| Research background In recent years, the incidence of lung cancer was rising in the global scope, and this trend was especially obvious in China. It had been reported that the incidence and mortality of lung cancer of many countries were significantly increasing. About 22 thousands new cases and 16 thousands deaths could be found in the United States.In China, the male lung cancer incidence and mortality were first of all malignant tumor and it was still increasing, which might be related to environmental pollution,smoking, medical diagnosis and treatment level development, and so on.With the development of medical science and new issues in the field of cancer constantly conquered, with the evelopment and popularization of minimally invasive surgery,chemical therapy,radiation therapy,interventional therapy and immune therapy, more and more cancer patients could get more effective treatment earlier.However, the treatment of patients with lung cancer and survival period were not satisfactory. The overall 5-year survival rate of lung cancer was still very low, about8% to 15%. Most lung cancer patients with advanced disease had already lost the chance of operation when they were found and begun treatment.About one-third of the first diagnosis of patients with lung cancer could accept surgery.Treatment and prognosis of lung cancer depended on the TNM staging. Both preoperative staging and after treatment staging depended on accurate mediastinal lymph node staging. The diagnosis of mediastinal lymph nodes was difficulty and blind spots to the clinicians.Because of mediastinal anatomy complexity 、organizational sources diversity 、 occuring frequently of benign and malignant lesions, conventional chest radiographic could not instead of pathologic examination and determine the nature of the lesion.The accuracy of CT(chest Computer Tomography,CT)was not high which relied on the measurement of lymph node size to diagnose. The PET/CT(positron emission tomography/computer tomography,PET/CT), which relied on the 18F-FDG(18 F-fluorodeoxy glucose, 18F-FDG))metabolic activity, had more false positives and false negatives.The ACCP(American college of chest physicians, ACCP) mediastinal staging lung cancer clinical guidelines recommended that if the paitent swith extensive mediastinal tumor invasion, the only CT imaging evaluation was usually enough and didn’t need to have the invasive examination to confirm. But for the isolated enlarged mediastinal and lung hilar lymph nodes, whatever the outcome of PET/CT was positive or negative,the guidelines emphasized invasive examination was necessary. The clinicians should base on that the easiest way to acquire the tissue samples for mediastinal and lung hilum lymph nodes in patients with lung cancer.The common biopsy method of mediastinal and lung hilar enlarged lymph node was CT-guided percutaneous pulmonary biopsy, mediastinoscope, thoracoscope, and so on.The CT-guided percutaneous pulmonary biopsy easily appeared pneumothorax,because of the pulmonary lesions moving with the breath, and surrounding the illness lung tissue was filled with inflation. The mediastinal and pulmonary hilum lesions lymphm nodes was near heart large blood vessels,and puncture needle through normal lung tissue was more, the CT-guided percutaneous pulmonary biopsy had an increased risk of bleeding and pneumothorax. Mediastinoscope was the gold standard in the diagnosis of mediastinal enlarged lymph nodes, which was mainly used in the diognosis of 1, 2R, 2L, 3, 4R, 4L and 7 group lymph nodes. Expanded mediastinoscope lymph nodes can be used for the diognosis of 5, 6 group lymph nodes. The research of domestic and foreign suggested the sensitivity, specificity and false negative rate by standard mediastinoscope was 96.4%, 100%, 3.6%. But because of the mediastinoscopy requiring hospitalization, general anesthesia,so the cost was high. The mediastinoscopy maight have the complication of hemorrhage, infection,pneumothorax, esophageal injury, etc.So it was difficult to carry out. The 8 group, 9group, 3 group after trachea and the back of the 7 group lymph nodes was the blind area of traditional mediastinoscopy,which was the main cause of false negatives.EBUS-TBNA(endobronchial ultrasound guided-transbronchial needle aspiration,EBUS-TBNA) was a new technology in recent years.It was first used clinically in2004. The EBUS-TBNA was presently important progress in the diagnosis of lung cancer staging method.In 2007 it was recommended as an important means of preoperative lymph node staging of lung Cancer by the NCCN(The National Comprehensive Cancer Network, NCCN) and the ACCP(The American College of Chest Physicians, ACCP). EBUS-TBNA had become the new standard for mediastinal lymph nodes staging of lung cancer.In recent years, the study indicated that EBUS-TBNA technology had a high diagnostic value in the mediastinal lymph node staging of lung cancer, and other benign disease such as sarcoidosis, lymphatic tuberculosis. It was recommended as an effective inspection method of mediastinal lymph nodes by the international guidelines.EBUS-TBNA was the fusion technique of ultrasound and fiberoptic bronchoscopy,solving only the blind problem of the c- TBNA(the conventional transbronchial needle aspiration,c- TBNA). The biopsy area of EBUS-TBNA was similar to the mediastinoscopy which was across the neck to operation.The 3p、10、ll group lymph nodes also could be punctured by EBUS-TBNA. The back of the 7group lymph nodes which was often difficult to reach for the mediastinoscopy, but it could easily be punctured by EBUS-TBNA. EBUS-TBNA could obtain enough tissue specimen for pathological examination. Beacause of local anesthesia for EBUS-TBNA, so it maight be small trauma and few complications. In 2011,Yasufuku scholar published a prospective study that was about comparing the value of in lung cancer mediastinum lymph nodes staging between EBUS-TBNA with mediastinoscopy.The results showed that the sensitivity, negative predictive value and accuracy of EBUS- TBNA and mediastinoscope was 81% and 79%, 91% and90%, 93% and 93%.The study showed that the EBUS-TBNA and mediastinoscope had the same diagnostic value in lung cancer mediastinum lymph nodes staging.In recent years, the people began to pay attention to analysis the ultrasonic characteristics of malignant lymph nodes and evaluated the predictive value. Due to the tumor cells infiltration in the lymph nodes, necrosis, fiber tissue hyperplasia, the echo distribution measured by EBUS might change comparing to the normal lymph nodes. Fujiwara scholar analyzed the EBUS signs of mediastinal lymph nodes,and found that the coagulation necrosis, circular, uneven echo,clear edge was in metastatic lymph nodes. On the other hand, they also found that the blood flow distribution within the lymph node could help determine the benign or malignant lymph nodes by color doppler ultrasound.So in our study, we would explore the value of EBUS-TBNA technology in the diagnosis of mediastinal enlarged lymph nodes. The value of the lung cancer mediastinal lymph node staging would be study beween EBUS-TBNA and PET/CT.On the other hand we would analyze the characteristic of the EBUS images between the benign and malignant lesions and its diagnosis value. The EBUS-TBNA tecnology might be sure as a higher diagnostic value in the diagnosis of benign and malignant mediastinal lymph nodes by this study.Objectives1. To discuss the diagnosis value of EBUS-TBNA in mediastinal and hilar enlarged lymph nodes. The Patients with mediastinal and hilar enlarged lymph nodes which inclouded lung cancer, metastatic tumor in lung cancer, sarcoidosis, and lymph node tuberculosis would be diagnosed by EBUS-TBNA. The sensitivity, specificity,positive predictive value, negative predictive value and accuracy of EBUS-TBNA would be analyzed by standard calculation formula.2. To explore the value of EBUS-TBNA and PET/CT which in mediastinal lymph node staging of the lung cancer. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the two ways would be analyzed by standard calculation formula. The best cut-off point of the PET/CT SUVmax was analyzed.3. To discuss the EBUS imaging features in benign and malignant lymph nodes,which inclouded the short diameter, medullary morphology, longitudinal/transverse diameter ratio, blood flow. The relationship between the ultrasound imaging features and the malignant lymph nodes would be analized. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS diagnosis would be analyzed bystandard calculation formula. The best cut-off point of the short diameter of lymph nodes was analyzed.Methods1 Object There were 210 patients with the mediastinum and hilum largen lymph nodes in chest CT(computed tomography, CT) to be studied,which from respiratory medicine department, oncology department, radiotherapy department and thoracic surgery in the First Affiliated Hospital of Zhengzhou University from July 1, 2014 to December 31, 2015. The paitents would be evaluated mediastinal lung lymph nodes by EBUS-TBNA,which was in bronchoscope department of the First Affiliated Hospital of Zhengzhou University. All of the paitents followed the inclusion criteria in this study.Inclusion criteria: The age of paitents was more than 18 years old; The patients with enlargement mediastinal lymph node in chest enhancement CT should be diagnosis; The paitents cardiopulmonary function were normal; The paitents could tolerate routine ultrasonic bronchoscope examination; The paitents should be informed consent.Exclusion criteria: The patients were with coagulation dysfunction and bleeding tendency; The patients were using antiplatelet aggregation or anticoagulant drugs treatment; The blood pressure of patients were higher than 140/90 mm Hg and it couldn not be controled by drugs; with severe arthmia. The patients were recent discovered myocardial ischemia and myocardial infarction, severe hypoxemia or respiratory insufficiency. The body base state of paitents was poor and the cardiopulmonary function of paitients was bad. The patients refused to sign the informed consent.This study had got the approval of the first affiliated hospital of zhengzhou university ethics committee, all patients were told preoperative examination and signed the informed consent.2. Equipment2.1 bronchoscope configuration The ultrasonic bronchoscopy was BF-UC260, the needle of EBUS-TBNA was NA-201SX-4022, Ultrasound image processing apparatus was EU-C2000(All from Japanese OLYMPUS company).2.2 PET/CT The 64(52) circular PET/CT was from the Germany Siemens Biograph True Point company. The HM-20 cyclotron and CFN-100 synthesis module was from Japan’s Sumitomo corporation. Medical cyclotron produced by positron emission type18F(fluorine-18,18F) radioactive isotope directly inputed the synthesis of automation.The 18F-PLT(18 F-thymidine nucleoside, 18F-PLT) and 18F-FDG(18 F-fluoro deoxidization glucose, 18F-FDG) were adopted by synthesis of the whole automatic chemical method, and it automatically completed the clinical quality control(the purity were not less than 98%). PET/CT examination required that patients were on an empty stomach more than 6 hours and the blood sugar was in normal range. The conventional whole body imaging would begin after intravenous FDG one hour.2.3 Preoperative examination The preoperative examination inclouded that the enhanced computer Tomography, blood routine, 4 items of blood coagulation which inclouded thrombin time, activated partial thrombin time, plasma fibrinogen, plasma prothrombin time and the ratio of international standardization, electrolyte, electrocardiogram and cardiac color ultrasound for excluding patients with cardiopulmonary diseases.PET/CT examinationrequired that patients were on an empty stomach more than6 hours and the blood sugar was in normal range(3.9 ~ 6.1mmol/l), scaned after intravenous injection of 18F-FDG(3.7 MBq / kg) for 1 hour. The image were analysized by more than 2 experienced nuclear medicine physicians. The ROI(region of interest, ROI) was in primary lung lesions which the radionuclide concentrated.The SUVmax(the maximum standardized uptake value, SUVmax) of ROI werecalculated by the computer software.2.4 Routine bronchoscope examination The patients were required to be sitting posture preoperatively. The 2% lidocaine was for anesthesia glottis and nasal pharyngeal by atomization inhalation. The patients were anesthetized glottis and airway with 2% lidocaine at all levels through fiberoptic bronchoscopy at Supine position. The paitents were monitoried pulse,blood oxygen saturation, heart rate real-time preoperative and intraoperative. After the observation of airway, the target lymph nodes were choosed to EBUS- TBNA.2.5 EBUS-TBNA examination The endoscopic ultrasonography was inserted through the mouth. The endoscopic probe was fixed in the target lymph nodes.The ultrasound examination and blood flow pattern was opened. The blood flow around the lesions sites was observed. According to the chest computer tomography and the echo characteristics of lymph nodes by EBUS. Then the meaningful lymph nodes were chosed to EBUS-TBNA. The lymph node location, number, shape and size were measured and recorded. According to obtain the specimens and puncture risk, each lymph node would be punctured 2-5 needles.2.6 Specimen processing The biopsy tissue strips was pushed out by probe. The specimen was placed on the filter paper, and was fixed in the formaldehyde solution for cytological examination. After the tissue strips were pushed, the remaining specimen were pushed on the glass sheet by syringes. The specimens were pressed to spread out on the two slides, one was fixed in 95% alcohol for pap stain, the other was to Diff-Quick dyeing for rapid diagnosis.The specimens were sent to TCT(thinprep cytologic test,TCT), Cytological smear, tissue embedding wax block slice for pathology examination,bacteriology smear and culture, anti-acid fast stain, mycobacterium tuberculosis DNA PCP(the polymerase chain reaction, PCR))etc. 2.7 Diagnostic criteria According to 2009 IASLC(The International Association for the Study of Lung Cancer, IASLC) Lymph node partition method to record the location of lymph nodes.The TNM staging of lung cancer by the AJCC(the American Joint Commitee on Cancer,AJCC) of version 7, PET/CT with SUVmax(maximum standard uptake values,SUVmax) not less than 2.5 was the malignant diagnosis standard.The Lymph node ultrasonic decision criteria:(1) short diameter: when the biggest cut of lymph node was detected, recorded the length of short diameter.(2)longitudinal/transverse diameter ratio: when the biggest cut of lymph node was detected by ultrasonic, messured the largest and shortest diameter of lymph node and the ratio of the above two.(3) blood flow, blood flow classification by Adler standard,the 0 level was for no blood flow signals.The Ⅰlevel was for a small amount of blood flow, visible only 1-2 dotted blood flow and the blood pipe diameter less than 1 mm.The Ⅱ level was the amount of blood flow and 3~4 major blood vessels was visible,the length of the radius was more than radius of lesions or small blood vessels. TheⅢ level was rich blood flow,and more than four major blood vessels were visible,and blood vessels were traffic into mesh each other.(4) lymph node medulla forms: it was divided into normal or destruction. When medullary was damaged, usually the central door structure of lymph node were damaged or disappeared, and appeared abnomal vasculars.3 statistics analyzing The SPSS l7.0 software was for statistical analysis. The chi-square test to evaluate ultrasonic feature differences in benign and malignant lymph nodes, which inclouded the lymph nodes short diameter ratio, longitudinal/transverse diameter,blood flow and medulla morphological measured by EBUS. The relationship was analysized between ultrasonic characteristics with benign and malignant lymph nodes by Logistic multi-factors analysising. The best cutoff point of lymph nodes short diameter to predict malignant and the best bound values of PET/CT SUVmax were analysized by ROC curve. The sensitivity, specific degree, positive predictive value,negative predictive value and accuracy of EBUS-TBNA, PET/CT and EBUS, which were calculated by standard formulus. Accuracy =(true positive + true negative)/total number of cases, sensitivity= true positive /(true positive + false negative), Specific degrees = true negative /(true negative + false positive), Positive predictive value = true positive /(true positive + false positive),Negative predictive value = true negative /(true negative + false negative).There was a significant difference when the P less than 0.05.Results1. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of EBUS-TBNA in lung cancer paitents with mediastinal metastasis lymph node respectively was 90.8%,100%,100%,93.8%,96.2%, which in outside pulmonary neoplasm respectively was 91.8%, 100%,100%, 97.4%, 95.9%, Which in lung cancer and outside pulmonary neoplasm respectively was 91.2%,100%, 100%,82.6%, 93.8%2. The diagnostic accuracy of EBUS-TBNA in lung cancer mediastinal lymph node staging was higher than that of PET/CT(90.6% vs 78.9%)(χ2=9.323,P=0.002)。3. That of EBUS-TBNA in paitents with negative PET/CT respectively was64.3%, 100%, 100%, 83.6%, 87.3%; that of EBUS- TBNA in patients with positive PET/CT respectively was 93.8%, 100%, 100%, 83.3%, 95.2%. 4. The accuracy of EBUS- TBNA in patients with pathological stage N0, N1, N2, N3 respectively was96.7%, 94.4%, 95.6%, 97.8%; The accuracy of PET/CT in patients with pathological stage N0, N1, N2, N3 respectively was 93.9%, 82.2%, 85.5%, 94.4%. The accuracy of EBUS- TBNA in patients with pathological stage N1, N2 was higher than that of PET/CT(all P<0.05)5. The lymph node malignancy rate of short diameter not less than 1.0cm,longitudinal/transverse diameter ratio less than 1.5, blood flow distribution Ⅱ~Ⅲlevel, abnormal medulla form, which was higher than short diameter less than 1.0 cm,longitudinal/transverse diameter more than 1.5, blood flow 0 ~Ⅰ, normal medulla form(79.8% vs 37.7%, 77.8% vs 44.6%, 84.7% vs 42.9%, 76.7% vs 42.9%)(all P﹤ 0.05).6. The logistic multifactor regression analysis suggested that short diameter not less than 1.0 cm, longitudinal/transverse diameter ratio less than 1.5, blood flow distribution Ⅱ~Ⅲ, abnormal medullary form were all related factors for malignant lymph node(P﹤0.05), and the OR values respectively was 0.223(95%CI = 0.132,0.375), 0.362(95%CI = 0.215, 0.609), 0.375(95% CI = 0.226, 0.2635), 0.253(95%CI = 0.146, 0.438).7. The accuracy in predicting malignant of that the short diameter not less than1.0 cm, longitudinal/transverse diameter ratio less than 1.5, blood flow distributionⅡ~Ⅲ level and abnormal medullary form, which was respectively 74.7%, 67.9%,67.8%, 67.5%. The accuracy of the above four factors combined was 89.3%, which was higher than that of single detection(P﹤0.05).8. ROC curve detection showed that the best cutoff point of the short diameter between the benign and malignant lymph node which measured by EBUS was 8.2mm, and which of PET/CT SUVmax was 4.5.Conclusions1. EBUS-TBNA has a higher clinical value in the diagnosis of mediastinal enlarge lymph node disease. The sensitivity, specificity and accuracy of EBUS-TBNA is higher, which in lung cancer, extra-pulmonary neoplasm, sarcoidosis and lymph node tuberculosis.2. The diagnostic value of EBUS-TBNA is higher in mediastinal lymph node staging of lung cancer compare with PET/CT, especially in which patients with pathological stage N1 / N2, and it still has certain diagnostic value in paitents which PET/CT is negative.3. The lymph nodes short diameter not less than 1 cm, longitudinal/transverse diameter less than 1.5, blood flow distribution Ⅱ~Ⅲ level, abnorm medulla formal,which are all independent risk factors for malignant.4.The optimal boundary value of short diameter is 8.2 mm. The optimal boundary value of PET/CT SUVmax is 4.5. |
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