| BackgroundWith increases in the clinical utilization of computed tomography(CT)in recent years,the pulmonary nodule detection rate has increased tremendously [1-3].In several large screening studies of lung cancer,the pulmonary nodule detection rate has increased from 8 to 51%.Malignant nodules account for 1.1 to 12% of these nodules[2].In fact,small pulmonary nodules,most of which have a diameter of < 7 mm and shows benign,can be detected by chest CT in most smokers[4].The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer.The best management strategy for lung nodules is not standardized[3],the clinical treatment process is very confusing.Therefore,an optimal risk assessment and management strategy for pulmonary nodules is urgently needed in clinical practice.As Fleishner association describes,pulmonary nodules is completely surrounded by aerated lung tissues,and observed in X-ray images as single shadow with well-defined margin with a diameter ? 3 cm.Nodules with a diameter less than 1 cm are defined as small nodules [5,6],those less than 8 mm as subcentimeter nodules,and those less than 4 mm as micronodules [7].They may be caused by lung cancer,metastatic carcinoma,infection,scarring or benign lesions [2].Early diagnosis of malignant nodules can significantly improve the five years survival rate of lung cancer,which is especially important for the treatment of lung cancer.Those nodules measuring less than 8 mm show little potential for malignancy in the near future,or have a long doubling time.Fleishner and the American College of Chest Physicians(ACCP)guidelines recommend that nodules measuring no more than 4 mm which is low risk do not need follow-up and the high-risk group was followed up with CT annually;those between 4 and 8 mm need follow-up with 2 to 3 CTs,and over 2 years,the nodules should be evaluated for malignancy based on changes in nodule volume and doubling time.Nodules measuring 8mm and above show a significantly increased risk of malignancy,which should be evaluated based on clinical data or prediction models.They are often definitively diagnosed on the basis of histological specimens obtained via biopsy [8].Although surgery is efficacious and associated with probably the best survival for early lung cancer,it aslo may lead to complications [2,9],and is not necessary for benign pulmonary nodules or later malignant changes.Many studies suggest that benign and malignant solitary pulmonary nodules can be accurately distinguished by PET-CT [10].However,FDG-PET can obtain the false positive results(10-25%)in most infectious or inflammatory diseases by activated macrophages;It also can obtain the false negative results in Carcinoid,alveolar cell carcinoma and mucinous tumor nodules due to the small nodule or low metabolic activity,because the metabolism of PET value may be normal or slight increasing [11].Fiberoptic bronchoscopy under fluoroscopy is a simple and safe way of biopsy,but the diagnostic value of peripheral pulmonary nodules is limited,because it is very difficult to reach the peripheral position of small pulmonary nodules,and lesions often not visible under fluoroscopy.It usually could not get enough tissue to completely excluded tumor [12].In recent years,endobronchial ultrasound,electromagnetic navigation bronchoscopy(ENB)and virtual navigation bronchoscopy lung biopsy(VBN)have been used to do lung biopsy.The positive rate is related to the size and position of pulmonary nodule,and the price is expensive,which has not been widely used.Moreover,non-diagnostic result can not be completely excluded tumor [13,14].Percutaneous lung biopsy has unique advantages as a kind of non-surgical biopsy,which is especially sensitive and specific for peripheral pulmonary nodules [2,9].While defining malignancy,its result also can guide the treatment in the case of benign lesions.However,malignancy cannot be completely excluded when its result shows negative [9].Meanwhile,excessive exposure to ray should be avoided during follow-up period for patients with pulmonary nodules.It can also lead to more psychological burden,and may delay the diagnosis and treatment if it is not possible to accurately assess the risk of pulmonary nodules [15].At present,most clinicians often diagnose the malignant or benign pulmonary nodules by using their own experience [16].Currently,the recommendation for estimating the pretest probability of malignancy in all patients with SPNs,whether qualitatively on the basis of clinical evaluations or quantitatively using validated models,remains valid [17.18].The existing risk prediction models of lung nodules mainly include the Mayo model,the VA cooperative study,the Herder model,the Brock model [16,19-21] and the PKUPH model in our country[22].Moreover,it is important to highlight that existing studies have not used more advanced imaging modalities to characterize pulmonary nodules in their analyse.However,there are no large samples or exact prediction models for assessing the cancer risk factors of SPNs,especially in the Chinese population [23].In this study,we retrospectively analyzed the clinical,pathological and imaging data of 1422 patients with SPNs who underwent CT guided percutaneous lung biopsy in our hospital over the past 5 years to screen the risk factors for malignant SPNs,establish a large sample of risk prediction model for solitary pulmonary nodules in China from a sample of consecutive patients(n = 1078)and test the model on data from a separate group of patients(n = 344).We also evaluated the accuracy and calibration of the Mayo Clinic and VA models,which were developed using North American or European populations to estimate the probability of malignancy,to determine whether any differences existed between our model and the Mayo and VA models with respect to cancer risk factors.Analysising the risk factors for complications to evaluate the safety and clinic value of CT guided percutaneous lung biopsy.The aims of this study is to standardize the diagnostic process,improve the early diagnosis and treatment of SPNs by combining with the risk factors and selecting the appropriate patients who is suitable to CT guided percutaneous lung biopsy under the guidance of the risk factors of SPNs.Methods1.ParticipantsWe retrospectively reviewed the Clinical,imaging and pathological datas from consecutive 1422 cases of patients with SPNs who underwent CT-guided needle biopsy in Southwest hospital who were from outpatient or inpatient department(Interventional Radiology Department,the First Hospital of the Third Military Medical University)from Jan 1st of 2011 to March 30 th of 2016(these data were obtained from the PACSKJLCT 08-SYSTEM,Chongqing,China).All the patients were divided into two groups,a development data set(assessed from Jan 1st of 2011 to April 30 th of 2015)and a validation data set(assessed from May 1st of 2015 to March 30 th of 2016).All patients enrolled in this study had pathological diagnostic reports.2.Clinic dataThese reports included clinical data regarding name,gender,ID,outpatient or inpatient,age,smoking history,history of smoking cessation,chief complaint,course of disease,previous medical histories and family histories,repeated percutaneous lung biopsy,bronchoscope,positron emission tomography and combined CT,surgical resction.Histopathological types of percutaneous lung biopsy,bronchoscope and surgical resction were collected.3.SPN CT characteristicsInformation regarding the following chest radiological data was collected for all patients: nodule size(average of the maximum length and width)[24.25],edge characteristics(i.e.,whether the edges featured spiculated protuberances,lobulation alone,spiculation alone,or lobulation and spiculation;and whether the edges were irregular or smooth)[7],density characteristics(i.e.,whether the nodules were solid,purely ground-glass,or partly solid;whether the nodules featured thin cavitations or thickened cavitations;and whether the nodules displayed necrosis and calcification)(Figure 1.)and location(i.e.,whether the nodules were located in the upper,middle or lower lobe).4.Pathologic diagnosisA malignant pathologic diagnosis was based on an examination of tissue obtained via biopsy or surgery.A definitive benign diagnosis was established when a specific benign etiology was confirmed pathologically through biopsy or surgery,when an SPN was found to have been radiographically stable for at least 2 years or when an SPN had been clearly absorbed within a short time.SPNs that did not meet these criteria and patients who did not have follow-up data were classified as undiagnosed.5.The procedure and complications of percutaneous lung biopsyAll the patients have a solitary pulmonary nodule through preoperative chest CT scan.If the nodule was near the pulmonary hila or a blood vessel,we performed enhanced CT of the lesion before or during the biopsy.An average 1 to 3 needles were used during the puncturing process to successfully obtain the samples.The needle depth,needle angle,the need to traverse fissures,No.of puncture pleural,No.of puncture tissue,needle time and the presence of emphysema with the development data set were also collected.Complications of percutaneous lung puncture contained pneumothorax(a little,middle and severe or chest tube insertion),hemorrhage(lung or pleural cavity)and other extremely serious complications.6.Statistical analysisAll statistical analyses,with the exception of those pertaining to the AUC graphs,which were performed using MedCalc,were conducted using SPSS ver.20.0(IBM).Significance was set at p < 0.05.Qualitative variables were expressed as absolute frequencies and percentages,and numerical variables were expressed as the mean ± SD.To assess the differences between the development data set and the validation data set,we analyzed numerical variables using independent samples T-tests,and we analyzed qualitative variables using a chi-square test.We performed logistic regression analysis using potential predictors,including sex,age,chief complaint,cigarette smoking status,previous medical history,family history,nodule size,edge characteristics,density and location,to identify the risk factors for malignant SPNs.A prediction model was developed using the development data set and was validated with the validation data set.We also compared each patient's final diagnosis to the probability of malignancy predicted by the Mayo Clinic and VA models.We assessed model accuracy by calculating the AUCs of ROC.When comparing the performances of the two models,we included patients only if a score was available for each model.We performed logistic regression analysis using potential predictors to identify the risk factors for complications of CT guided percutaneous lung biopsy for SPNs.ResultsA total of 1422 consecutive patients with SPNs were enrolled in this study.The development data set included 1078 patients who were evaluated from Jan 1st of 2011 to April 30 th of 2015,and a separate validation data set included 344 patients who were evaluated from May 1st of 2015 to March 30 th of 2016.All patients enrolled in the study successfully underwent lung biopsy and had biopsy pathology results.1.Clinical data1.1 Demographic data:In the development data set(647 men and 431 women aged 17-87 years,mean 55.41 ± 11.94 years),414 patients had a smoking history and the average smoking index was 38.95 ± 39.71 pack years.54 patients had a history of cancer.In the validation data set(196 men and 148 women aged 13-85 years,mean 55.34 ± 11.24 years),112 patients had a smoking history and the average smoking index was 35.81±20.63 pack years.16 patients had a history of cancer.There were no significant differences between the two groups with respect to the above data(p > 0.05).1.2 SPNs CT characteristics:In the development data set,the average size of the SPNs was 18.43 ± 5.03 mm(ranged from 4.625 mm-29.965 mm),and 98.42% of SPNs were > 8 mm.There were 244,234,83 and 76 cases with the edges of spiculated protuberances,spiculation alone,or lobulation and spiculation,smooth respectively.There were 42 cases with calcification.In the validation data set,the average size of the SPNs was 18.16 ± 5.05 mm(ranged from 5.87 mm-29.515 mm),and 97.67% of SPNs were > 8 mm.There were no significant differences between the two groups with respect to SPN size(p > 0.05).There were 88,73,35 and 76 cases with the edges of spiculated protuberances,spiculation alone,or lobulation and spiculation,smooth respectively.There were 12 cases with calcification.There were no significant differences between the two groups(p > 0.05).In the development data set,there were 363 and 78 cases with the edges of the lobulation alone,irregular respectively.In the validation data set,there were 70 and 46 cases with the edges of the lobulation alone,irregular respectively.The proportion of the former is less than that of the latter(p<0.05).1.3 Histopathology:In the development data set,721 cases of SPNs were malignant lesions(66.883%).There were 539 cases of adenocarcinoma,accounting for about 50% of the total.196 cases were benign lesions(18.182%),include 45 cases of benign tumor,90 cases of tuberculosis,12 cases of fungal infection,and 49 cases of absorption of pneumonia.161 cases of SPNs were non-diagnostic results(14.935%).Among the 721 malignant cases,5 were diagnosed by repeat lung biopsy,and 3 were diagnosed by surgical resection.In the validation data set,236 cases were malignant lesions(68.605%),50 cases were benign lesions(14.535%),and 58 cases were non-diagnostic results(16.860%).There were no significant histopathological differences between the two groups(p > 0.05).There were 169 cases of adenocarcinoma,accounting for about 50% of the total.50 cases were benign lesions(14.535%),include 17 cases of benign tumor,24 cases of tuberculosis,6 cases of fungal infection,and 3 cases of absorption of pneumonia.58 cases of SPNs were non-diagnostic results(14.935%).There were no significant histopathological differences between the two groups(p > 0.05).2.Logistic regression analysis of the risk factors for malignant SPNsFemale gender(OR 3.893,95% CI 1.372-2.319,p < 0.001),age(OR 1.784,95% CI 1.858-8.155,p < 0.001),pack-years of smoking(OR 1.756,95% CI 1.139-2.707,p < 0.05),a previous history of malignancy(OR 3.382,95% CI 1.512-6.283,p < 0.05),nodule size(OR 2.319,95% CI 1.494-3.599,p < 0.001),lobulated and spiculated edges(OR 13.433,95% CI 2.512-71.833,p < 0.001),lobulation alone(OR 2.203,95% CI 1.100-4.416,p < 0.05)and spiculation alone(OR 1.556,95% CI 0.766-3.162,p < 0.05)were risk factors for malignant SPNs,whereas irregular edges(OR 0.276,95% CI 0.101-0.753,p < 0.05)and calcification(OR 0.106,95% CI 0.028-0.410,p < 0.05)were protective factors for malignant SPNs.2.1 Equations for models estimating the pre-test probability of malignant SPNsWe used the following equation in our model: X =-6.173+1.207*Gender+0.580*Age(years)+ 0.520*Pack-year-0.226*Previous extrathoracic disease-0.685*Previous chronic lung disease except cancer+2.739*Malignancy history+0.933*Diameter(mm)+ 0.702*Lobulation + 0.466* Spiculation+ 21.060*Lobulation and Spiculation-1.428*Irregular edges-2.062* Calcification.factors:sex(male 1,female 2),previous medical histories(yes 1,no 0),Image characteristics(yes 1,no 0),Age(<40:1,40-50:2;50-60:3;60-70:4;>70:5)?X:0-30% low risk,30-65% indeterminate risk,>65% high risk.2.2 Receiver operating characteristic(ROC)curve analysis of the Area Under the Curves(AUC values)of the prediction modelsThe AUC values,sensitivity and specificity of our model in the development data set(0.807 ± 0.015,95% CI 0.778-0.834,85.71%,60.36%)and validation data set(0.784 ± 0.027,95% CI 0.731-0.831,70.10%,78.57%)were significantly different from those of the Mayo model(0.566 ± 0.022,95% CI 0.53-0.6,71.99%,41.91%;0.649 ± 0.037,95% CI 0.59-0.706,82.63%,53.57%,p<0.001)and VA model(0.636 ± 0.02,95% CI 0.601-0.669,66.11%,53.01%;0.599 ± 0.036,95% CI 0.539-0.657,63.40%,57.14%,p<0.001).3.The benign or malignant accuracy of percutaneous lung biopsy compared with PET-CT and surgical procedures in the development data set:There were 171 cases of SPNs underwent CT guided percutaneous lung biopsy and PET-CT.The benign or malignant results with them were medium consistency(kappa = 0.534,p<0.001),but the false positive and false negative rate of PET-CT is higher.There were 186 cases of SPNs who underwent CT guided percutaneous lung biopsy and surgery.Among them,169 cases of malignant pathological results whose were confirmed by surgery were diagnosed by percutaneous lung biopsy.In the 17 cases of nondiagnostic pathological results that were diagnosed by percutaneous lung biopsy,4 cases was cancer and the other 14 cases were benign lesions that were confirmed by surgery.There was no significant difference of them in the pathological results(p>0.05).4.Complications of CT guided percutaneous lung biopsy for solitary pulmonary nodules4.1 The operation procedure of CT guided percutaneous lung biopsy in the development data setThe average needle depth was 3.23 ± 1.87 cm,and the average puncture angle was 63.85±16.70°.There were 143 case of SPNs have a history of COPD or pulmonary bullae,accounting for 13.27% of the total.48 cases puncture acrossed oblique fissure,accounting for 4.45% of the total;995 cases had got 1 tissue specimen,83 patients had got 2 or above tissue specimens(7.7%).974 patients were punctured through the pleura for one times,and 104 patients were punctured through the pleura for more times.There was no significant difference between the malignant group and non-malignant group(p>0.05).The average puncture time was 10.38±8.44 s,and the average puncture time of the malignant group was 9.97 ± 8.25 s,and the average puncture time in the non-malignant group was 11.23 ± 8.77 s,and the malignant group was significantly shorter than that in the non cancer group(p<0.05).4.2 Complications of CT guided lung biopsyAmong all the patients enrolled in this study(n = 1422),235 cases of pneumothorax(16.53%),and 125 cases hemorrhage of the lung(8.79%)or 58 cases of pleural cavity(4.08%)were the major complications of percutaneous lung biopsy.206 patients had little pneumothorax,17 patients had moderate pneumothorax,12 patients had massive pneumothorax or were treated with closed thoracic drainage.Subcutaneous emphysema occurred in 14 patients after percutaneous lung biopsy.120 patients had little hemorrhage of the lung(width of CT 2-4cm),5 patients had moderate hemorrhage of the lung(width of CT >4cm).58 patients had hemorrhage of the pleural cavity(4.08%),53 cases were little,the others were moderate or above.2 cases of extremely serious complication were 1 case of asphyxia and 1 case of cerebral infarction after puncturing.And then,the two patients were recovery after therapy.No cases of fatal air embolism or death occurred.4.3 The risk factors for complications of CT guided percutaneous lung biopsy with SPNs in the development data setThe risk of pneumothorax was mainly associated with acrossing oblique fissure(Exp(B)6.080,95% CI 3.141-11.773,p < 0.001),COPD or bulla(Exp(B)4.202,95% CI 2.747-6.428,p < 0.001),location of lower lobes(Exp(B)2.971,95% CI 2.039-4.329,p < 0.001)and middle lobes(Exp(B)1.791,95% CI 1.005-3.192,p < 0.05),and the depth(Exp(B)1.145,95% CI 1.048-1.251,p < 0.05),angle(Exp(B)1.015,95% CI 1.013-1.024,p < 0.05),time with the needle(Exp(B)1.022,95% CI 1.004-1.041,p < 0.05).Besides,we found that the risk of hemorrhage was mainly associated with upper lobe(Exp(B)3.796,95% CI 1.900-7.584,p < 0.001),No.of puncture tissue(Exp(B)2.927,95% CI 1.304-6.570,p < 0.05),needle depth(Exp(B)1.573,95% CI 1.387-1.785,p < 0.001),age(Exp(B)1.027,95% CI 1.004-1.051,p < 0.05)and the size of SPNs(Exp(B)0.948,95% CI 0.900-0.998,p < 0.05).Conclusion1.SPNs in female patients,as well as SPNs featuring a combination of lobulated and spiculated edges or lobulated edges alone,should be evaluated carefully due to the probability that they are malignant.2.We established the largest sampling risk prediction model of SPNs in a Chinese cohort.This model is particularly applicable to SPNs > 8 mm in size.3.Though validated by our different populations,the accuracy of our risk prediction model is high.The sensitivity and specificity of our model were significantly higher than those of Mayo model and VA model.4.Percutaneous lung biopsy under CT guidance is safety,and has high clinic value and low risk of complications for SPNs.The more old patients,small pulmonary nodules,patients with COPD or bullae,depth of puncture needle,ascrossing oblique fissure,the more probability of complications occur. |
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