contrast - enhanced dynamic computed tomography ( ct ) scans of lung cancers provide non - invasive quantitative information regarding perfusion patterns that can be used for the differential diagnosis between malignant and benign pulmonary lesions . moreover , shim et al . showed that peak enhancement of 110 hounsfield units ( hu ) of stage t1 lung cancers on dynamic ct were significantly associated with the presence of mediastinal or hilar nodal metastasis . however , dynamic ct findings of lung adenocarcinoma are affected not only by tumor angiogenesis but also by fibrosis within the tumor . in a recent study , iwano et al . showed that the degree of fibrosis within a stage i lung adenocarcinoma tumor could affect the enhanced pattern on dynamic ct . that is , there was a negative correlation between the amount of fibrosis and the enhancement grade at the early phase of contrast - enhanced dynamic ct in solid types of lung adenocarcinomas . in addition , maeshima et al . reported that the degree of fibrosis within a tumor was a useful prognostic factor for patients with small lung adenocarcinomas ( maximum diameter 30  mm ) . this indicated that preoperative dynamic ct may be able to noninvasively predict the prognoses of patients with small lung adenocarcinomas . therefore , in this study , we focused on the pathological prognostic factors ( lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement ) of small lung adenocarcinomas and compared these results with the findings of contrast - enhanced dynamic ct scans . this retrospective study was approved by our institutional review board with a waiver for informed consent . we reviewed the medical records , postoperative pathological records , and preoperative multidetector row computed tomography ( mdct ) images of patients who underwent surgical lung resections for primary lung adenocarcinomas 30  mm in diameter in our hospital between may 2006 and december 2010 . hilar lung adenocarcinomas and nonsolid types of adenocarcinoma that were invisible on mediastinal window settings for thoracic ct were excluded . patients heavier than 80  kg were also excluded because the concentration of contrast medium used per unit body mass was lower . we recorded patient characteristics ( age and body weight ) from medical records and tumor characteristics ( size , location , scar grade , and tnm classification ( union for international cancer control ( uicc ) 7th edition ) from pathological records . the scar grade based on the report of maeshima et al . is recorded routinely in our hospital in the pathological records as an index of fibrosis in adenocarcinoma : grade 1 , adenocarcinoma without a desmoplastic reaction ; grade 2 , sparse desmoplastic reaction ; grade 3 , dense desmoplastic reaction with diameter of 10  mm ; grade 4 , dense desmoplastic reaction with diameter > 10  mm . we selected 108 consecutive patients with small peripheral lung adenocarcinomas for analysis ( 68 males and 40 females ; mean age 67 years ; age range 4384 years ) . table 1characteristics of patients and tumorscharacteristicsvalueage ( years ) , mean    sd67    8body weight ( kg ) , mean    sd56.8    9.2tumor size ( mm ) , mean    sd20.6    5.9pulmonary lobe ( n )  right upper lobe41  right middle lobe6  right lower lobe19  left upper lobe26  left lower lobe16pathological stage ( n )  i84  ii12  iii11  iv1scar grade ( n )  grade 126  grade 255  grade 318  grade 49 characteristics of patients and tumors all ct scans were performed with a 64-channel mdct scanner ( aquilion64 ; toshiba medical systems , tokyo , japan ) in the craniocaudal direction with inspiratory apnea . the gantry rotation time was 0.5  s. the reconstruction thickness was 1  mm using a standard algorithm . the volume ct dose index ( ctdivol ) was about 30 mgy for one scan . iodine calibration was not performed ; routine calibration against air and water was performed in accordance with the manufacturers recommendations . vascular access was by a cubital vein with a 20-g needle . for vessel enhancement , 96  ml of nonionic contrast medium ( optiray 320 , 320  mg i / ml ioversol , tyco healthcare , tokyo , japan , or iopamiron 370 , 370  mg i / ml iopamidol , bayer healthcare , tokyo , japan ) was used at a flow rate of 3.0  ml / s . ioversol was used for 71 patients with body weight 60  kg and iopamidol was used for 34 patients with body weight > 60  kg . for 3 patients with body weights 40  kg , 80  ml of ioversol was used at a flow rate of 2.5  ml / s . the injection was immediately followed by a saline chaser bolus of 24  ml at the same flow rate using a dual - barrel power injector ( dual shot gx , nemoto kyorindo , tokyo , japan ) . for the early phase , the scan delay was evaluated by an automatic bolus tracking system with a circular region of interest ( roi ) localized on the descending aorta at the level of tracheal bifurcation . for the delayed phase , the scan delay was 90  s after the start of contrast medium injection . this preoperative ct scan protocol was approved as a routine scan by an institutional conference comprised of respiratory medicine , thoracic surgery and radiology . ct images were displayed on a commercial pacs viewer ( rapideye station , toshiba medical systems , tokyo , japan ) at mediastinal window settings ( window width of 350 hu and window center of 40 hu ) . for the quantitative analysis of each ct image , the rois were placed on 3 images of 1-mm slice thickness in the central part of the tumor , and the median value of 3 rois was recorded . a chest radiologist with 16 years of experience reading thoracic cts drew polygonal rois over the tumor without knowledge of the pathological findings . the roi was drawn as large as possible in order to minimize noise , but care was taken to avoid partial volume effects ( figs . , the reader magnified the image for display on the viewer , and drew the lines of rois inside the boundary of tumors . the attenuation values of both the early phase and the delayed phase of enhanced ct minus the baseline plain ct attenuation were defined as early and delay . thus , tumors with a high early enhancement ratio were substantially enhanced in the early phase . at the same time , the delay times of the enhanced ct images on which rois were drawn were recorded from the dicom image tag . lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were not observed in the pathological findings . ( d ) the attenuation value at delayed phase was 72 hu . the early enhancement ratio was 45.8% . lymphatic permeation , and vascular invasion , and pleural involvement were observed in the pathological findings . ( d ) the attenuation value at delayed phase was 71 hu . the early enhancement ratio was 35.1% . mediastinal lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were observed in the pathological findings . lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were not observed in the pathological findings . ( a ) adenocarcinoma tumor of scar grade 3 in the right lower lobe . ( b ) ( d ) the attenuation value at delayed phase was 72 hu . the early enhancement ratio was 45.8% . lymphatic permeation , and vascular invasion , and pleural involvement were observed in the pathological findings . ( a ) adenocarcinoma tumor of scar grade 3 in the right upper lobe . ( b ) mediastinal lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were observed in the pathological findings . we reviewed the medical records , postoperative pathological records , and preoperative multidetector row computed tomography ( mdct ) images of patients who underwent surgical lung resections for primary lung adenocarcinomas 30  mm in diameter in our hospital between may 2006 and december 2010 . hilar lung adenocarcinomas and nonsolid types of adenocarcinoma that were invisible on mediastinal window settings for thoracic ct were excluded . patients heavier than 80  kg were also excluded because the concentration of contrast medium used per unit body mass was lower . we recorded patient characteristics ( age and body weight ) from medical records and tumor characteristics ( size , location , scar grade , and tnm classification ( union for international cancer control ( uicc ) 7th edition ) from pathological records . the scar grade based on the report of maeshima et al . is recorded routinely in our hospital in the pathological records as an index of fibrosis in adenocarcinoma : grade 1 , adenocarcinoma without a desmoplastic reaction ; grade 2 , sparse desmoplastic reaction ; grade 3 , dense desmoplastic reaction with diameter of 10  mm ; grade 4 , dense desmoplastic reaction with diameter > 10  mm . we selected 108 consecutive patients with small peripheral lung adenocarcinomas for analysis ( 68 males and 40 females ; mean age 67 years ; age range 4384 years ) . table 1characteristics of patients and tumorscharacteristicsvalueage ( years ) , mean    sd67    8body weight ( kg ) , mean    sd56.8    9.2tumor size ( mm ) , mean    sd20.6    5.9pulmonary lobe ( n )  right upper lobe41  right middle lobe6  right lower lobe19  left upper lobe26  left lower lobe16pathological stage ( n )  i84  ii12  iii11  iv1scar grade ( n )  grade 126  grade 255  grade 318  grade 49 characteristics of patients and tumors all ct scans were performed with a 64-channel mdct scanner ( aquilion64 ; toshiba medical systems , tokyo , japan ) in the craniocaudal direction with inspiratory apnea . the gantry rotation time was 0.5  s. the reconstruction thickness was 1  mm using a standard algorithm . the volume ct dose index ( ctdivol ) was about 30 mgy for one scan . iodine calibration was not performed ; routine calibration against air and water was performed in accordance with the manufacturers recommendations . vascular access was by a cubital vein with a 20-g needle . for vessel enhancement , 96  ml of nonionic contrast medium ( optiray 320 , 320  mg i / ml ioversol , tyco healthcare , tokyo , japan , or iopamiron 370 , 370  mg i / ml iopamidol , bayer healthcare , tokyo , japan ) was used at a flow rate of 3.0  ml / s . ioversol was used for 71 patients with body weight 60  kg and iopamidol was used for 34 patients with body weight > 60  kg . for 3 patients with body weights 40  kg , 80  ml of ioversol was used at a flow rate of 2.5  ml / s . the injection was immediately followed by a saline chaser bolus of 24  ml at the same flow rate using a dual - barrel power injector ( dual shot gx , nemoto kyorindo , tokyo , japan ) . for the early phase , the scan delay was evaluated by an automatic bolus tracking system with a circular region of interest ( roi ) localized on the descending aorta at the level of tracheal bifurcation . for the delayed phase , the scan delay was 90  s after the start of contrast medium injection . this preoperative ct scan protocol was approved as a routine scan by an institutional conference comprised of respiratory medicine , thoracic surgery and radiology . ct images were displayed on a commercial pacs viewer ( rapideye station , toshiba medical systems , tokyo , japan ) at mediastinal window settings ( window width of 350 hu and window center of 40 hu ) . for the quantitative analysis of each ct image , the rois were placed on 3 images of 1-mm slice thickness in the central part of the tumor , and the median value of 3 rois was recorded . a chest radiologist with 16 years of experience reading thoracic cts drew polygonal rois over the tumor without knowledge of the pathological findings . the roi was drawn as large as possible in order to minimize noise , but care was taken to avoid partial volume effects ( figs . , the reader magnified the image for display on the viewer , and drew the lines of rois inside the boundary of tumors . the attenuation values of both the early phase and the delayed phase of enhanced ct minus the baseline plain ct attenuation were defined as early and delay . thus , tumors with a high early enhancement ratio were substantially enhanced in the early phase . at the same time , the delay times of the enhanced ct images on which rois were drawn were recorded from the dicom image tag . 
 figure 1(a ) adenocarcinoma tumor of scar grade 2 in the left upper lobe . lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were not observed in the pathological findings . ( d ) the attenuation value at delayed phase was 72 hu . the early enhancement ratio was 45.8% . lymphatic permeation , and vascular invasion , and pleural involvement were observed in the pathological findings . ( d ) the attenuation value at delayed phase was 71 hu . the early enhancement ratio was 35.1% . mediastinal lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were observed in the pathological findings . ( a ) adenocarcinoma tumor of scar grade 2 in the left upper lobe . ( b ) lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were not observed in the pathological findings . ( d ) the attenuation value at delayed phase was 72 hu . the early enhancement ratio was 45.8% . lymphatic permeation , and vascular invasion , and pleural involvement were observed in the pathological findings . ( a ) adenocarcinoma tumor of scar grade 3 in the right upper lobe . ( b ) ( d ) the attenuation value at delayed phase was 71 hu . the early enhancement ratio was 35.1% . mediastinal lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement were observed in the pathological findings . we statistically compared the early enhancement ratios between the presence and absence of each pathological finding ( lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement ) by t tests . patients were then divided into 2 groups based on the early enhancement ratio : early enhancement ( early enhancement ratio 50% , n  =  41 ) and delayed enhancement ( early enhancement ratio < 50% , n  =  67 ) . clinical characteristics ( age , weight , and tumor size ) were compared by t tests . for all adenocarcinomas evaluated , the mean    sd of early , delay , and the early enhancement ratio were 20    15 hu , 45    18 hu , and 44    32% , respectively . the scan delay times ranged from 20 to 36  s ( mean  =  27  s ) at the early phase and from 91 to 95  s ( mean  =  92  s ) at the delayed phase . table 2 shows the results for the early enhancement ratios for the presence and absence of 4 pathological findings . the early enhancement ratio in the group with lymph node metastasis was significantly lower than that in the group without lymph node metastasis ( p  <  0.001 ) . the early enhancement ratio in the group with lymphatic permeation was significantly lower than that in the group without lymphatic permeation ( p  =  0.002 ) . the early enhancement ratio in the group with vascular invasion was significantly lower than that in the group without vascular invasion ( p  =  0.002 ) . the early enhancement ratio in the group with pleural involvement was lower than that in the group without pleural involvement , although the difference was not significant ( p  =  0.089 ) . table 2comparisons of early enhancement ratios between the presence and absence of pathological findingspathological findingspresent(+ ) or absent ( )nearly enhancement ratio ( % ) p valuelymph node metastasis(+)2124.9    16.1<0.001()8748.6    33.5lymphatic permeation(+)2230.0    18.20.002()8647.5    34.1vascular invasion(+)1626.5    20.10.002()9247.0    33.1pleural involvement(+)5739.0 comparisons of early enhancement ratios between the presence and absence of pathological findings p values were determined by t tests . table 3 shows the results for comparisons between early enhancement tumors and delayed enhancement tumors . there were no significant differences between the 2 groups for patients characteristics ( age , body weight ) and tumor size . for the pathological findings , lymph node metastasis , lymphatic permeation , and vascular invasion were significantly more frequent in the delayed enhancement tumors than in the early enhancement tumors ( p  <  0.001 , p  =  0.008 , and p  =  0.005 , respectively ) . however , there were no significant differences between the 2 groups for pleural involvement ( p  =  0.515 ) . in addition , higher scar grade neoplasms were significantly more frequent in the delayed enhancement neoplasms ( p  =  0.001 ; fig . 4 ) . 
 figure 4bar chart showing the numbers of each scar grade of adenocarcinomas in the early enhancement group ( n  =  41 ) and delayed enhancement group ( n  =  67 ) . higher scar grade neoplasms were significantly more frequent in the delayed enhancement neoplasms ( p  =  0.001 ) . table 3comparisons between early enhancement tumors ( early enhancement ratio 50% ) and delayed enhancement tumors ( early enhancement ratio < 50%)early enhancement tumorsdelayed enhancement tumorsp valuenumber of cases4167age ( years)67    967    70.687weight ( kg)58.9    10.055.5    8.60.067tumor size ( mm)19.3    6.121.4    5.70.079pathological findings  lymph node metastasis ( n12)1 ( 2.4)20 ( 29.9)<0.001  lymphatic permeation ( ly1)3 ( 7.3)19 ( 28.4)0.008  vascular invasion ( v1)1 ( 2.4)15 ( 22.4)0.005  pleural involvement ( pl13)20 ( 48.8)37 ( 55.2)0.515numbers in parentheses are percentages . p values for age , weight , and tumor size were determined by t tests . bar chart showing the numbers of each scar grade of adenocarcinomas in the early enhancement group ( n  =  41 ) and delayed enhancement group ( n  =  67 ) . higher scar grade neoplasms were significantly more frequent in the delayed enhancement neoplasms ( p  =  0.001 ) . comparisons between early enhancement tumors ( early enhancement ratio 50% ) and delayed enhancement tumors ( early enhancement ratio < 50% ) numbers in parentheses are percentages . p values for age , weight , and tumor size were determined by t tests . several histopathological studies have shown that the amounts of intratumoral fibrosis were significantly correlated with patients prognoses . classified small lung adenocarcinomas into 6 subtypes based on tumor growth patterns and showed that active fibroblastic proliferation in the scar was an important prognostic factor for peripheral - type small adenocarcinomas of the lung . maeshima et al . adopted the scar grade as a semi - quantitative index of fibrosis within lung adenocarcinoma and reported that it was significantly correlated with the pathological stage and prognosis of patients with small adenocarcinomas in the lung . in addition , they reported that the relationship between the scar grades was significantly associated with lymph node metastasis , lymphatic permeation , vascular invasion , and pleural invasion . therefore , if we can noninvasively evaluate the degree of intratumoral fibrosis and the prognosis based on preoperative diagnostic imaging , it may be useful for planning the therapeutic strategies for patients with small adenocarcinomas . many investigators have reported that nonsolid type adenocarcinomas on high - resolution ct , which included no fibrosis , had better prognoses . however , there has been little in the way of radiological methods to quantify the amounts of intratumoral fibrosis in solid types of lung adenocarcinomas . contrast enhancement of small lung adenocarcinomas in the early phase , when the contrast agent is predominantly in the intravascular component , is negatively correlated with the degrees of fibrosis within the neoplasms . this may result from the smaller intratumoral blood spaces and blood flow in those neoplasms with abundant fibrosis , resulting in an absolutely lower volume of contrast inflow into this type of tumor . in contrast , when there are enhancements in the delayed phase , when contrast enhancement depends primarily on extravascular  extracellular components , neoplasms with abundant internal fibrosis show prominent enhancement in the delayed phase due to an increased extravascular  extracellular component . . showed that contrast - enhanced dynamic ct findings could semi - quantify fibrosis in solid and partly solid types of adenocarcinomas . that is , the early enhancement ratio of a dynamic ct was significantly and negatively correlated with the degree of fibrosis within the neoplasms . therefore , we also adopted the early enhancement ratio as an index of intratumoral contrast enhancement in the present study . as a result , the group of delayed enhancement neoplasms with early enhancement ratios < 50% included significantly more adenocarcinomas with extensive fibrosis . as noted above , maeshima et al . reported that the degree of fibrosis within small lung adenocarcinomas was significantly correlated with the pathological stage and the prognosis of the patients . they indicated that a preoperative dynamic ct could noninvasively predict the prognosis of patients with lung adenocarcinoma . therefore , in the present study , we also investigated the possible correlation between the preoperative dynamic ct findings and the postoperative histopathological findings that affect prognosis . based on our results , the early enhancement ratios of neoplasms that had lymph node metastasis , lymphatic permeation , and vascular invasion were significantly lower . in addition , in those neoplasms with low early enhancement ratios ( < 50% ) , lymph node metastasis , lymphatic permeation , and vascular invasion were significantly more frequent . these findings indicate that dynamic ct findings of small adenocarcinoma are useful for predicting prognosis . in addition , a dynamic ct may be able to noninvasively evaluate intratumoral fibrosis and predict prognosis before surgery ; the scar grade can predict prognosis only after surgery . our data demonstrated that even a small adenocarcinoma could metastasize to hilar or mediastinal lymph nodes . if we can predict high invasiveness of a tumor by preoperative dynamic ct findings , we may prevent residual lymph node metastases by means of proper removal of the lymph nodes . the early enhancement ratio was significantly correlated with vascular and lymphatic vessel invasion , but was not significantly correlated with pleural involvement . we suggest the reason is that pleural involvement is influenced not only by tumor progression but also by the distance between the tumor and the pleura . in addition , the early enhancement ratio might reflect factors involved with tumor vessel invasion . several studies have reported that vascular endothelial growth factor ( vegf ) , which promotes proliferation of tumor blood and lymphatic vessels , affected the dynamic ct findings of lung adenocarcinomas . further investigation is needed to determine the relationship between fibrosis and angiogenesis in lung adenocarcinoma . first , we reviewed postoperative pathological records to evaluate the pathological prognostic factors , although we did not evaluate survival rates after surgery . however , many studies have provided evidence that lymph node metastasis , lymphatic permeation , and vascular invasion are prognostic factors for peripheral lung adenocarcinomas . second , we investigated dual - phase dynamic scans using single - source mdct in this study . recently , several studies have demonstrated the usefulness of perfusion ct imaging using dual - source mdct for the differentiation between benign and malignant lesions and the assessment of tumor angiogenesis . third , we could not use automatic segmentation software to measure the attenuation value of whole tumor . as an alternative , we measured the 3 rois in the central part of the tumor . therefore , our results may contain some measurement error although the roi was drawn as large as possible in order to minimize noise , but care was taken to avoid partial volume effects . in conclusion , there was a significant correlation between the early enhancement ratio of enhanced dynamic ct and the pathological prognostic factors of small lung adenocarcinomas . in those tumors with low early enhancement ratios ( < 50% ) , lymph node metastasis , lymphatic permeation , and vascular invasion were significantly more frequent .
abstractabstract purpose : to compare pathological prognostic factors of small lung adenocarcinomas with findings of contrast - enhanced dynamic computed tomography ( ct ) scans . materials and methods : we evaluated 108 patients with lung adenocarcinomas    30  mm in diameter who underwent dynamic ct scans ( 8096  ml of contrast material , 2.53  ml / s injection ) and tumor resections . 
 attenuation values of both the early phase ( 2036  s after injection ) and delayed phase ( 9195  s ) of enhanced ct minus baseline plain ct attenuation were defined as early and delay . 
 the early enhancement ratio was defined as early/delay100 ( % ) . 
 we statistically compared the early enhancement ratios between the presence and absence of each pathological finding ( lymph node metastasis , lymphatic permeation , vascular invasion , and pleural involvement ) . 
 patients were divided into 2 groups based on early enhancement ratios : ratio 50% ( n  =  41 ) and ratio < 50% ( n  =  67 ) and we statistically compared these 2 groups . 
 results : the early enhancement ratios in the group with lymph node metastasis , lymphatic permeation , and vascular invasion were significantly lower than in the group without these findings ( 24.9% vs 48.6% ; p  < 
 0.001 , 30.0% vs 47.5% ; p  =  0.002 , and 26.5% vs 47.0% ; p  =  0.002 , respectively ) . 
 lymph node metastasis , lymphatic permeation , and vascular invasion were significantly more frequent in tumors with a ratio < 50% than in tumors with ratio 50% ( p  <  0.001 , p  =  0.008 , and p  =  0.005 , respectively ) . 
 conclusions : there was a significant correlation between the early enhancement ratio of enhanced dynamic ct and the pathological prognostic factors in small lung adenocarcinomas .