Comparison And Optimization Of A Variety Of Detection Methods Of Insulinoma

Objective1. To compare common ultrasonic, ultrasonic imaging and endoscopic ultrasound, enhanced CT, MRI, angiography enhanced CT, intraoperative exploration, intraoperative ultrasound and their joint inspecting differences in insulin tumor, so as to select reasonable imaging examination method to guide the operation.2. To compare the actual long diameter of insulinoma from pathological examination to the measured long diameter values using conventional ultrasound, contrast-enhanced ultrasound, endoscopic ultrasonography, contrast-enhanced CT, enhanced MRI, CT angiography, intraoperative exploration, and intraoperative ultrasound detection, and to evaluate the accuracy of various methods for measuring insulinoma long diameter.Methods1. Object of study and groupingFrom September 2012 to January 2015 clinical data of 26 patients in our hosptial diagnosed with insulinoma and further confirmed by operation and pathology were collected, including gender, age, Whipple triad, insulin release index, C peptide, starvation test,5 hours or 7 hours OGTT test, conventional ultrasound, contrast-enhanced ultrasound, endoscopic ultrasonography, contrast-enhanced CT, enhanced MRI, CT angiography, intraoperative exploration, intraoperative ultrasound, and pathology. These 26 cases were classified into three gorups:benign tumor (24 cases), malignant insulinoma (1 cases), and islet cell hyperplasia (1 cases). Due to the small sample size of malignant insulinoma (1 case) and islet cell hyperplasia (1 case) groups, we will only give a brief description to them. We will focus on the analysis of the 24 cases of benign insulinomas.2. Conventional ultrasound examination methodThe ultrasound system used is Acuson sequioa 512 color Doppler with 4C1 transducer proble atfrequency range of 3～5.0MHz. Examination was performed under fasting state to observe the location, size, boundary state, echo, and blood supply condition of the pancreatic lesion.3. Contrast enhanced ultrasound methodThe same system in 2 is used. Low mechanical index contrast pulse sequence (contrast pulse sequencing, CPS) was used for contrast enhancement. The ultrasound contrast agent used is Sono Vue (Bracco, Italy; main ingredient:six sulphur hexafluoride microbubbles (SF6), mean diameter of micro bubble:2.5 μm; pH:4.5～ 7.5).Agent was disolved with oscillation mixing in 5ml saline before use.2.4ml of dissolved agent was injected quickly through the superficial vein on elbow, followed by rapid injection of 5ml saline. Ultrasonic inspection method:conventional ultrasound inspection was first performed under fasting condition to observe pancreatic lesion location, size, boundary, echo, and blood supply. Subsequently CPS technology was used for ultrasonic angiography. According to the patients’ BMI, the mechanical index was adjusted in a range between 0.12 and 0.18. The pancreatic lesions and the injection process and strength change were monitored continuously in real-time and recordings were made.4. Endoscopic ultrasonography methodThe device used is a Pentax FG-36UX color ultrasonic endoscope with color doppler imaging and doppler spectrum analysis function, variable7.5MHz ultrasonic frequency.and convex fan scanning mode. Endoscopic ultrasonography methods:after 12 hours fasting, pharyngeal local anesthesia was applied, probe was lowed to reach the descending duodenum and duodenal papilla. Water bag is withdrawn gradually and at the same time each part of the pancreas (in order of head, neck, body and tail), portal vein, splenic vein, superior mesenteric artery, superior mesenteric vein, and the splenic vein are scanned.5. Enhanced CTA Siemens Somatom Definition with dual source CT scanner (120kV,360mA; thickness 5.0mm, interval 5.0mm) is used to scan sequentially in arterial phase, portal venous phase, and delayed phase from lower pole double kidney to the diaphragm. The contrast agent used is non-ionic iodine Ultravist 370 100ml, injected through elbow vein with high Lok syringe at 5ml/s.20～25 seconds after injection the arterial phase scan was started,65 econds for portal venous phase scan, and 155 seconds for delayed scanning, each phase of scan was performed in one breath holding.6. Enhanced MRIGE Signa Eecite with 3.0T superconduct MR scanner was used. Plain scan imaging sequences include:axial single shot fast spin echo (SSFSE) T2WI (TR 807ms, TE 86.9ms), axial fat suppressed T2WI, axial dual echo T1WI (TR 230ms, TE 2.4ms and 5.8ms) and coronal fast imaging steady-state acquisition (FIESTA) T2WI (TR 4.0ms, TE 1.3ms). Enhanced scan imaging sequence includes:axial liver acquisition volume acceleration (LAVA) T1WI. The contrast agent is Gd-DTPA, at a dose of O.lmmol/kg body weight. Axial scan slice thickness is 8.0mm, interval 10.0mm, axial enhanced LAVA sequence thickness is 3.6mm, interval 1.8mm.7. CT angiographyINNOVA 3100 Flat-panel Digital X-ray Angiography system and Siemens Sensation 16 slice CT scanner are used. Operation process:after conventional inguinal area disinfection with towel applied, and 1% lidocaine 10ml for local anesthesia, penerate the right femoral artery using the modified Seldinger’s technology, import 4F arterial sheath, and then insert the 4F artery catheter through celiac artery, gastroduodenal artery, splenic artery, dorsal pancreatic artery, and superior mesenteric artery to perform angiography CT check (120kV,360mA; thickness 5.0mm, interval 5.0mm). Contrast agent used was non-ionic iopromide (370mgI/ml), injection rate for celiac artery, splenic artery, superior mesenteric artery is 5ml/s,25ml in total; 3ml/s rate for gastro duodenal artery, dorsal pancreatic artery and 15ml in total; 5ml/s for hepatic artery in patients with hepatic metastasis, and 25ml in total. The induction ducts used are Cobra, Yashiro or hepatic duct catheter. After inspection compression bandage was applied in the right inguinal region to the extent that pluse was palpable on the right femoral artery, and dorsalis pedis artery.8. Intraoperative explorationExploration during operation is carried out in the following order:exploration of pancreas surface, pancreas body and tail, pancreatic head, exploration of pancreatic uncinate process, and exploration outside pancreas.9. Intraoperative ultrasoundFor ultrasound in open operation we used Philips HD15000 with CL157 intraoperative probe (frequency 7-15MHz). Probe was wrapped with disposable saline-filled sterile plastic wrap. Kocher method was used to free duodenal, open the gastrocolic ligament to fully reveal pancreas, and to continuously scan along the pancreas longitudinally and transversely. When the lesion had severe adhesion and infiltration of lesions with surrounding tissue and was not easy to separate, the probe can be placed on the gastrocolic ligament surface or scan can be performed by applying pressure on stomach. Intraoperative laparoscopic ultrasonography:Philips IU22 color Doppler ultrasonography system was used with Lap 9-5 intraoperative probe (frequency 5～9.0MHz). The probe was sterilized using epoxy ethane gas. Laparoscopic ultrasonography operation hole located at the right upper and right middle abdomen. If necessary, an auxiliary hole could be made below the xiphoid. The ultrasonic probe was dispatched through the laparoscopic ultrasonography operation hole into the abdominal cavity, and placed directly on the surface of pancreas. Scan was performed from pancreatic head to the tail vertically and horizontally from multi-direction, multiple angles repeately. When lesion was found, multi-sectioned observations were made on the condition of blood flow and the features in the two-dimensional gray scale sonographic images, and attentions were paid to the relationship between the lesions and the pancreatic duct and common bile duct, adjacent blood vessels, and adjacent organs and other important structures.10. Pathological examinationSampling:multi-point sampling, avoiding the hemorrhage and necrosis area. The specimens were fixed in 10% formalin, embedded in paraffin, HE staining, and observed under microscope. Immunohistochemical MaxVision two-step method was used, the antibodies used are:CgA, Syn antibody, CDP9.5, S-100, insulin, gastrin, insulin, glucagon (purchased from Fuzhou Maixin company). The instructions on the kit were followed, DAB color, hematoxylin staining, with positive and negative control. Image interpretation:mitosis is selected as the 50 eyes from where the tumor cells are most concentrated.10 eyes were calculated to get a clear percentage; Ki-67 labeling index should be in the strongest region to count 500 to 2000 cells, and calculate percentage. The pathological report:should contain the origin of tissue, tumor location, tumor size, tumor number, invasion range (around the organs, blood vessel, nerve and so on), margin, lymph node; mitotic index, Ki-67 index, synaptophysin, CgA etc. Conclusion:the pathology should contain the pathological results, NET marker expression, proliferation and pathological staging.11. Statistical analysisThe SPSS 22.0 statistical software is used for statistical analysis. The positive detection rate of each inspection method as well as their combination in detecting benign insulinoma were compared by binomial exact test, P≤ 0.05 for the difference having statistical significance. Each method for measuring benign insulinoma long diameter and the actual pathological long diameter were compared using MANOVA of repeated measuring, P≤ 0.05 for the difference having statistical significance.Results1. For benign insulinoma, positive detection rate of conventional ultrasound, contrast-enhanced ultrasound, endoscopic ultrasonography, contrast-enhanced CT, enhanced MRI, CT angiography, intraoperative exploration, and intraoperative ultrasonography were 41.7%、83.3%、79.2%、79.2%、87.5%、79.2%、83.3%、 91.7% respectively. For conventional ultrasound combined with contrast enhanced ultrasound, conventional ultrasound combined with endoscopic ultrasound, conventional ultrasound combined with enhanced CT, conventional ultrasound combined with enhanced MRI, conventional ultrasound combined with CT angiography, conventional ultrasound combined with intraoperative exploration, conventional ultrasound combined with intraoperative ultrasound, contrast-enhanced ultrasound combined with endoscopic ultrasound, contrast enhanced ultrasound and enhanced CT, contrast enhanced ultrasound and enhanced MRI, ultrasound angiography combined with CT angiography, contrast enhanced ultrasound combined with intraoperative exploration, contrast enhanced ultrasound combined with intraoperative ultrasound, endoscopic ultrasound combined with contrast enhanced CT, endoscopic ultrasound combined with contrast enhanced MRI, endoscopic ultrasound combined with CT angiography, endoscopic ultrasound combined with intraoperative exploration, endoscopic ultrasonography combined with intraoperative ultrasound, enhanced CT combined with enhanced MRI, enhanced CT combined with CT angiography, enhanced CT combined with intraoperative exploration, enhanced CT combined with intraoperative ultrasound, enhanced MRI combined with CT angiography, enhanced MRI combined with intraoperative exploration, enhanced MRI combined with intraoperative ultrasound, angiography CT combined with intraoperative exploration, CT angiography combined with intraoperative ultrasound, and intraoperative exploration combined with intraoperative ultrasound, the positive detection rate were 83.3%、83.3%、79.2%、87.5%、91.7%、87.5%、95.8%、 87.5%、91.7%、95.8%、91.7%、91.7%、95.8%、91.7%、95.8%、87.5%、 87.5%、95.8%、95.8%、95.8%、95.8%、95.8%、95.8%、95.8%、100%、 91.7%、95.8%、91.7% respectively. For contrast-enhanced ultrasound combined with contrast-enhanced CT combined with enhanced MRI, endoscopic ultrasound combined with contrast-enhanced CT combined with enhanced MRI, contrast-enhanced CT combined with enhanced MRI combined with CT angiography, the positive detection rate of benign insulinoma before operation were 100%.2. In our study, for each inspection method, the positive detection rate of intraoperative ultrasound was the highest, the difference (Kappa test) having statistical significance compared with intraoperative exploration, the difference (Kappa test) having no statistical significance compared with other inspection methods. When two kinds of inspection methods combined, the positive detection rate of enhanced MRI combined with intraoperative ultrasound was 100%, the difference (Kappa test) having no statistical significance compared with other inspection methods and their joint. For preoperative imaging, the positive detection rate of enhanced MRI was the highest, the difference (Kappa test) having no statistical significance compared with other inspection methods. When two kinds of inspection methods combined before operation, the positive detection rate of contrast-enhanced ultrasound combined with enhanced MRI, endoscopic ultrasound combined with combined with enhanced MRI, contrast-enhanced CT combined with enhanced MRI, contrast-enhanced CT combined with CT angiography were the highest. The difference (Kappa test) had statistical significance among enhanced MRI, contrast-enhanced ultrasound combined with enhanced MRI, endoscopic ultrasound combined with combined with enhanced MRI, contrast-enhanced CT combined with enhanced MRI. The difference (Kappa test) had no statistical significance between enhanced MRI and contrast-enhanced CT combined with CT angiography. When three kinds of inspection methods combined before operation, the positive detection rate of contrast-enhanced ultrasound combined with contrast-enhanced CT combined with enhanced MRI, endoscopic ultrasound combined with contrast-enhanced CT combined with enhanced MRI, contrast-enhanced CT combined with enhanced MRI combined with CT angiography were 100%, the difference (Kappa test) having no statistical significance compared with other inspection methods and their joint.3. Conventional ultrasound, contrast-enhanced ultrasound, endoscopic ultrasonography, contrast-enhanced CT, enhanced MRI, CT angiography, intraoperative ultrasound, and intraoperative exploration for measuring benign insulinoma long diameter and the actual pathological long diameter were compared, for the difference having no statistically significant difference, P> 0.05.4. For the 1 case of malignant insulinoma, conventional ultrasound, contrast-enhanced ultrasound, endoscopic ultrasonography, contrast-enhanced CT, enhanced MRI, CT angiography, intraoperative exploration, and intraoperative ultrasonography are able to detect the tumor precisely.5. For the 1 case of islet cell hyperplasia, conventional ultrasound, contrast- enhanced ultrasound, endoscopic ultrasonography, contrast-enhanced CT, enhanced MRI, CT angiography, intraoperative exploration, and intraoperative ultrasonography failed to detect the lesions.Conclusions1. In our study, for each inspection method, the positive detection rate of intraoperative ultrasound was the highest,91.7%, when two kinds of inspection methods combined, the positive detection rate of enhanced MRI combined with intraoperative ultrasound was the highest,100%.2. For preoperative imaging, the positive detection rate of enhanced MRI was the highest,87.5%. When three kinds of inspection methods combined before operation, the positive detection rate of contrast-enhanced ultrasound combined with contrast-enhanced CT combined with enhanced MRI, endoscopic ultrasound combined with contrast-enhanced CT combined with enhanced MRI, contrast-enhanced CT combined with enhanced MRI combined with CT angiography were 100%, further enhancing the positive detection rate of benign insulinoma before surgery.3. In order to improve the preoperative positive detection rate of benign insulinoma, we suggest that enhanced MRI should be selected first. Because CT angiography is invasive, and endoscopic ultrasound needs for the ultrasound probe into the stomach to make the patient feel unwell, we recommend that doctors further combine with enhanced CT and contrast-enhanced ultrasound to improve the preoperative positive detection rate of benign insulinoma when enhanced MRI fail to detect the benign insulinoma.4. Intraoperative exploration and intraoperative ultrasound can further confirm the location of benign insulinoma when operation, and intraoperative ultrasound can further observe the relationship between benign insulinoma and surrounding structures, for example, pancreatic duct, thus guiding the surgery better.5. malignant insulinoma is large and easily detecting by various method, but need to alert missing the metastases.6. Islet cell hyperplasia is not easy to find by a variety of imaging examination, splenic vein segment blood and so on helps to locate.7. The size of benign insulinoma is accurate by various inspection methods.