【作者】 杨玉海；

【导师】 柳澄；

【作者基本信息】 山东大学 ， 影像医学与核医学， 2011， 博士

【摘要】 目的：利用ROC曲线(receiver operating characteristic curve,受试者运行特征曲线)分析方法,评价多层螺旋CT(multi-slice spiral computed tomography, MSCT)和18F-FDG PET/CT在鉴别孤立性肺结节(solitary pulmonary nodule, SPN)良恶性中的应用价值,进而探讨孤立性肺结节的综合性影像学诊断的可靠性和可行性,以及在孤立性肺结节的影像学检查中多层螺旋CT和18F-FDG PET/CT如何优化选择和联合应用的问题。材料与方法：行多层螺旋CT检查的孤立性肺结节217个,均经手术和／或穿刺活检组织病理结果或随访结果证实,由3位资深的CT诊断医师以随机顺序对每个孤立性肺结节的多层螺旋CT图像进行仔细地独立阅读和分析,评价结果采用意见一致性原则。在阅片时,观察者不被告知任何临床资料,不被限制读片时间,不改变读片习惯。首先,观察者根据自己的经验和主观印象,将孤立性肺结节按五等级法进行评价：1=肯定良性,2=可能良性,3=不确定,4=可能恶性,5=肯定恶性。然后,依据孤立性肺结节各种特征性的多层螺旋CT表现对其进行综合评分,将孤立性肺结节常见的与其良恶性倾向密切相关的各CT征象作为评分基础,评分标准为：具有显著恶性倾向为1、具有不显著恶性倾向为0.5、无恶性倾向或具有良性倾向为O。行PET/CT检查的孤立性肺结节98个,均经手术和／或穿刺活检组织病理结果或随访结果证实,用目测法和半定量法对18F-FDG PET/CT图像进行阅读和分析。首先,由3位资深的核医学医师以随机顺序对所有孤立性肺结节的18F-FDG PET/CT图像分别予以独立阅片,评价结果采用意见一致性原则。在阅片时,观察者不被告知任何临床资料,不被限制读片时间,不改变读片习惯。通过目测,对每个孤立性肺结节的放射性摄取程度根据五等级法做出分析和评价：0=无放射性摄取,1=放射性摄取程度低于纵隔,2=放射性摄取程度接近纵隔,3=放射性摄取程度介于纵膈与肝脏之间,4=放射性摄取程度高于肝脏。然后,将相同大小的感兴趣区(region of interest, ROI)分别置于孤立性肺结节和对侧肺的相应正常部位,孤立性肺结节的ROI选择FDG摄取最强的部位,分别测量孤立性肺结节ROI(T)和对侧正常肺ROI(N)的放射性活度(activity), ROI大小应包括最大活度值90%以上的区域,再计算对比率(contrast ratio, CR),将其作为每个孤立性肺结节的FDG放射性摄取指标：CR=(T—N)/(T+N)。同时,测量并由计算机程序自动计算出每个孤立性肺结节ROI的标准摄取值(standardized uptake value,SUV=放射性活度／注射计量／体重),以与CR值进行对照。将通过上述方法的影像学图像资料分析所得出的结果,分别与孤立性肺结节的病理或随访结果(即所谓“金标准”)对照,再根据孤立性肺结节的最大径(D),以2.Ocm<D≤3.0cm和D≤2.0cm分组,分别进行分类计数。按照分类计数结果,以孤立性肺结节的多层螺旋CT评价等级、综合评分值和PET/CT的目测等级、CR值分别作为分类值,用Microsoft Excel 2007软件分别绘制各自评价孤立性肺结节良恶性的ROC曲线。采用Z检验对ROC曲线下面积(area under curve,AUC)进行统计学分析,P<0.05,认为差异具有统计学意义。根据约登(Youden)指数,选取多层螺旋CT综合评分和PET/CT的CR值各自鉴别孤立性肺结节良恶性诊断的最佳阈值,将多层螺旋CT评分≥最佳阈值的孤立性肺结节定义为阳性、评分<最佳阈值的孤立性肺结节定义为阴性,将PET/CT的CR≥最佳阈值的孤立性肺结节定义为阳性、CR<最佳阂值的孤立性肺结节定义为阴性。将评价结果与孤立性肺结节的病理或随访结果(“金标准”)进行对照,在多层螺旋CT或PET/CT上表现为阳性的恶性结节和良性结节分别定义为真阳性(TP)和假阳性(FP)、表现为阴性的恶性结节和良性结节分别定义为假阴性(FN)和真阴性(TN)。分别计算各自的灵敏度、特异度、准确度、阳性预测值和阴性预测值(灵敏度=TP/TP+FN,特异度=TN/TN+FP,准确度=TP+TN/TP+FP+TN+FN,阳性预测值=TP/TP+FP,阴性预测值=TN/TN+FN).采用x2检验进行统计学分析和比较,P<0.05,认为差异具有统计学意义。行18F-FDG PET/CT检查的98个孤立性肺结节,均在前一周时间内进行了规范的多层螺旋CT检查,通过对每个孤立性肺结节的多层螺旋CT和18F-FDG PET/CT图像的综合性分析,根据每个孤立性结节的评价等级以及由多层螺旋CT综合评分或PET/CT的CR值与相应的最佳阈值比较而获得的评价结果,将孤立性肺结节的良恶性诊断进行两种检查方法的联合评价。按照一致性原则,将在多层螺旋CT和18F-FDG PET/CT图像上良恶性评价一致的孤立性肺结节,仍然维持其良恶性诊断。在多层螺旋CT和18F-FDG PET/CT图像上良恶性评价不一致的孤立性肺结节,采取以下原则进行评价：如果多层螺旋CT的评价等级为5(即肯定恶性),则不考虑PET/CT的FDG摄取程度,将该孤立性肺结节定性为恶性；如果多层螺旋CT的评价等级为1(即肯定良性),则不考虑PET/CT的FDG摄取程度,将该孤立性肺结节定性为良性；如果多层螺旋CT的评价等级为2、3、4(即不能确定恶性或良性)时,则依据PET/CT的FDG摄取程度评价孤立性肺结节的良恶性,若PET/CT的评价等级为2、3、4(即18F-FDG摄取程度为中等以上,甚至高于肝脏)或CR≥最佳阈值则该孤立性肺结节被定性为恶性,若PET/CT的评价等级为0、1(即18F-FDG摄取程度低于纵隔,甚至无放射性摄取)且CR<最佳阈值则该孤立性肺结节被定性为良性,亦即PET/CT的评价结果否决了多层螺旋CT的评价结果。将联合评价结果与孤立性肺结节的病理或随访结果(“金标准”)进行对照,计算相应的灵敏度、特异度、准确度、阳性预测值和阴性预测值,并与单独PET/CT的评价效能加以比较,采用x2检验进行统计学分析,P<0.05,认为差异具有统计学意义。结果：行多层螺旋CT检查的217个孤立性肺结节,恶性结节146个,良性结节71个。所有恶性结节均经手术和／或穿刺活检病理结果证实,包括腺癌123个(其中包含细支气管肺泡癌11个、瘢痕癌2个)、鳞癌12个、小细胞癌5个大细胞癌3个、单发转移瘤3个；良性结节包括结核19个、错构瘤16个、非特异性炎症15个、肺隐球菌病6个、炎性假瘤3个、神经纤维瘤1个,均经手术和／或穿刺活检病理结果证实,另有11个孤立性肺结节经正规抗炎或抗结核治疗后缩小或消失而定性为良性结节。恶性结节最大径1.0～3.0cm,良性结节最大径0.8-3.0cm,分别平均为1.92cm和1.87cm,差异无统计学意义。行PET/CT检查的98个孤立性肺结节,恶性结节69个,良性结节29个。所有恶性结节均经手术和／或穿刺活检病理结果证实,包括腺癌47个(其中包含细支气管肺泡癌6个、瘢痕癌2个)、鳞癌9个、小细胞癌5个、大细胞癌6个、单发转移瘤2个；良性结节包括结核12个、错构瘤5个、非特异性炎症5个、肺隐球菌病3个、炎性假瘤3个,均经手术和／或穿刺活检病理结果证实,另有1个孤立性肺结节经正规抗结核治疗后缩小而定性为良性结节。恶性结节最大径1.0-3.0cm,良性结节最大径0.8-3.0cm,分别平均为1.81cm和1.78cm,差异无统计学意义。多层螺旋CT评价2.0cm<D≤3.0cm孤立性肺结节良恶性的效能优于评价D≤2.0cm孤立性肺结节良恶性的效能,用多层螺旋CT综合评分评价2.0cm<D≤3.0cm和D≤2.0cm孤立性肺结节良恶性的最佳阈值分别为3.5和2.5,应用各自的最佳阈值,多层螺旋CT评价孤立性肺结节良恶性的诊断效能相应改善。多层螺旋CT评价最大径为2.0cm<D≤3.0cm孤立性肺结节良恶性,五等级法的诊断效能优于CT综合评分法；多层螺旋CT评价最大径为D≤2.0cm孤立性肺结节良恶性,综合评分法的诊断效能稍优于五等级法。18F-FDG PET/CT评价2.0cm<D≤3.0cm、D≤2.0cm孤立性肺结节良恶性的诊断效能基本相同,目测法和半定量法均是如此。以半定量法PET/CT评价2.Ocm<D≤3.0cm和D≤2.0cm孤立性肺结节良恶性的最佳阈值均为CR=0.45,且以半定量法PET/CT评价2.0cm<D≤3.0cm和D≤2.0cm孤立性肺结节良恶性的诊断效能稍优于目测法。评价最大径为2.0cm<D≤3.0cm孤立性肺结节的良恶性,18F-FDG PET/CT半定量法与多层螺旋CT的诊断效能无显著差异,而目测法则略逊于多层螺旋CT的诊断效能,多层螺旋CT的特异度较高；评价最大径为D≤2.0cm孤立性肺结节的良恶性,18F-FDG PET/CT的半定量法和目测法均优于多层螺旋CT的诊断效能,PET/CT的特异度较高。多层螺旋CT和18F-FDG PET/CT联合评价孤立性肺结节良恶性的诊断效能与单独的PET/CT相比显著提高,多层螺旋CT和18F-FDG PET/CT联合评价孤立性肺结节良恶性的灵敏度、特异度、准确度、阳性预测值、阴性预测值分别为97.10%、93.10%、95.92%、97.10%、93.10%。结论：随着多层螺旋CT的逐渐广泛应用,越来越多的孤立性肺结节被发现,虽然其大多数为良性,但是在孤立性肺结节的鉴别诊断中,肺癌仍然构成其重要的考虑内容,进一步检查或处理的目的是准确地鉴别良、恶性结节,以确保适当的治疗方案。因此,影像学检查的一个主要目的就是尽最大可能地准确鉴别孤立性肺结节的良恶性,一方面使恶性结节尽快得以切除,以阻止其继续生长和发生转移而影响患者预后,另一方面可使良性结节避免被施行不必要的创伤性检查和手术,防止患者承受不必要的医疗花费、痛苦和风险。近年来,多层螺旋CT和PET/CT已经明显改善了孤立性肺结节影像特征的显示和评价。本研究采用ROC曲线分析方法综合评价多层螺旋CT和PET/CT在鉴别孤立性肺结节良恶性方面的诊断效能,显示多层螺旋CT和PET/CT均具有明显的应用价值,但是对于不同大小、不同性质的孤立性肺结节来说,多层螺旋CT和PET/CT之间及其不同评价方法之间的诊断效能均存在差别,评价结果存在不同程度的不一致现象,将PET/CT和多层螺旋CT图像进行综合性分析和联合评价可明显提高孤立性肺结节良恶性鉴别诊断的准确性。本研究说明ROC分析方法在综合运用多层螺旋CT和PET/CT所提供的影像信息、全面评价孤立性肺结节的良恶性方面具有显著应用价值,使孤立性肺结节的良恶性评价结果得到明显改善,将评价结果与恶性概率等临床资料相结合,一定能为孤立性肺结节患者提供合理的处理策略和方案。更多还原

【Abstract】 Objective:To compare the role of MSCT (multi-slice spiral computed tomography) with 18F-FDG PET/CT (positron emission tomography, PET) in the imaging diagnosis to differentiate malignant from benign solitary pulmonary nodules (SPNs) with the use of receiver operating characteristic curve (ROC) analysis, by which to probe into the clinical use of the comprehensive imaging diagnosis in the characterization of a solitary pulmonary nodule (SPN) in order to answer the problem how to select the optimal project on the single or combining use of MSCT and F-FDG PET/CT in the clinical management of solitary pulmonary nodules.Materials and Methods:A retrospective study was performed involving the patients referred for the characterization of solitary pulmonary nodule with MSCT and 18F-FDG PET/CT between February 2001 and February 2011, for whom a pathologic diagnosis or follow-up result was available. In the study,217 solitary pulmonary nodules were examined with MSCT and 98 solitary pulmonary nodules were examined with 18F-FDG PET/CT, which were confirmed pathologically by surgery and/or needle biopsy or by follow-up.The MSCT or PET/CT images were read in consensus. The MSCT images of all 217 solitary pulmonary nodules were assessed and graded by three senior radiologists on the basis of malignant likelihood of morphological and density characteristics. The PET/CT images of all 98 solitary pulmonary nodules were interpreted by three nuclear medicine physicians. The blinded interpretation of MSCT or PET/CT images was performed. The radiologists and nuclear medicine physicians were all unaware of the patient’s history and PET/CT image findings or MSCT image results each other. Each observer independently read the MSCT or PET/CT images in random order. The observers were given unlimited time to view the images in each case and were allowed to vary their viewing distance. The solitary pulmonary nodules were analyzed by location, texture, axial dimension, and density or metabolic activity and visually scored on a 5-point scale from benign to malignant. According to the MSCT images, the solitary pulmonary nodules were scored as follows:1=definitely benign; 2= probably benign; 3=equivocal; 4=probably malignant; 5=definitely malignant. According to the PET/CT images, the locations of areas of abnormal tracer (18F-FDG) uptake were recorded and the degree of uptake was scored as follows:0=no uptake; 1=less than mediastinum; 2=equal to mediastinum; 3=between mediastinum and liver; 4=higher than liver. At the same time, MSCT images were evaluated and calculated the comprehensive score according to every morphological sign as follows: 1=definitely malignant likelihood; 0.5=probably or equivocal malignant likelihood; 0=definitely benign likelihood. Correspondingly, 18F-FDG PET/CT data were evaluated semi-quantitatively on the basis of the contrast ratio (CR) obtained as follows. The regions of interest (ROIs) were placed around the areas of abnormal uptake in the nodules and contra-lateral normal lung. Highest activities in the tumor ROI (T) and in the contra-lateral normal lung ROI (N) were measured. The CR was calculated by (T—N)/(T+N) in each nodule as an index of 18F-FDG uptake. In addition, the maximum standardized uptake value (SUVmax) was determined and analyzed respectively.Receiver operating characteristic curve (ROC) analysis was used to evaluate the observer’s performance in differentiating malignant from benign solitary pulmonary nodules by MSCT and 18F-FDG PET/CT. According to the size of maximum diameter (D), The solitary pulmonary nodules were classified as 2.0cm<D≤3.0cm and D≤2.0cm. The receiver operating characteristic (ROC) curves were respectively constructed and the optimal thresholds were determined for the diagnosis of characterization with regard to solitary pulmonary nodules of 2.0cm<D≤3.0cm and D≤2.0cm. ROC analysis was used to evaluate the efficiency of MSCT or 18F-FDG PET/CT in differentiating malignant from benign solitary pulmonary nodules. The area under the curve (AUC) was used as an index of diagnostic efficiency with MSCT or 18F-FDG PET/CT. A statistical analysis was done according to AUC values by Z-test. In the statistical analysis, a value of P<0.05 were considered significant.The optimal thresholds were selected with Youden’s index on the ROC curves. By the criterion of optimal thresholds, the solitary pulmonary nodules were defined as positive or negative. The results of MSCT and PET/CT were compared with pathological or follow-up results respectively. Positive MSCT and PET/CT findings with malignancy and benign nodules were defined as true positive (TP) and false positive (FP), respectively. Negative MSCT and PET/CT findings with malignancy and benign nodules were defined as false negative (FN) and true negative (TN), respectively. The diagnostic values of MSCT and PET/CT were assessed by calculating sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV). Sensitivity was calculated as TP/TP+FN, specificity as TN/TN+FP, accuracy as TP+TN/TP+FP+TN+FN, positive predictive value as TP/TP+FP, and negative predictive value as TN/TN+FN. All data were analyzed for significance by using the x2-test, values of P<0.05 were accepted as significance.The comprehensive imaging diagnosis in the characterization of a solitary pulmonary nodule was given by combining MSCT with PET/CT images. The images were interpreted as benign or malignant in consensus. In case of concordance between MSCT and PET/CT interpretation, the classification did not differ from the MSCT and PET/CT findings. The MSCT and PET/CT images were jointly reviewed. The combining interpretation could be described with the following rules:If the MSCT score was 5 (definitely malignant), then the solitary pulmonary nodule was considered malignant, regardless of the 18F-FDG uptake. If the MSCT score was 1 (definitely benign), then the solitary pulmonary nodule was considered benign, regardless of the 18F-FDG uptake. If the MSCT score was 2,3,4 (could not affirm to be malignant or benign), then the solitary pulmonary nodule was determined the nature according to the 18F-FDG uptake as follows. The solitary pulmonary nodule was considered malignant if the PET/CT rating was 2,3,4 (moderate uptake to uptake higher than the liver) or CR≥optimal thresholds, and the solitary pulmonary nodule was considered benign if the PET/CT rating was 0,1 (no uptake or uptake less than mediastinum) and CR<optimal thresholds. In these cases, the PET/CT findings overruled the MSCT findings. The diagnostic values of combining MSCT with PET/CT findings were assessed by calculating sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV). All data were analyzed and compared with single PET/CT by using the x2-test, values of P<0.05 were accepted as significance.Results:There were 146 malignant nodules and 71 benign nodules in the 217 solitary pulmonary nodules which were scanned by MSCT. There were 69 malignant nodules and 29 benign nodules in the 98 solitary pulmonary nodules which were examined by 18F-FDG PET/CT. All of malignant nodules were pathologically confirmed. The benign nodules were proved pathologically or by follow-up.Using pathology and follow-up results as the reference standard, the efficiency of MSCT as to the solitary pulmonary nodules of 2.0cm<D≤3.0cm excelled that as to the solitary pulmonary nodules of D≤2.0cm. The efficiency of MSCT by the 5-point scale method is better as to the nodules of 2.0cm<D≤3.0cm, and the efficiency of MSCT by comprehensive score was better as to the nodules of D≤2.0cm. The optimal thresholds of MSCT score were respectively 3.5 and 2.5 in the solitary pulmonary nodules of 2.0cm<D≤3.Ocm and D≤2.0cm. The efficiency of 18F-FDG PET/CT did not have significant difference in the solitary pulmonary nodules of 2.0cm<D≤3.0cm and D≤2.0cm, but the semi-quantitative analysis on the basis of CR was better than the visual analysis in characterizing a solitary pulmonary nodule. The optimal thresholds of CR were 0.45 all in the solitary pulmonary nodules of 2.0cm<D≤3.0cm and D≤2.0cm.As to the solitary pulmonary nodules of 2.0cm<D≤3.0cm, the efficiency of semi-quantitative analysis by PET/CT did not have significant difference from MSCT, but the visual analysis by PET/CT was a little inferior to MSCT. MSCT had the higher specificity (P<0.05 for PET/CT). In the solitary pulmonary nodules of D≤2.0cm, the efficiency of semi-quantitative analysis and visual analysis by PET/CT was better than MSCT. The specificity of PET/CT was higher (P<0.05 for MSCT).The comprehensive imaging diagnosis by combining MSCT images with PET/CT images demonstrated a more excellent performance in classifying solitary pulmonary nodules as benign or malignant. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of combining diagnosis by MSCT and 18F-FDG PET/CT were 97.10%,93.10%,95.92%,97.10%, 93.10%(P<0.05 for PET/CT).Conclusion:With the increasing use of MSCT, more solitary pulmonary nodules are being detected. Although the majority of these nodules are benign, lung cancer constitutes an important consideration in the differential diagnosis of solitary pulmonary nodules. The goal of management is to correctly differentiate malignant from benign nodules to ensure appropriate treatment. Recent technological advances in imaging, including MSCT and PET/CT, have improved nodule characterization and surveillance. Our study found MSCT and PET/CT all have a high accuracy for characterization of solitary pulmonary nodules. The usefulness of ROC analysis was obvious in the differential diagnosis of solitary pulmonary nodules with the comprehensive imaging characteristic obtained by MSCT and PET/CT. MSCT and PET/CT are synergistic to play an important role in the solitary pulmonary nodules not to be definitely diagnosed by MSCT. It is favorable for us to combine the diagnosis of solitary pulmonary nodules by MSCT and PET/CT with the malignant probability and to improve the treatment project of solitary pulmonary nodules in clinical practice. As a result, management strategies for the imaging evaluation of the solitary pulmonary nodules will continue to be evolved.更多还原