【作者】 黄文才；

【导师】 陆建平；

【作者基本信息】 第二军医大学 ， 影像医学与核医学， 2011， 博士

【摘要】 胰腺癌是严重威胁几类生命的癌症之一。在21世纪的今天，胰腺癌的诊治仍然是一个亟待解决的重大医学难题。胰腺癌患者临床预后极差，手术根治性切除是当前治疗胰腺癌唯一有效的治疗手段。但大多数患者在得到诊断时已经处于病情进展期，而仅有10—150%的患者具备接受手术切除的条件。长期以来，国内外学者一直努力致力于提高胰腺癌诊断水平，但包括B超，cT或MRI等各种检查手段对胰腺癌早期诊断的敏感性和特异性仍明显不够。目前，随着高场磁共振成像（MRI）系统、高性能梯度以及并行成像技术的发展，包括磁共振波谱（MRS）和弥散加权成像（【）WI)在内的多项MRI新技术开始越来越多地用于胰腺疾病的诊断评价。本研究中，我们在3T场强条件下对胰腺癌进行了DWI，质子¹HMRS和组织病理学研究，通过与慢性肿块型胰腺炎患者和正常对照组的比较对胰腺癌的I)WI、¹H MRS和病理组织学特征进行了分忻，并初步探讨了应用表观扩散系数（ADc）值和胆碱类代谢物（ccM）定量分忻对预测胰腺癌分化程度和增殖活性的可能性。第一部分：胰腺癌在体¹H MRS研究：与肿块型胰腺炎和正常胰腺的比较目的通过与肿块型胰腺炎和正常胰腺的比较，分忻胰腺癌的在体¹H磁共振波谱（MRS）特征并探讨胰腺代谢物比值定量分忻对胰腺癌的诊断价值。方法经医学伦理委员会批准并在获得患者的知情同意后，共27例胰腺癌（男／女，15／12；年龄，62．2±12．0岁）、11例肿块型慢性胰腺炎（男／女，7／4；年龄，52．5±11．4岁）及20例健康志愿者（男／女，15／5；平均年龄，38．6±17-2岁）被纳入接受单体素’H—MRS研究。胰腺癌、肿块型胰腺炎患者¹H．MRs检查与获得病理诊断的时间间隔不超过2周。分别对胰腺癌、肿块型胰腺炎和正常胰腺组织中的脂质相对含量（rLip，为脂质峰下面积与0—6pM所有峰下面积之比）和胆碱类代谢物（ccM）与各氨酸盐复台物（G1x）比值（ccM／G1x）进行定量分忻与比较，并采用操作者特征曲线（R0c）分忻进一步评价各代谢物指标在胰腺癌与肿块型胰腺炎鉴别诊断中的价值。结果与正常胰腺相比，胰腺癌’H．MRs以大的残余H：0峰和较小的Lip峰为特征，ccM峰大小不一，可能与肿瘤分化程度及肿瘤成分的不均质性有关；肿块型慢性胰腺’H．MRs以Lip峰大而突出，残余H₂O峰较小。正常胰腺组ccM／Glx比值（0．592±0．233；n=20）显著高于胰腺癌（0．367±0．094；n=27）（P=0．007）和肿块型慢]性胰腺炎（0．446：=0．039；n 11）（P 0．021）；两两比较，胰腺癌CCM／GIx比值比肿块型慢性胰腺炎更低（P 0．011）。肿块型慢性胰腺炎的相对脂质含量（rLip，0．725：=0．059）较正常胰腺高（0．645：=0．096），有统计学差异（P=0．020）；胰腺癌rLip值（0．420：=0．164）低于正常胰腺和肿块型慢性胰腺炎（P<0．001）。rLip以0．647作为截点值来鉴别胰腺癌与肿块型胰腺炎，ROC分忻中获得的敏感性和特异性分别为90．9％和92．6％；CCM／GIx以0．423作为截点值来鉴别胰腺癌和肿块型胰腺炎，ROC分忻得到的敏感性和特异性分别为81．8％和70．4％。结论：和正常胰腺和肿块型胰腺炎相比较，胰腺癌的·H波谱以脂质峰降低、残留水峰增加为特征；胰腺癌的胆碱类化台物含量和相对脂质含量减低。代谢物定量分忻对鉴别胰腺癌和肿块型慢性胰腺炎有重要价值。第二部分：AIIC值定量分析在胰腺癌诊断中的应用价值目的：通过与正常胰腺、肿块型胰腺炎比较，分忻胰腺癌在3T磁共振DWI上的影像特征现；探讨表观扩散系数（ADC）值定量分忻在胰腺癌定性诊断中的价值。方法：研究对象包括胰腺癌患者27例（男／女，15／12；年龄，62．2±12．0岁）、慢性肿块型胰腺炎患者（男／女，7／4；年龄，52．5±11．4岁）11例和健康志愿者20名（男／女，15／5；年龄，38．6±17．2岁）。对所有研宄对象，连续实施两组b值（b 0，500；0，1000s／mm。）不同的胰腺DWI检查。应用圆形感兴趣区（ROI）测量胰腺病灶和正常胰腺ADC值（ADC5 00．ADCl000）；并按公式rADC（ADC500--ADCl00（））／ADC500计算出ADC500与ADCl㈣间的变化率（rADC）。结果：在b⁵00或b-1000 s／mm2DWI图像上，胰腺癌与肿块型胰腺炎呈高信号肿块。同类ADC值比较，胰腺癌（ADC500，1．264：=0．153；ADCl000，1．111±0．133）和肿块型胰腺炎（ADC500 1．352：=0．114；ADCl㈣，1．210：=0．093）的ADC值低于正常胰腺组织（ADC5 00．1．983：=0．172；ADCl㈣，1．658：=0．145），两两比较均有显著性差异（P<0．001）。胰腺癌的ADC500和ADCl㈣较肿块型胰腺炎更低，P值分别为0．045和0．03。胰腺癌的ADC值变化率（rADC，[％]）为9．78：=3．50，低于肿块型慢性胰腺炎（12．76：=1．90）（P 0．116）和正常胰腺（17．62：=4．76）（P<0．001）。肿块型慢性胰腺炎和正常胰腺rADC相比也有统计学差异（P=0．003）。在ROC分忻，ADC5【)（）、ADCl㈣和rADC对鉴别胰腺癌和肿块型慢性胰腺炎的敏感性分别为72．7％、74．1％、72．7％，特异性分别为74．1％、81．8％、66．7％。结论：胰腺癌肿块内水分子扩散受限及做循环灌注减少较肿块型胰腺炎更为显著。I)WI结台ADc值定量分忻能为胰腺癌的诊断及其与肿块型胰腺炎的鉴别提供做观病理组织学方面的重要信息。第三部分：胰腺癌胆碱类代谢物、ADC值和I(i．67标记指数相关性研究目的：比较不同分化度胰腺癌的胆碱类代谢物（ccM）含量、ADc值和k一67标记指数，并进一步研究胰腺癌胆碱类代谢物含量、ADc值与k一67标记指数的相关性。方法：复习病理证实的胰腺癌患者（男／女，12／9；平均年龄62．8±12．6岁）21例，在手术前MRI/vIRs和术后病理组织学检查资料。对不同分化程度的胰腺癌的ccM含量、肿瘤ADc值和k一67抗原标记指数进行比较（Mann—whimev u检验），并进一步探讨胰腺癌ccM含量、ADc值与k一67抗原表达的相关性。结果：21例胰腺癌中，高一中分化胰腺癌14例（其中高分化癌3例），低分化腺癌7例；高一中度分化胰腺癌的k一67标记指数（40．99±7．56）显著小于低分化胰腺癌（59．91±8．61），P值等于0．（）(】1。胰腺单体素’H．MR。s研究中，14例高一中度分化胰腺癌的ccM／Glx比值为54．5±19．7，明显低于低分化胰腺癌的ccM／Glx比值（0．441±0．080）（P=0．019）。在高6值DWI成像，高一中度分化胰腺癌ADc值平均为1．085±0．161，与低分化胰腺癌的ADc值（1．146±0．062）相比无显著性差异（P=0—322）。直线相关检验表明，胰腺癌ccM／Glx比值大小与胰腺癌k一67标记指数有显著的相关性（P=0．017）；而胰腺癌的ADc值与k一67标记指数无显著的相关性（P=0．255）。结论：低分化胰腺癌的k一67标记指数、ccM／Glx比值显著高于高一中分化胰腺癌；胰腺癌的ccM／Glx比值与其k一67抗原表达水平具有显著相关性。因此，我们认为胰腺’H MRS在预测肿瘤分化程度、评价胰腺癌增殖活性方面有潜在的应用价值。更多还原

【Abstract】 Pancreatic cancer is one of the most lethal human cancers and continues to be a major unsolved health problem at the start of the 21st century. It is well known that the 5-year survival rate of patients with pancreatic adenocarcinoma is dismal. When obtaining initial diagnosis, less than 10-15% of patients still preserve an opportunity to surgical resection, which is the only potential curative treatment. Although much effort has been devoted to improve early detection of pancreatic adeno carcinomas, the sensitivity to detect pancreatic cancer is still insufficient with conventional techniques including tumor-associated antigen testing, ultrasonography, CT and MR imaging. With recent development of the high-field MR systems, high-performance gradient and parallel imaging technique, MR spectroscopy (MRS) and MR diffusion-weighted imaging (DWI) are increasingly used to evaluate diseases involving abdominal organs. In this study, pancreatic DWI, proton MRS and histopathological examination were performed for patients with pancreatic carcinoma, as well for patients with mass-forming chronic pancreatitis and healthy volunteers for control. Our purpose was to evaluate the usefulness of DWI and proton MRS in the diagnosis of pancreatic carcinoma, and to explore the value of apparent diffusion coefficient (ADC) and metabolite quantification in predicting the differentiation degree and proliferation activity for pancreatic carcinoma.Part I: In vivo ~1H MR Spectroscopy of Pancreatic Carcinoma at 3T: with Mass-forming Chronic Pancreatitis and Normal Pancreas in ComparisonObjective: In this part, our purpose was to analyze the !H MR spectroscopic features of in-vivo pancreatic carcinoma, and to explore the value of metabolite quantification in differentiating pancreatic carcinoma from mass-forming chronic pancreatitis.Methods: This study protocol had been approved by our institutional Medical Ethics Committee. With informed consent, single-voxel pancreatic !H MR spectroscopic examination was performed for 27 patients with pancreatic carcinoma (M/F, 15/12; age, 62.2±12.0 years) and 11 patients with mass-forming chronic pancreatitis (M/F, 7/4; age, 52.5±11.4 years), and for 20 healthy volunteers (M/F, 15/5; mean age, 38.6±17.2 years) for control. !H-MR spectroscopic features of pancreatic carcinoma, mass-forming chronic pancreatitis and normal pancreas were pictured; moreover, the relative lipid content (rLip, the ratio of lipid peak area divided by peak areas from 0 to 6 ppm), choline-containing metabolites (CCM) to glutamate and glutamine complex (Glx) ratio (CCM/Glx) were compared between three groups. Furthermore, ROC analysis was made to determine the diagnostic value of metabolite quantification in differenting pancreatic carcinoma from mass-forming chronic pancreatitis.Results: In comparison with normal pancreas, !H spectrum of the pancreatic carcinoma was characterized by large residual water (H2O) resonance peak and small lipid peak; CCM of the pancreatic carcinoma was reduced and varied in size, likely due to the difference in tumor differentiation degree and the heterogeneity in tumor constituents; however, mass-forming chronic pancreatitis presented with an enlarged lipid peak and reduced residual H2O. CCM/Glx ratio of the pancreatic carcinoma (0.367±0.094 [mean±SD]; n=27) was lower than that of mass-forming chronic pancreatitis (0.446±0.039; n=ll) (P=0.011). CCM/Glx ratios of both pancreatic carcinoma and mass-forming pancretitis were significantly lower than that of normal pancreas (0.592±0.233; n=20), with P values of 0.007 and 0.021 respectively. The rLip value of pancreatic carcinoma (0.420±0.164) was lower than those of chronic pancreatitis (P<0.001) and normal pancreas (P<0.001). Significant difference (P=0.020) was also revealed in rLip value between mass-forming pancreatitis (0.725±0.059) and normal pancreas (0.645±0.096). For differentiating pancreatic carcinoma from mass-forming pancreatitis, rLip obtained sensitivity of 90.9% and specificity of 92.6% when using 0.647 as the optimal cut-off value; while CCM/Glx obtained sensitivity of 81.8% and specificity of 70.4% when using cut-off value of 0.423.Conclusion: In !H spectrum, pancreatic carcinoma presented with a decrease of CCM concentration and relative lipid content, as well as an increase of residual water, when compared to normal pancreas and mass-forming chronic pancreatitis. !H MR spectroscopy with metabolite quantification was of potential value in differentiating pancreatic carcinoma from mass-forming chronic pancreatitis.Part II: Usefulness of ADC Quantification in Differentiation between Pancreatic Carcinoma and Mass-forming Chronic Pancreatitis Objective: To explore the imaging features of pancreatic carcinoma in 3-T MR diffusion-weighted imaging (DWI), and to determine the efficacy of ADC quantification for differentiating pancreatic carcinoma from mass-forming chronic pancreatitis.Methods: Our study subjects consisted of 27 patients with pancreatic carcinoma (M/F, 15/12; age, 62.2±12.0 years), 11 patients with mass-forming chronic pancreatitis (M/F, 7/4; age, 52.5±11.4 years) and 20 healthy volunteers (M/F, 15/5; age, 38.6±17.2 years). For all of them, twice pancreatic DWIs with two different sets of b values (0, 500 and 0, 1000 s/mm2) were performed consecutively. ADC values (ADC500, ADC1000) of pancreatic carcinoma, mass-forming pancreatitis and normal pancreas were measured using a circular region of interest (ROI), and rADC was calculated according to the formula: rADC = (ADC500—ADC1000)/ADC500. The diagnostic performance of ADCs and rADC (the rate of variance between ADC500 and ADC1000) were evaluated using ROC analysis.Results: Both pancreatic carcinoma and mass-forming pancreatitis were revealed as high-attenuation mass lesions on DWI with b value of 500 or 1000 s/mm2. The ADCs of pancreatic carcinoma (ADC500, 1.264±0.153; ADC1000, l.lll±0.133) and mass-forming pancreatitis (1.352±0.114; 1.210±0.093) were lower than those of the normalpancreatic tissues (1.983±0.172; 1.658±0.145) (PO.001). Compared to mass-forming pancreatitis, pancreatic carcinoma exhibited an even lower ADC1000 (P=0.045) and ADC500 values (P=0.03). The rADC (%) of pancreatic carcinoma was 9.78±3.50, significantly lower than those of mass-forming pancreatitis (12.76±1.90, P=0.116) and normal pancreas (17.62±4.76, P<0.001). Significant difference was revealed in rADC between the mass-forming pancreatitis and normal pancreas (P=0.003). In ROC analysis, ADC500, ADC1000 and rADC respectively obtained sensitivity of 72.7%, 74.1% and 72.7% and specificity of 74.1%, 81.8% and 66.7% for differentiating pancreatic carcinoma from mass-forming chronic pancreatitis.Conclusion: Pancreatic carcinoma was characterized by more restricted water diffusion (lowered ADC) and lowered microvascular perfiision (lowered rADC) than mass-forming chronic pancreatitis in DWI. DWI combined with ADC quantification might be a potentially useful technique in the diagnosis of pancreatic carcinoma by providing histological information in vivo.Part III: Correlation of Choline-containing Metabolites (CCM), ADC Value and Ki-67 Labeling Index in Pancreatic CarcinomaObjective: To investigate the difference between well-to-moderately and poorly differentiated pancreatic carcinoma in Choline-containing metablites (CCM) content, ADC value and Ki-67 labeling index, and to determine whether there is a correlation of CCM content, ADC value with the Ki-67 protain expression.Materials and methods: Preoperative MRI/MRS and postoperative histopathologic results of 21 patients with pancreatic carcinoma (M/F, 12/9; age, 62.8±12.6 years) were reviewed. CCM content, ADC value and Ki-67 labeling index of tumors with varied differentiating grades were compared using Mann-Whitney U test; and the correlation of CCM, ADC and Ki-67 labeling index were determined using linear regression analysis.Results: In postoperative histopathologic examination, 14 and 7 pancreatic carcinoma were respectively diagnosed as well-to-moderately differentiated and poorly differentiated tumors; the Ki-67 labeling index of well-to-moderately differentiated tumors (40.99±7.56) was lower than that of poorly differentiated (59.91±8.61) (P=0.001). In single-voxel !H-MRS study, the CCM/Glx ratio of well-to-moderately differentiated tumors (54.5±19.7) was significantly lower than that of poorly differentiated (0.441±0.080) (P=0.019). No significant difference was revealed in ADC values between well-to-moderately differentiated (1.08 5±0.161 s/mm2) and poorly differentiated pancreatic carcinoma (1.146±0.062 s/mm2) (P=0.322) in DWI with b value of 1000 mm2/s. There is a significant linear correlation (P=0.017) between CCM/Glx ratio and Ki-67 labeling index, but no significant correlation between ADC value and Ki-67 labeling index (P=0.255).Conclusion: !H MRS may have potential value in predicting the differentiation degree and proliferation activity of pancreatic carcinoma.更多还原