Application Of ¹⁸F-FDG And ¹⁸F-FCH PET/CT In Pancreatic Cancer

Objective:Pancreatic cancer（PC） is one of the leading causes of death from cancer worldwide and is steadily increasing in incidence.Despite decades of effort, the 5-year survival rate remains no more than 5%. In the USA, pancreatic cancer ranks fourth in causes of death from cancer. In recent years in China, especially in the economically developed areas, such as Shanghai City.The incidence of pancreatic cancer has increased significantly. According to statistics, China’s pancreatic cancer accounts for the world was 15.68%, the morbidity and mortality of malignant tumor were in top ten.Traditional imaging diagnostic technologies such as computed tomography（CT）, endoscopic ultrasonography（EUS）,magnetic resonance imaging（MRI）,abdominal ultrasound and 18F-FDG PET/CT may be used for the purpose of preoperative diagnosis and staging of PC. Over the years, positron emission tomography（PET） has played an important role in oncology, especially in the diagnosis, staging and prognosis prediction of tumors. However, there is no consensus with regard to the role of PET in PC now. FDG as glucose analogue, is the most widely used radiotracer. 18F-FDG PET/CT is routinely used in the diagnosis and stage of many kinds of carcinoma, but it is remains suboptimal when refers to differential diagnosis of PC and Pancreatitis.To evaluate pancreatic carcinoma distant metastasis, the status of PET/CT is still controversial according to the current research. Guidelines for the diagnosis and treatment of pancreatic cancer（2014） recommended pancreatic CT as the preferred examination in patients with pancreatic tumors.18F-FDG PET/CT can not take the place of status of CT or MRI. It may be used when patients with large pancreaticmass or suspected lymph node metastasis or serum CA19-9 level was significantly increased. Positron imaging agents such as ¹⁸F-FCH , belongs to the choline agents, has been used in the diagnosis of many kinds of malignancies and achieved good results,such as for brain tumors, lung cancer, esophageal cancer, colon cancer and prostate cancer,et al. Currently,the characteristics of ¹⁸F-FCH biodistribution and whether it may be used to diagnose pancreatic cancer, and to evaluate distant metastasis of lymph node are still unknown. So this study is aimed to 18F- FDG and ¹⁸F-FCH pancreatic PET/CT imaging and to evaluate its effectiveness comprehensive diagnosis of pancreatic cancer.This research include three parts.Part one: Construction of pancreatic cancer model The nude mice were selected for this research. To implant human CFPAC-1 cell lines to the right forelimb of nude mice subcutaneously and observe the tumor growth dynamically. Histological examination was performed on tumor sections after four weeks.Part two: 1)The research of biodistribution of ¹⁸F-FCH in Kunming mice.After tail vein injection of ¹⁸F-FCH ,the Kunming mice were killed in 5, 10, 20, 40, 60, 90 min respectively, and then measured the radioactivity of brain, heart, liver, lung, spleen, kidney, bone, muscle and other tissues.2)To study the biodistribution of ¹⁸F-FCH , 18F-FDG in nude mice after tail vein injection 10 min and 60 min respectively.To perform nude mice bearing implanted tumor 18F-FDG, and ¹⁸F-FCH PET/CT examination respectively, 10 min and 60 min after the tail vein injection of ¹⁸F-FCH , 18F-FDG respectively by Siemens Biograph Truepoint 64 PET/CT system. To compare the uptakes of 18F-FDG and ¹⁸F-FCH in implanted tumor and other organs, and to evaluate preliminarily the diagonostic efficacy of these radiotracers in implanted tumor.Part three: The clninical usefulness research of 18F-FDG and ¹⁸F-FCH PET/CT in pancreatic cancer.To retrospective analysis the imaging results of 18F-FDG, ¹⁸F-FCH PET/CT of the 118 cases of patient suspicious pancreatic cancer, and to explore the comprehensive diagnostic efficiency of pancreatic cancer.Materials and Methods:1.The construction and identification of pancreatic cancer model. Implanted human CFPAC-1 cell lines to the right forelimb of 40 nude mice（age:6⁸ weeks,weight 15¹8g）subcutaneously and observe the tumor growth.and 1 nude mice was selected randomly and be killed 4 weeks after implantation, histological examination was performed on tumor sections.2.The research of ¹⁸F-FCH biodistribution in Kunming mice,, the research of biodistribution and PET imaging of ¹⁸F-FCH , 18F-FDG in nude mice beraring implanted tumor.（1）24 Kunming mice were killed in 5, 10, 20, 40, 60, 90 min respectively, and then measured the radioactivity of brain, heart, liver, lung, spleen, kidney, bone, muscle and other tissues, calculated each samples injected activity per gram of tissue%.（2） Twenty four nude mice with implanted tumor were divided into 4 groups randomly, group A1, A2, B1, B2, 6 nude mice in every group. After the tail vein injection of of 18F-FDG, group A1 were killed at 10 min, and group A2 were killed at 60 min respectively. and group B1 were killed 10 min postinjection of ¹⁸F-FCH , group B2 were killed 60 min postinjection of of ¹⁸F-FCH .The uptake（%ID/g） of tumors and normal organs or tissues were measured.Twelve nude mice with implanted tumor were divided into 2 groups randomly, group A and group B, 6 nude mice in every group, group A perfomed 18F-FDG PET/CT examination, group B performed 18F- FCH PET/CT examination. The maximum standard uptake values（SUVmax） of tumor, other normal organs or tissues were calculated and compared.3.To retrospective analysis the imaging results of ¹⁸F-FDG, ¹⁸F-FCH PET/CT of the 118 cases of patient suspicious pancreatic cancer,and to explore the comprehensive diagnostic efficiency of pancreatic cancer.from January 2011 to August 2014. Include to explore the role of 18F-FDG PET/CT and ¹⁸F-FCH PET/CT image in pancreatic benign and malignant lesions; To discuss the staging value of 18F-FDG PET/CT image in patients with pancreatic cancer;To analyse the value of CA 19-9 in diagnosing pancreatic cancer.（1）All patients performed 18F-FDG PET/CT examination, thirty patients performed ¹⁸F-FCH PET/CT examination within 1 week after 18F-FDG PET/CT examination.（2）All the images were visually inspected and analyzed semi-quantitatively, and the maximum standard uptake values of pancreatic cancer primary lesions, regional lymph nodes and distal metastases were measured and compared, and the sensitivities and specificities of different tracers PET/CT in diagnosing primary lesions, regional lymph nodes and distal metastasis were also calculated and compared.（3）To explore the diagnostic value of Serum CA19-9 measurement of pancreatic cancer.4.Statistically analyse: SPSS17.0 software bag was selected, and the differences of mean of different groups were analyzed with T test, and the differences of rates of different groups were analyzed with chi-square test. ROC analysis was also used to analyze the data. P values less than 0.05 were considered as statistical significance.Results:1. The rate of nude mice tumor construction was 92.5%（37/40）. The tumor nodule was about 4 millimeters in diameter 14 days after the implantation of CFPAC-1 cell lines. The tumor grow rapidly since the 3rd week, and the tumor volume was above 200 cubic milliliter.The diameter of nodule were about 15 mm,18mm at 28 days and 35 days. At the early stage, the shape of transplantation tumor was round,then gradually become irregular. The tumor was hard texture, the center part was necrosis and liquefaction with gray sectional color. Histological pathological mitosis were seen, and there were abundant in the vascular lesions.2. The biodistribution of ¹⁸F-FCH in Kunming mice, the research of biodistribution and PET imaging of ¹⁸F-FCH , 18F-FDG in nude mice bearing implanted tumor.（1） The radioactivity mainly accumulated in the kidneys, liver, pancreas, spleen, gastrointestinal tract and heart. Other organs such as the brain, lungs, heart, muscles and bones were in lower uptake degree. Most organs reach its radioactive peak within 5min and then decreasing or in a relatively stable state. The most radioactivities（%ID/g） of ¹⁸F-FCH were found in kidney, and the secondly was found in liver, and then the pancreas and spleen, and the least was found in muscles and blood.（2） The biodistribution of 18F-FDG and ¹⁸F-FCH in nude mice bearing implanted tumor. 1) The ¹⁸F-FCH mainly accumulated in the kidneys, liver, pancreas, spleen, gastrointestinal tract and heart. Other organs such as the brain, lungs, heart, muscles,bones and tumor were in lower uptake degree. The most radioactivities（%ID/g） of 18F-FDG were found in myocardium, and the secondly was found in tumor, and then the kidney and spleen, and the least was found in blood and muscles.2) The uptake（%ID/g） of 18F-FDG in implanted tumor is higher than those of ¹⁸F-FCH and there were statistically differences between those of 18F-FDG and ¹⁸F-FCH , and all the P values were less than 0.01. 3) There were statistically differences between all the uptakes（%ID/g） of 18F-FDG and ¹⁸F-FCH in other normal organs, and all the P values were less than 0.01.（2） PET/CT imaging results of 18F-FDG and ¹⁸F-FCH in nude mice bearing implanted tumor.1) The implanted tumors uptaked much more 18F-FDG than ¹⁸F-FCH . SUVmax was 3.75, 0.37, and There was statistically difference between 18F-FDG and ¹⁸F-FCH （P<0.01）.2) Besides the tumor,18F-FDG mainly accumulated in the kidneys, liver, and heart. The ¹⁸F-FCH mainly accumulated in the kidneys, liver and spleen, The difference was statistically significant（t=6.636, 9.391, 6.182, P=0.000）.3.（1） In all of 118 patients who were suspected pancreatic cancer, 84 cases appear abnormal 18F-FDG accumulated in the pancreas,and 65 cases of pancreatic cancer were diagnosed.The final diagnosis in the study was based on pathological or cytological diagnosis（n=31） and clinical and/or diagnostic imaging follow-up for at least 6 months（n=34）. 1 cases of lymphoma, 3 cases of pancreatic tuberculosis, 1 cases of islet cell tumor, 1 cases of autoimmune pancreatitis, the remaining 13 cases of pancreatitis. 34 patients with no obviously 18F-FDG uptake, including 2 pancreatic cancer cases（1 cases of pancreatic head moderately differentiated adenocarcinoma, 1 cases of pancreatic tail cystadenocarcinoma）.The other 32 cases were benign lesions, 25 cases of chronic pancreatitis and 7 cases of pancreatic cyst. 46 cases of pancreatic cancer were diagnosed with regional lymph node metastasis, liver metastasis in 12 cases, 10 cases of peritoneal metastasis, lung metastasis in 3 cases, 5 cases of adrenal metastasis, bone metastasis in 8 cases. There were 11 cases with finnal clinical stage I, stage II 26 cases, stage III 22 cases, 8 cases of stage IV.（2） The sensitivity, specificity and accuracy of ¹⁸F-FCH PET/CT examination for diagnosing pancreatic cancer were 97.0%, 62.7%, and 82.2% respectively. Thepositive predictive rate was 77.3%, the negative predictive rate was 94.1%. SUVmax values of pancreatic cancer（4.56±1.50） was higher than that of benign pancreatic lesions（1.92±0.96）, and the difference between pancreatic cancer and benign pancreatic lesions was statistically significant, t=-11.486, p=0.001（bilateral）. The area under the ROC was 0.943, standard error was 0.017, the 95% confidence interval was（0.909 0.977）. According to the data, with a cut-off value of 2.4 of the SUVmax the sensitivity, specificity of ¹⁸F-FCH PET/CT were 97.0%, 62.7%.84 cases appear abnormal 18F-FDG accumulated in the pancreas, and among them, 30 patients underwent ¹⁸F-FCH PET/CT examination within one week. There was 1 case of tuberculosis and 4 chronic pancreatitis patients showed high uptake of ¹⁸F-FCH , the other 25 cases were pancreatic cancer patients, the abnormal 18F-FDG accumulated lesions uptake less ¹⁸F-FCH than normal pancreatic area, and expressed as relative radioactive rarefaction region. ¹⁸F-FCH distributed homogeneously in the residual pancreas, the overall radioactive uptake degree was slightly lower than that of liver.In all of 67 cases of pancreatic cancer, 37 patients underwent operation treatment and lymph node dissection. Among them 25 cases were confirmed by pathology with lymph node metastasis, the sensitivity, specificity and accuracy of 18F-FDG PET/CT to diagnose the lymph node metastasis of pancreatic cancer, were 36.0%, 83.3% and 51.4%. In 67 cases of pancreatic cancer patients, 18F-FDG PET/CT diagnosed 12 cases with liver metastasis, peritoneal metastasis in 10 cases, lung metastasis in 3 cases, 5 cases of adrenal metastasis, bone metastasis in 8 cases.30 cases of pancreatic cancer patients received ¹⁸F-FCH PET/CT examination, except for 1 cases of tuberculosis and 4 chronic pancreatitis patients showed high uptake of 18F- FCH, the other 25 cases showed no obvious pancreatic tumor and metastatic lymph node uptake of ¹⁸F-FCH . Among them there were 8 patients who subsequently underwent operation treatment and lymph node dissection, pathology proved no regional lymph node metastasis. ¹⁸F-FCH PET/CT imaging characteristics: normal pancreatic tissue uptake obviously ¹⁸F-FCH , the pancreatic boundaries and the surrounding tissue were clear, the whole pancreas radioactive concentration degree was slightly lower than that of liver. ¹⁸F-FCH in vivo radioactive concentrationdistribution degree from high to low were kidney > liver > pancreas >spleen. Unlike 11C-FCH, more radioactive ¹⁸F-FCH distribution was seen in the bladder.72 patients underwent the measurement of serum CA19-9.The sensitivity, specificity and accuracy of serum CA19-9 examination for diagnose pancreatic cancer were 80.4%, 51.9%, 72.2%, and positive predictive rate of 74.51%, negative predictive rate of 66.67%. The serum CA19-9 values of pancreatic cancer（409.80±258.24） were higher than that of benign pancreatic disease（23.63 + 11.35）, The difference was statistically significant, t=10.015, p=0.001（bilateral）. Combined application of 18F-FDG PET/CT imaging and detection of serum CA19-9, can improve the sensitivity,specificity and accuracy of diagnosis（84.4%,69.2%, 76.4%）.Conclusions:1.The sensitivity, specificity and accuracy of ¹⁸F-FCH PET/CT examination for diagnosing pancreatic cancer were 97.0%, 62.7%, and 82.2% respectively. The positive predictive rate was 77.3%, the negative predictive rate was 94.1%. The sensitivity of 18F-FDG PET/CT for the diagnosis regional lymph nodes was poor.The sensitivity, specificity and accuracy of 18F-FDG PET/CT to diagnose the lymph node metastasis of pancreatic cancer were 36.0%, 83.3% and 51.4%.2.¹⁸F-FCH PET/CT detection of tumor is based on the tumor cell proliferation, faster growth rate and choline uptake rate. 18F-FDG PET/CT detection of tumor is based on tumor cell anaerobic glycolysis acceleration, the uptake of glucose is higher. The experimental results show that 18F- FCH in pancreatic cancer and its metastases lesion showed low uptake than the pancreas normal tissues.¹⁸F-FCH PET/CT may clearly display the normal pancreatic tissue morphology, profile and boundary, in contrast to pancreatic cancer, although the theory was unknown, lesions and normal pancreatic tissue properties was different. ¹⁸F-FCH may be used as a negative imaging agent to display of pancreatic cancer and its metastases from different aspects, but its effectiveness needs to be further studied.3.The sensitivity, specificity and accuracy of serum CA19-9 examination for diagnose pancreatic cancer were 80.4%, 51.9%, 72.2%, and positive predictive rate of 74.51%, negative predictive rate of 66.67%. The serum CA19-9 values of pancreatic cancer were higher than that of benign pancreatic disease. Combined application of 18F-FDG PET/CT imaging and measurement of serum CA19-9, can improve the sensitivity,specificity and accuracy of diagnosis（84.4%,69.2%, 76.4%）.