分别为87.5%、71.4%、82.3%、100% ,N0、N1期诊断准确率分别为78.6%、75.0%。(5)仅术前CT扫描检测T分期的一致性较差(Kappa值<0.4),术前CT扫描检测N分期、术前EUS检测T、N分期及两者联合应用检测T、N分期的一致性均较好(0.4 结论: (1) EUS对食管癌术前诊断T、N分期的准确率较高,尤其对T早期诊断的准确率比较高。(2)以淋巴结短径≥7.5mm作为阳性淋巴结的诊断界点,可能提高判断淋巴结转移的准确性。(3) EUS与CT联合应用,能够较准确的进行食管癌临床分期。
第三部分:食管癌三维适形放疗GTV-T体积与临床分期及预后的相关性分析
目的:应用肿瘤体积大小评价食管癌临床分期标准的准确性、符合程度及与预后的关系
方法:收集2001年7月至2006年12月在我院接受根治性三维适形放疗(3DCRT)的375例食管癌患者的临床资料,参照食管钡餐造影及电子胃镜检查结果,于TPS系统CT体层图像,准确勾画肿瘤靶区,测算肿瘤长度、横径及体积大小,对该组病例进行GTV-T分期,选择出合适的GTV-T体积分级标准,并结合区域淋巴结转移情况进行临床分期,分析验证其准确性、符合程度,以期为食管癌治疗前分期及预后评估提供依据。
结果:(1)随访截至2010年12月31日,随访率为94.7%。自放疗之日起计算,全组1、3、5年局控率分别为80.5%、53.7%、44.9%,生存率分别为67.2%、29.4%、19.0%,中位生存期19个月。(2)与病理T分期对应,将GTV-T体积按≤30cm3、>30～≤60cm3、>60～≤90cm3、>90cm3分为四级, 5年生存率之间比较,T3与T4级之间差异无显著性意义(P=0.556),其余各T分级之间的生存差异具有显著性,(P<0.001),按T1、T2、T3+4进行GTV-T体积三分级,各组间差异均具有显著性意义(χ2=48.73,P=0.000)。(3)该组食管癌患者临床N0分期217例,5年生存率为24.5%,N1-2期患者158例,5年生存率10.4%,两者比较,差异具有显著性意义(χ2=32.71,P=0.000)。(4)对应GTV-T体积T1、T2、T3+4三分级,将食管癌临床分期对应分为Ⅰ、Ⅱ、Ⅲ期,将出现N2期或远处转移的患者,全部归入Ⅳ期,5年生存率分别为32.7%、25.8%、10.6%、6.9%,生存差异具有显著性意义(χ2=75.68,P=0.000)。(5)单因素分析显示疗前进食情况、肿瘤长度、病变横径、GTV-T体积、N分期、临床分期、近期疗效、急性放射性食管炎、急性放射性肺炎均为影响预后因素。Cox多因素分析显示GTV-T体积、N分期、急性放射性食管炎、疗前进食情况及化疗为独立预后影响因素。
结论:(1)GTV-T按T1、T2、T3+4三分级法能较好的反映预后生存。(2)无区域淋巴结转移N0者较有区域或非区域淋巴结转移N1-2者预后好。(3)对应GTV-T三分级的临床四分期法,亦能较好的反应预后生存。(4)GTV-T体积、N分期、急性放射性食管炎、疗前进食情况及化疗为独立预后影响因素。
第四部分:PTTG和MMP-9蛋白表达在食管癌临床分期中的价值
目的:研究PTTG和MMP-9在食管癌组织中的表达和相关性,探讨PTTG在食管癌侵袭转移中的作用及与食管癌临床分期的关系。
方法:应用免疫组化SP法检测84例食管癌组织中PTTG和MMP-9的蛋白表达情况,并结合临床病理参数进行分析。
结果:(1)PTTG在食管癌组织中的阳性表达率为69.05%,MMP-9在食管癌组织中的阳性表达率为61.90%。PTTG和MMP-9蛋白表达呈正相关,相关系数r=0.588(。2)PTTG蛋白在T3-4期患者阳性表达率83.33%,高于T1-2期阳性表达率54.76%(P=0.004)。MMP-9蛋白在T3-4期患者阳性表达率80.95%,高于T1-2期阳性表达率42.86%(P=0.000)。(3)PTTG蛋白在有淋巴结转移组阳性表达率为97.06%,高于无淋巴结转移组50.00%(P=0.000)。MMP-9蛋白在有淋巴结转移组阳性表达率为91.18%,高于无淋巴结转移组42.00%(P=0.000)。(4)发生远处转移者PTTG蛋白阳性表达率高于未发生远转者,分别为100.0%和61.76%(P=0.001)。MMP-9蛋白阳性表达率也高于未发生远转者,分别为93.75%和54.41%,(P=0.002)。(5)临床Ⅲ-Ⅳ期PTTG阳性表达率为96.00%,高于Ⅰ-Ⅱ期者57.63%(P=0.000)。临床Ⅲ-Ⅳ期MMP-9阳性表达率为96.00%,高于Ⅰ-Ⅱ期者47.46%(P=0.000)。(6)PTTG蛋白表达与T分期、N分期、TNM分期的相关系数r分别为0.309、0.500、0.380,均呈正相关,P<0.05。MMP-9蛋白表达与T分期、N分期、TNM分期的相关系数r分别为0.392、0.497、0.457,均呈正相关,P<0.05。(7)EUS结合PTTG和MMP-9蛋白阳性指数进行分期,其检测T、TNM分期及EUS单独应用检测比较,与术后病理分期的一致性系数Kappa值未见明显差异。EUS单独应用判定N分期时,N0期与N1期患者生存未见明显差异;EUS与蛋白表达结合判定N分期时,N0期与N1期患者预后出现显著性差异,P<0.05。
结论:(1)PTTG和MMP-9蛋白在食管癌组织中均呈高表达,且两者蛋白表达呈正相关。(2)有淋巴结转移者较无淋巴结转移者PTTG和MMP-9蛋白表达阳性率明显增加,提示其高表达与食管癌淋巴结转移状态密切相关。(3)PTTG和MMP-9蛋白表达与食管癌临床分期显著正相关,肿瘤期别越晚,表达越高,提示PTTG和MMP-9在食管癌发生、发展及侵袭转移过程中起重要作用。
Esophageal carcinoma is one of the most frequently malignant tumors suffered by human beings, and leads to death of about 300,000 people annually worldwide. China is known as a country with high incidence rate of esophageal carcinoma, and each year about 160,000 people die due to this diaease, the number of death patients caused by esophageal carcinoma were nearly a quarter by all sorts of malignancies. The rates of incidence and death were very high, however, most of the patients have been classified as middle and late phase when they come to hospital for examination, and no chances were cured by operation, so the radiotherapy have been the major treatment measures. Clinical staging is an important prognosis factor after radiotherapy for esophageal carcinoma. At present, there are no accepted standards about clinical stage for esophageal carcinoma patients with non-operational treatment. Nowsdays, it has been a focused problem how to select a reasonable treatment according to the preoperatial clicial stage, and how to improve treatment effect and precisely evaluat prognosis.
It is generally known that pathological TNM stage can predict the prognosis of esophageal carcinoma patients. However, most of the patients have been classified as middle and late phase when they come to hospital for examination and clinical treatment, and no chances treated by surgery. There is no accutate TNM stage available for these group patients. Presently, some scholars have suggested some standards based on CT image and barium esophagogram, which resulted in a better evaluating prognosis of non-operation esophageal carcinoma, but these standards were relevantly complicated, and it was not convenient enough to use in clinic practice. Therefore, this study is planning to use the volume of primary tumor which indicated by CT image and barium esophagogram as the standards of T stage for those non-operational patients with esophageal carcinoma.
According to most studies, there have been clinical stage of esophageal carcinoma based on CT or combining CT with EUS, PET. But there have no one stage system combining the imaging parameters and tumor molecule marker of esophageal carcinoma. Therefore, in this study we combined traditional imaging parameters and molecule biological activities in clicial stage of esophageal carcinoma. The purpose was to supply the theory foundation of selecting reasonable treatment in esophageal carcinoma preoperation, provide evidence to individual treatment in term of evidence-based-medicine, to improve long-term survival and quality of esophageal carcinoma patients.
Part 1: Explore the value of 18F-FDG , PET/CT and CT scan for the clinical stage of esophageal carcinoma
Objective: To evaluate the sensitivity, specificity and accuracy of 18F-FDG, PET/CT and CT were used for T and N stage for esophageal carcinoma, determine the value of stage prior to operation of esophageal carcinoma, and explore the SUV value evaluating prognosis of esophageal carcinoma.
Methods: PET/CT and CT scan as well as T and N stage were carried out for 29 cases of preoperative esophageal carcinoma patients, those results were analyzed and compared with postoperative pathological TNM stage. Meantime, the constructed images were transmitted to 3D Treatment Planning System. Each primary lesion target volume was defined respectively according to different criteria. The size of target volume and the dose-volume of normal tissue were compared.
Results: (1) Primary lesion length of esophageal carcinoma was measured by using different ways,which following as: CT>PET/CTsuv2.5>esophageal barium esophagogram > PET/CT40%suvmax > electronic endoscopy. The length measured by using PET/CTsuv2.5 was close to that with esophageal barium esophagogram. (2) The accuracy rates of diagnosis the T and N stage were 44.8% and 93.1% for PET/CT scan preoperative esophageal carcinoma,and 69.0% and 79.3% for CT scan respectively. CT scan diagnosis the T stage was obviously higher than PET/CT in term of determining T staging, while PET/CT scan diagnosis the N stage was higher than CT, but there was no significantly difference. (3) The Kappa values for preoperative PET/CT scan in T and N stage compared with postoperative pathological T and N stage were 0.254 and 0.948 respectively. Meantime,the Kappa values of CT scan were 0.568 and 0.704 respectively. It was clear that only the Kappa value of preoperative PET/CT scan in T stage was poor (Kappa value<0.4), the Kappa values for PET/CT scan in N stage, as well as preoperative CT scan in T and N stage were good (Kappa value>0.4). (4) The SUV values were increasing with the lesion volume and length of PCT/CTsuv2.5 becoming bigger, and the correlation coefficient were 0.803 and 0.726 respectively. The survival was better when patients with SUV value<9.0 than those with SUV value≥9.0. (5) In term of protecting the normal tissue, using PET/CTsuv2.5 image to defined target volum has a certain advantage over that using CT image alone.
Conclusion: (1) The lesion length of GTV referenced by CT image was the longest, PET/CT40%suvmax was the shortest. The length of PET/CTsuv2.5 was close to with esophageal barium esophagogram. (2) CT was better than PET/CT in term of determining clinical T stage of esophageal carcinoma, while PET/CT diagnosis the N stage was higher than CT, but no significantly difference.(3) The SUV value were increasing with the lesion volume and length becoming bigger, SUV 9.0 of esophageal carcinoma may be regarded as a practical indexes to determine prognosis. (4)It is hopeful to increase accuracy defining GTV targe range according to the length area of PET/CTsuv2.5.
Part 2: Comparison of endoscopic ultrasonography with computed tomography in the clinical stage of esophageal carcinoma
Objective: To compare endoscopic ultrasonography (EUS) with computed tomography (CT) and combined application of both in preoperative T, N stage of esophageal carcinoma.
Methods: 48 patients with respectable thoracic esophageal carcinoma received both EUS and CT examination preoperatively, on both of which the T and N stage were compared with the postoperative pathological TNM stage.
Results: (1) The diagnosis accuracy rates were 77.1%(37/48)and 75.0%(36/48)for T and N stage with preoperational EUS of esophageal carcinoma respectively, furthermore the accuracy rates were 87.5%, 57.1%, 94.1% and 100% for stage T1, T2, T3 and T4 respectively, and the accuracy rates were 78.6% and 70.0% for stage N0 , N1. (2) The diagnosis accuracy rates were 52.1%(25/48)and 77.1%(37/48)for T and N stage with preoperational CT of esophageal carcinoma respectively, furthermore the accuracy rates were 37.5%, 33.3%, 81.2% and 100% for stage T1, T2, T3 and T4 respectively, and the rates were 78.6%, 75.0% for stage N0 , N1. (3) It was obviously that diagnosis accuracy rate was higher in EUS than CT for T1-2 stage(χ2=5.586,P=0.018), but no clearly difference between T3-4 and N stage(P>0.05). (4) The diagnosis accuracy rates were 79.2%(38/48)and 77.1%(37/48)for T and N stage with preoperational EUS combined CT of esophageal carcinoma respectively, among which the accuracy rates were 87.5%, 71.4%, 82.3% and 100% for stage T1, T2, T3 and T4 respectively, and the rates were 78.6%, 75.0% for stage N0 , N1. (5) It was clear that only the Kappa value of preoperative CT scan in T stage was poor (Kappa value<0.4), the Kappa values for CT scan in N stage, as well as preoperative EUS in T and N stage were good (0.4 Conclusion: (1) The diagnosis accuracy rates to esophageal carcinoma in T and N stage were rather high, particularly in term of early diagnosis in T stage. (2) With a short diameter≥7.5mm lymph node-positive lymph nodes as a diagnostic criteria, the detection accuracy increased probably. (3) Combined application of EUS and CT may improve accuracy clinical stage to esophageal carcinoma.
Part 3: Correlation analysis between GTV-T volume and clinical stage and prognosis of esophageal carcinoma patients treated by three-dimensional conformal radiotherapy(3DCRT)
Objective: To evaluate the accuracy of clinical stage of esophageal carcinoma and to assess prognosis applying the size of tumor volume.
Methods: From Jul 200l to Dec 2006, 375 patients with esophageal carcinoma treated by 3DCRT were retrospectively analyzed. In consideration of the results of esophageal barium esophagogram and electronic endoscopy, We sketched target area, measured tumor length, horizontal diameter and volume in CT image of TPS system. GTV-T stage was carried out to these patients as classification standard of clinical T stage of esophageal carcinoma. We proposed the clicial stage of these patients combining lymph node metastasis, furthermore we evaluated the accuracy of the classification standard referencing prognosis of these patients.
Results: (1) The foIlow up rate was 94.7% by Dec 2010. The 1-,3-and 5-year local control rates were 80.5%, 53.7% 44.9% respectively.The 1-,3-and 5-year survival rates were 67.2% ,29.4% 19.0% respectively, with a median survival time of 19 months.(2) Corresponding to pathological stage T, GTV-T volume were classified with 4 levels according to≤30cm3,>30～≤60cm3,>60～≤90cm3 and>90cm3. According to survival curve of patients, there was no significantly difference between stage T3 and T4(P=0.556), while obvious differences among other stages T(P<0.001). GTV-T volume were classified with 3 levels according to T1, T2 and T3+4, there was significantly difference among each groups(χ2=48.73,P=0.000). (3) The 5-year survival rate was 24.5% of 217 cases of N0 stage esophageal carcinoma patients , while the rate was 10.4% of 158 cases of N1-2 stage patients. There was significantly difference between two group(sχ2=32.71,P=0.000). (4) Clinical stage of esophageal carcinoma were divided into stageⅠ,ⅡandⅢaccording to stage T1, T2 and T3+4 of GTV-T volume. The patients were classified as stageⅣ, who were N2 stage or distant metastasis. The 5-year survival rate were 32.7%, 25.8%,10.6% and 6.9% respectively(χ2=75.68,P=0.000). (5) Univariate analysis showed that the degree of dysphagia, tumor length, the largest diameter of lesion in CT image, T stage, N stage, clinical TNM stage, short-term effect, grades of acute irradiated esophagitis and grades of acute irradiated pneumonery were prognostic factors.Multivariate analysis revealed tumor length, clinical TNM stage, chemotherapy and grades of acute irradiated esophagitis were independent prognostic factors.
Conclusion: (1) GTV-T volume was a good prognosis factor according to three-class by stage T1, T2 and T3+4. (2) The patients of stage N0 had a better prognosis than stage N1-2 in esophageal carcinoma. (3) In responding to GTV-T three-class stage, clinical four-class stage could reflect prognosis survival better. (4) Tumor length, clinical TNM stage, chemotherapy and grades of acute irradiated esophagitis were independent prognostic factors.
Part 4: The value of protein expression PTTG and MMP-9 with clinical stage of esophageal carcinoma
Objective: To explore the function of PTTG and MMP-9 protein expression in invasion and metastasis of esophageal carcinoma, and evaluate their relationship with clinical stage of esophageal carcinoma.
Methods: Immunohistochemistry SP was used to check the protein expression of PTTG and MMP-9 in biopsy tissue specimen of 84 cases esophageal carcinoma, and analysed the relationship between protein expression level and clinical stage grades.
Results: (1) Positive rates of PTTG and MMP-9 protein expression were 69.05% and 61.90% in biopsy tissue of esophageal carcinoma. There have a correlation between the protein expression of PTTG and MMP-9(r=0.588,p=0.000). (2) Positive rate of PTTG protein expression was 83.33% in stage T3-4,which was higher than that in stage T1-2 54.76%(P=0.004). Positive rate of MMP-9 protein expression was 80.95% in stage T3-4,which was higher than that in stage T1-2 42.86%(P=0.000). (3) Positive rate of PTTG protein expression was 97.06% in lymph metastasis group,which was higher than that in non-lymph metastasis group 50.00%(P=0.000). Positive rate of MMP-9 protein expression was 91.18% in lymph metastasis group,which was higher than that in non-lymph metastasis group 42.00%(P=0.000). (4) Positive rate of PTTG protein expression was 100% in patients with distant metastasis,which was higher than that no distant metastasis 61.76%(P=0.001). Positive rate of MMP-9 protein expression was 93.75% in patients with distant metastasis,which was higher than that no distant metastasis 54.41%(P=0.002). (5) Positive rate of PTTG protein expression was 96.00% in clinical stageⅢ-Ⅳ,which was higher than that in stageⅠ-Ⅱ57.63%(P=0.000). Positive rate of MMP-9 protein expression was 96.00% in clinical stageⅢ-Ⅳ,which was higher than that in stageⅠ-Ⅱ47.46%(P=0.000). (6) The correlation coefficient were 0.309, 0.500, 0.380 between PTTG protein expression and Stage T, N, TNM respectively, and presented the positive correlation, (P<0.05). The correlation coefficient were 0.392, 0.497, 0.457 between MMP-9 protein expression and Stage T, N, TNM respectively, and presented the positive correlation, too (P<0.05). (7) It was showed that the long-term survival rate of stage T1-2, stageⅠ-Ⅱwere higher than those of stage T3-4, stageⅢof the total 48 poseoperative esophageal carcinoma patients, while it was no significantly difference compaired with N0 and N1 stage.
Conclusion: (1) PTTG and MMP-9 protein were showed high expression in biopsy tissue of esophageal carcinoma, and the two sorts of protein expression had a positive correlation. (2) Positive rate of PTTG and MMP-9 protein expression were obviously higher in patients with lymph node metastasisthan protein than those without lymph node metastasis. It was showed that high protein expression was correlation to lymph node metastasis status. (3) Protein expression of PTTG and MMP-9 were positively correlation to clinical stage of esophageal carcinoma. The later the tumor stage, the higher the expression, illustrated PTTG and MMP-9 genes playing an important role in occurring, development, invasion and metastasis of esophageal carcinoma.
众所周知,食管癌手术病理TNM分期标准能准确指导预后,但多数患者就诊时已为中晚期,失去手术治疗机会,因此不能准确地进行TNM分期。目前已有学者提出根据CT和食管钡餐造影为基础的分期标准,对指导食管癌预后有较好的参考价值,但分期标准比较复杂,临床应用不够方便,为此拟根据CT扫描和钡餐造影显示的肿瘤体积大小作为T分期的标准,为非手术治疗食管癌提供更简便、更理想的临床分期方法。
目前国内外已有根据食管癌CT或CT结合EUS、PET的临床分期,但尚未检索到食管癌影像学分期与肿瘤分子标志物结合的分期系统,因此该分期的提出既考虑了传统影像学指标,又结合了代表食管癌生物学行为的分子指标,争取为食管癌疗前准确地选择治疗方案提供坚实的理论基础,在个体化治疗方面提供循证医学的证据,以此来改善食管癌患者的长期生存及生存质量,为攻克食管癌这一世界难题迈上新的台阶!
第一部分:18F-FDG PET/CT和CT对食管癌临床分期的价值
目的:评价18F-FDG PET/CT和CT判定食管癌T、N分期的敏感性、特异性及准确性,确定PET/CT在食管癌术前分期中的价值,并探讨SUV值与食管癌预后的相关性。
方法:29例食管癌患者术前均行PET/CT和CT扫描,分别进行T、N分期,并与术后病理分期进行对照分析。同时将重建图像传输至三维治疗计划系统,参照不同标准分别勾画靶区,比较不同标准下靶区勾画的差异及对正常组织受量的影响。
结果:(1)不同检测方法所得病变长度依次为CT>PET/CTsuv2.5>食管钡餐造影>PET/CT40%suvmax>电子胃镜;与食管钡餐造影长度最为接近的是PET/CTsuv2.5长度。(2)与术后病理证实的T、N分期结果比较,PET/CT扫描对食管癌术前T、N分期诊断准确率分别为44.8%和93.1%,CT扫描对食管癌术前T、N分期诊断的准确率分别为69.0%和79.3%。CT扫描对判断T分期的准确率明显高于PET/CT,PET/CT扫描对判断N分期的准确率虽高于CT,但未显示出统计学差异。(3)术前PET/CT扫描检测的T、N分期与术后病理T、N分期的一致性系数Kappa值分别为0.254和0.948;术前CT扫描检测的T、N分期与术后病理T、N分期的一致性系数Kappa值分别为0.568和0.704;仅术前PET/CT扫描检测T分期的一致性较差(Kappa值<0.4);术前PET/CT扫描检测N分期、术前CT扫描检测T、N分期一致性均较好(Kappa值>0.4)。(4) SUV值与PCT/CTsuv2.5显示病变长度及体积呈正相关,r值分别为0.803及0.726;SUV值<9.0患者预后好于SUV值≥9.0患者。(5)采用PET/CTsuv2.5图像勾画靶区,较CT图像勾画靶区后制定的放疗计划,在降低周围正常组织受量方面具有一定优势。
结论:(1) CT勾画的GTV长度最长,PET/CT40%suvmax最短,PET/CTsuv2.5与食管钡餐造影显示的长度最为接近。(2)CT在判断食管癌临床T分期方面较PCT/CT具有一定优势,PET/CT扫描对判断N分期的准确率虽高于CT,但未显示出统计学差异。(3) SUV值与食管癌病变长度、体积及分期成正相关;SUV临界值9.0可以作为一项实用的判断预后指标。(4)依据PET/CTsuv2.5勾画靶区,有望提高GTV勾画的准确性和精确性。
第二部分:超声内镜结合CT扫描在食管癌临床分期中的应用
目的:比较超声内镜(EUS)、CT扫描及两者联合应用在判定胸段食管癌术前T、N分期中的应用价值。
方法: 48例手术治疗食管癌患者术前均行EUS检查和CT扫描,同时分别进行T、N分期,并与术后病理分期进行对照分析。
结果: (1)食管癌术前EUS检查T、N分期的诊断准确率分别为77.1%(37/48)、75.0%(36/48),其中T1、T2、T3、T4期诊断准确率分别为87.5%、57.1%、94.1%、100% ,N0、N1期诊断准确率分别为78.6%、70.0%。(2)食管癌术前CT检查T、N分期的诊断准确率分别为52.1%(25/48)和77.1%(37/48),其中T1、T2、T3、T4期诊断准确率分别为37.5%、33.3%、81.2%、100% ,N0、N1期诊断准确率分别为78.6%、75.0%。(3) EUS对判断T1-2期的准确率明显高于CT(χ2=5.586,P=0.018),而对于T3-4期及N分期的判断两者则无明显差别(P>0.05)。(4)EUS联合CT检查T、N分期的诊断准确率分别为79.2%(38/48)和77.1%(37/48),其中T1、T2、T3、T4期诊断准确率分别为87.5%、71.4%、82.3%、100% ,N0、N1期诊断准确率分别为78.6%、75.0%。(5)仅术前CT扫描检测T分期的一致性较差(Kappa值<0.4),术前CT扫描检测N分期、术前EUS检测T、N分期及两者联合应用检测T、N分期的一致性均较好(0.4
第三部分:食管癌三维适形放疗GTV-T体积与临床分期及预后的相关性分析
目的:应用肿瘤体积大小评价食管癌临床分期标准的准确性、符合程度及与预后的关系
方法:收集2001年7月至2006年12月在我院接受根治性三维适形放疗(3DCRT)的375例食管癌患者的临床资料,参照食管钡餐造影及电子胃镜检查结果,于TPS系统CT体层图像,准确勾画肿瘤靶区,测算肿瘤长度、横径及体积大小,对该组病例进行GTV-T分期,选择出合适的GTV-T体积分级标准,并结合区域淋巴结转移情况进行临床分期,分析验证其准确性、符合程度,以期为食管癌治疗前分期及预后评估提供依据。
结果:(1)随访截至2010年12月31日,随访率为94.7%。自放疗之日起计算,全组1、3、5年局控率分别为80.5%、53.7%、44.9%,生存率分别为67.2%、29.4%、19.0%,中位生存期19个月。(2)与病理T分期对应,将GTV-T体积按≤30cm3、>30～≤60cm3、>60～≤90cm3、>90cm3分为四级, 5年生存率之间比较,T3与T4级之间差异无显著性意义(P=0.556),其余各T分级之间的生存差异具有显著性,(P<0.001),按T1、T2、T3+4进行GTV-T体积三分级,各组间差异均具有显著性意义(χ2=48.73,P=0.000)。(3)该组食管癌患者临床N0分期217例,5年生存率为24.5%,N1-2期患者158例,5年生存率10.4%,两者比较,差异具有显著性意义(χ2=32.71,P=0.000)。(4)对应GTV-T体积T1、T2、T3+4三分级,将食管癌临床分期对应分为Ⅰ、Ⅱ、Ⅲ期,将出现N2期或远处转移的患者,全部归入Ⅳ期,5年生存率分别为32.7%、25.8%、10.6%、6.9%,生存差异具有显著性意义(χ2=75.68,P=0.000)。(5)单因素分析显示疗前进食情况、肿瘤长度、病变横径、GTV-T体积、N分期、临床分期、近期疗效、急性放射性食管炎、急性放射性肺炎均为影响预后因素。Cox多因素分析显示GTV-T体积、N分期、急性放射性食管炎、疗前进食情况及化疗为独立预后影响因素。
结论:(1)GTV-T按T1、T2、T3+4三分级法能较好的反映预后生存。(2)无区域淋巴结转移N0者较有区域或非区域淋巴结转移N1-2者预后好。(3)对应GTV-T三分级的临床四分期法,亦能较好的反应预后生存。(4)GTV-T体积、N分期、急性放射性食管炎、疗前进食情况及化疗为独立预后影响因素。
第四部分:PTTG和MMP-9蛋白表达在食管癌临床分期中的价值
目的:研究PTTG和MMP-9在食管癌组织中的表达和相关性,探讨PTTG在食管癌侵袭转移中的作用及与食管癌临床分期的关系。
方法:应用免疫组化SP法检测84例食管癌组织中PTTG和MMP-9的蛋白表达情况,并结合临床病理参数进行分析。
结果:(1)PTTG在食管癌组织中的阳性表达率为69.05%,MMP-9在食管癌组织中的阳性表达率为61.90%。PTTG和MMP-9蛋白表达呈正相关,相关系数r=0.588(。2)PTTG蛋白在T3-4期患者阳性表达率83.33%,高于T1-2期阳性表达率54.76%(P=0.004)。MMP-9蛋白在T3-4期患者阳性表达率80.95%,高于T1-2期阳性表达率42.86%(P=0.000)。(3)PTTG蛋白在有淋巴结转移组阳性表达率为97.06%,高于无淋巴结转移组50.00%(P=0.000)。MMP-9蛋白在有淋巴结转移组阳性表达率为91.18%,高于无淋巴结转移组42.00%(P=0.000)。(4)发生远处转移者PTTG蛋白阳性表达率高于未发生远转者,分别为100.0%和61.76%(P=0.001)。MMP-9蛋白阳性表达率也高于未发生远转者,分别为93.75%和54.41%,(P=0.002)。(5)临床Ⅲ-Ⅳ期PTTG阳性表达率为96.00%,高于Ⅰ-Ⅱ期者57.63%(P=0.000)。临床Ⅲ-Ⅳ期MMP-9阳性表达率为96.00%,高于Ⅰ-Ⅱ期者47.46%(P=0.000)。(6)PTTG蛋白表达与T分期、N分期、TNM分期的相关系数r分别为0.309、0.500、0.380,均呈正相关,P<0.05。MMP-9蛋白表达与T分期、N分期、TNM分期的相关系数r分别为0.392、0.497、0.457,均呈正相关,P<0.05。(7)EUS结合PTTG和MMP-9蛋白阳性指数进行分期,其检测T、TNM分期及EUS单独应用检测比较,与术后病理分期的一致性系数Kappa值未见明显差异。EUS单独应用判定N分期时,N0期与N1期患者生存未见明显差异;EUS与蛋白表达结合判定N分期时,N0期与N1期患者预后出现显著性差异,P<0.05。
结论:(1)PTTG和MMP-9蛋白在食管癌组织中均呈高表达,且两者蛋白表达呈正相关。(2)有淋巴结转移者较无淋巴结转移者PTTG和MMP-9蛋白表达阳性率明显增加,提示其高表达与食管癌淋巴结转移状态密切相关。(3)PTTG和MMP-9蛋白表达与食管癌临床分期显著正相关,肿瘤期别越晚,表达越高,提示PTTG和MMP-9在食管癌发生、发展及侵袭转移过程中起重要作用。
Esophageal carcinoma is one of the most frequently malignant tumors suffered by human beings, and leads to death of about 300,000 people annually worldwide. China is known as a country with high incidence rate of esophageal carcinoma, and each year about 160,000 people die due to this diaease, the number of death patients caused by esophageal carcinoma were nearly a quarter by all sorts of malignancies. The rates of incidence and death were very high, however, most of the patients have been classified as middle and late phase when they come to hospital for examination, and no chances were cured by operation, so the radiotherapy have been the major treatment measures. Clinical staging is an important prognosis factor after radiotherapy for esophageal carcinoma. At present, there are no accepted standards about clinical stage for esophageal carcinoma patients with non-operational treatment. Nowsdays, it has been a focused problem how to select a reasonable treatment according to the preoperatial clicial stage, and how to improve treatment effect and precisely evaluat prognosis.
It is generally known that pathological TNM stage can predict the prognosis of esophageal carcinoma patients. However, most of the patients have been classified as middle and late phase when they come to hospital for examination and clinical treatment, and no chances treated by surgery. There is no accutate TNM stage available for these group patients. Presently, some scholars have suggested some standards based on CT image and barium esophagogram, which resulted in a better evaluating prognosis of non-operation esophageal carcinoma, but these standards were relevantly complicated, and it was not convenient enough to use in clinic practice. Therefore, this study is planning to use the volume of primary tumor which indicated by CT image and barium esophagogram as the standards of T stage for those non-operational patients with esophageal carcinoma.
According to most studies, there have been clinical stage of esophageal carcinoma based on CT or combining CT with EUS, PET. But there have no one stage system combining the imaging parameters and tumor molecule marker of esophageal carcinoma. Therefore, in this study we combined traditional imaging parameters and molecule biological activities in clicial stage of esophageal carcinoma. The purpose was to supply the theory foundation of selecting reasonable treatment in esophageal carcinoma preoperation, provide evidence to individual treatment in term of evidence-based-medicine, to improve long-term survival and quality of esophageal carcinoma patients.
Part 1: Explore the value of 18F-FDG , PET/CT and CT scan for the clinical stage of esophageal carcinoma
Objective: To evaluate the sensitivity, specificity and accuracy of 18F-FDG, PET/CT and CT were used for T and N stage for esophageal carcinoma, determine the value of stage prior to operation of esophageal carcinoma, and explore the SUV value evaluating prognosis of esophageal carcinoma.
Methods: PET/CT and CT scan as well as T and N stage were carried out for 29 cases of preoperative esophageal carcinoma patients, those results were analyzed and compared with postoperative pathological TNM stage. Meantime, the constructed images were transmitted to 3D Treatment Planning System. Each primary lesion target volume was defined respectively according to different criteria. The size of target volume and the dose-volume of normal tissue were compared.
Results: (1) Primary lesion length of esophageal carcinoma was measured by using different ways,which following as: CT>PET/CTsuv2.5>esophageal barium esophagogram > PET/CT40%suvmax > electronic endoscopy. The length measured by using PET/CTsuv2.5 was close to that with esophageal barium esophagogram. (2) The accuracy rates of diagnosis the T and N stage were 44.8% and 93.1% for PET/CT scan preoperative esophageal carcinoma,and 69.0% and 79.3% for CT scan respectively. CT scan diagnosis the T stage was obviously higher than PET/CT in term of determining T staging, while PET/CT scan diagnosis the N stage was higher than CT, but there was no significantly difference. (3) The Kappa values for preoperative PET/CT scan in T and N stage compared with postoperative pathological T and N stage were 0.254 and 0.948 respectively. Meantime,the Kappa values of CT scan were 0.568 and 0.704 respectively. It was clear that only the Kappa value of preoperative PET/CT scan in T stage was poor (Kappa value<0.4), the Kappa values for PET/CT scan in N stage, as well as preoperative CT scan in T and N stage were good (Kappa value>0.4). (4) The SUV values were increasing with the lesion volume and length of PCT/CTsuv2.5 becoming bigger, and the correlation coefficient were 0.803 and 0.726 respectively. The survival was better when patients with SUV value<9.0 than those with SUV value≥9.0. (5) In term of protecting the normal tissue, using PET/CTsuv2.5 image to defined target volum has a certain advantage over that using CT image alone.
Conclusion: (1) The lesion length of GTV referenced by CT image was the longest, PET/CT40%suvmax was the shortest. The length of PET/CTsuv2.5 was close to with esophageal barium esophagogram. (2) CT was better than PET/CT in term of determining clinical T stage of esophageal carcinoma, while PET/CT diagnosis the N stage was higher than CT, but no significantly difference.(3) The SUV value were increasing with the lesion volume and length becoming bigger, SUV 9.0 of esophageal carcinoma may be regarded as a practical indexes to determine prognosis. (4)It is hopeful to increase accuracy defining GTV targe range according to the length area of PET/CTsuv2.5.
Part 2: Comparison of endoscopic ultrasonography with computed tomography in the clinical stage of esophageal carcinoma
Objective: To compare endoscopic ultrasonography (EUS) with computed tomography (CT) and combined application of both in preoperative T, N stage of esophageal carcinoma.
Methods: 48 patients with respectable thoracic esophageal carcinoma received both EUS and CT examination preoperatively, on both of which the T and N stage were compared with the postoperative pathological TNM stage.
Results: (1) The diagnosis accuracy rates were 77.1%(37/48)and 75.0%(36/48)for T and N stage with preoperational EUS of esophageal carcinoma respectively, furthermore the accuracy rates were 87.5%, 57.1%, 94.1% and 100% for stage T1, T2, T3 and T4 respectively, and the accuracy rates were 78.6% and 70.0% for stage N0 , N1. (2) The diagnosis accuracy rates were 52.1%(25/48)and 77.1%(37/48)for T and N stage with preoperational CT of esophageal carcinoma respectively, furthermore the accuracy rates were 37.5%, 33.3%, 81.2% and 100% for stage T1, T2, T3 and T4 respectively, and the rates were 78.6%, 75.0% for stage N0 , N1. (3) It was obviously that diagnosis accuracy rate was higher in EUS than CT for T1-2 stage(χ2=5.586,P=0.018), but no clearly difference between T3-4 and N stage(P>0.05). (4) The diagnosis accuracy rates were 79.2%(38/48)and 77.1%(37/48)for T and N stage with preoperational EUS combined CT of esophageal carcinoma respectively, among which the accuracy rates were 87.5%, 71.4%, 82.3% and 100% for stage T1, T2, T3 and T4 respectively, and the rates were 78.6%, 75.0% for stage N0 , N1. (5) It was clear that only the Kappa value of preoperative CT scan in T stage was poor (Kappa value<0.4), the Kappa values for CT scan in N stage, as well as preoperative EUS in T and N stage were good (0.4
Part 3: Correlation analysis between GTV-T volume and clinical stage and prognosis of esophageal carcinoma patients treated by three-dimensional conformal radiotherapy(3DCRT)
Objective: To evaluate the accuracy of clinical stage of esophageal carcinoma and to assess prognosis applying the size of tumor volume.
Methods: From Jul 200l to Dec 2006, 375 patients with esophageal carcinoma treated by 3DCRT were retrospectively analyzed. In consideration of the results of esophageal barium esophagogram and electronic endoscopy, We sketched target area, measured tumor length, horizontal diameter and volume in CT image of TPS system. GTV-T stage was carried out to these patients as classification standard of clinical T stage of esophageal carcinoma. We proposed the clicial stage of these patients combining lymph node metastasis, furthermore we evaluated the accuracy of the classification standard referencing prognosis of these patients.
Results: (1) The foIlow up rate was 94.7% by Dec 2010. The 1-,3-and 5-year local control rates were 80.5%, 53.7% 44.9% respectively.The 1-,3-and 5-year survival rates were 67.2% ,29.4% 19.0% respectively, with a median survival time of 19 months.(2) Corresponding to pathological stage T, GTV-T volume were classified with 4 levels according to≤30cm3,>30～≤60cm3,>60～≤90cm3 and>90cm3. According to survival curve of patients, there was no significantly difference between stage T3 and T4(P=0.556), while obvious differences among other stages T(P<0.001). GTV-T volume were classified with 3 levels according to T1, T2 and T3+4, there was significantly difference among each groups(χ2=48.73,P=0.000). (3) The 5-year survival rate was 24.5% of 217 cases of N0 stage esophageal carcinoma patients , while the rate was 10.4% of 158 cases of N1-2 stage patients. There was significantly difference between two group(sχ2=32.71,P=0.000). (4) Clinical stage of esophageal carcinoma were divided into stageⅠ,ⅡandⅢaccording to stage T1, T2 and T3+4 of GTV-T volume. The patients were classified as stageⅣ, who were N2 stage or distant metastasis. The 5-year survival rate were 32.7%, 25.8%,10.6% and 6.9% respectively(χ2=75.68,P=0.000). (5) Univariate analysis showed that the degree of dysphagia, tumor length, the largest diameter of lesion in CT image, T stage, N stage, clinical TNM stage, short-term effect, grades of acute irradiated esophagitis and grades of acute irradiated pneumonery were prognostic factors.Multivariate analysis revealed tumor length, clinical TNM stage, chemotherapy and grades of acute irradiated esophagitis were independent prognostic factors.
Conclusion: (1) GTV-T volume was a good prognosis factor according to three-class by stage T1, T2 and T3+4. (2) The patients of stage N0 had a better prognosis than stage N1-2 in esophageal carcinoma. (3) In responding to GTV-T three-class stage, clinical four-class stage could reflect prognosis survival better. (4) Tumor length, clinical TNM stage, chemotherapy and grades of acute irradiated esophagitis were independent prognostic factors.
Part 4: The value of protein expression PTTG and MMP-9 with clinical stage of esophageal carcinoma
Objective: To explore the function of PTTG and MMP-9 protein expression in invasion and metastasis of esophageal carcinoma, and evaluate their relationship with clinical stage of esophageal carcinoma.
Methods: Immunohistochemistry SP was used to check the protein expression of PTTG and MMP-9 in biopsy tissue specimen of 84 cases esophageal carcinoma, and analysed the relationship between protein expression level and clinical stage grades.
Results: (1) Positive rates of PTTG and MMP-9 protein expression were 69.05% and 61.90% in biopsy tissue of esophageal carcinoma. There have a correlation between the protein expression of PTTG and MMP-9(r=0.588,p=0.000). (2) Positive rate of PTTG protein expression was 83.33% in stage T3-4,which was higher than that in stage T1-2 54.76%(P=0.004). Positive rate of MMP-9 protein expression was 80.95% in stage T3-4,which was higher than that in stage T1-2 42.86%(P=0.000). (3) Positive rate of PTTG protein expression was 97.06% in lymph metastasis group,which was higher than that in non-lymph metastasis group 50.00%(P=0.000). Positive rate of MMP-9 protein expression was 91.18% in lymph metastasis group,which was higher than that in non-lymph metastasis group 42.00%(P=0.000). (4) Positive rate of PTTG protein expression was 100% in patients with distant metastasis,which was higher than that no distant metastasis 61.76%(P=0.001). Positive rate of MMP-9 protein expression was 93.75% in patients with distant metastasis,which was higher than that no distant metastasis 54.41%(P=0.002). (5) Positive rate of PTTG protein expression was 96.00% in clinical stageⅢ-Ⅳ,which was higher than that in stageⅠ-Ⅱ57.63%(P=0.000). Positive rate of MMP-9 protein expression was 96.00% in clinical stageⅢ-Ⅳ,which was higher than that in stageⅠ-Ⅱ47.46%(P=0.000). (6) The correlation coefficient were 0.309, 0.500, 0.380 between PTTG protein expression and Stage T, N, TNM respectively, and presented the positive correlation, (P<0.05). The correlation coefficient were 0.392, 0.497, 0.457 between MMP-9 protein expression and Stage T, N, TNM respectively, and presented the positive correlation, too (P<0.05). (7) It was showed that the long-term survival rate of stage T1-2, stageⅠ-Ⅱwere higher than those of stage T3-4, stageⅢof the total 48 poseoperative esophageal carcinoma patients, while it was no significantly difference compaired with N0 and N1 stage.
Conclusion: (1) PTTG and MMP-9 protein were showed high expression in biopsy tissue of esophageal carcinoma, and the two sorts of protein expression had a positive correlation. (2) Positive rate of PTTG and MMP-9 protein expression were obviously higher in patients with lymph node metastasisthan protein than those without lymph node metastasis. It was showed that high protein expression was correlation to lymph node metastasis status. (3) Protein expression of PTTG and MMP-9 were positively correlation to clinical stage of esophageal carcinoma. The later the tumor stage, the higher the expression, illustrated PTTG and MMP-9 genes playing an important role in occurring, development, invasion and metastasis of esophageal carcinoma.
引文
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