recent advances in computed tomography ( ct ) scanning technology have enabled the detection of many lung cancers , particularly adenocarcinoma , at an earlier and potentially more curable stage than was previously possible .
however , the true clinical significance of small tumors found through screening is unknown , as no differences in mortality between screened and unscreened individuals have been observed [ 2 , 3 ] .
thus , treatment strategies for small tumors displaying ground - glass opacity ( ggo ) remain controversial .
the purpose of this study is to evaluate the one - dimensional quantitative ct value of ggo on high - resolution ct ( hrct ) images using computer - aided diagnosis to retrospectively select  follow - up or resection  strategies for ggo .
between april 2001 and march 2010 , a total of 54 nodules with ggo in 52 patients were resected at our hospital . during this period , we recommended resection of ggo lesions that did not decrease in size during 3  months of follow - up .
pathologic specimens demonstrated adenocarcinoma in 47 nodules , atypical adenomatous hyperplasia ( aah ) in 4 nodules , and lymphoproliferative disorder in 1 nodule . of these ,
44 nodules in 42 patients with pure or mixed ggos 2  cm in size were evaluated in this retrospective analysis .
pure ggo was defined as a shadow completely occupied by a hazy increased attenuation of the lung , with reservation of the bronchial and vascular margins in the lesion with no solid regions on hrct .
mixed ggo was defined as a heterogeneous attenuation with a solid portion obscuring the underlying vascular markings .
un - enhanced ct scans were performed from lung apices to bases during breath holding at mid - inspiration using a ct scanner ( aquilion 64 , toshiba , tokyo , japan ) .
the helical scanning protocol was as follows : 120  kvp ; 200  ma ; 0.5-s scanning time ; window level , 500 hounsfield units ( hu ) ; window width , 1.600  hu ; and a 512    512 matrix corresponding to a pixel size of approximately 0.6  mm .
hrct images were reconstructed at 0.5  mm intervals with a high - spiral - frequency algorithm ( bone algorithm ) .
maximum diameter and one - dimensional mean ct ( m - ct ) value of this diameter were measured using a computer graphics support system ( hope / drable - ex .
fujitsu , tokyo , japan ) that displays a ct density profile across the tumor ( fig .  1).fig .  1the ct image with a profile of the density across the tumor .
the profile of pure ggo revealed an almost flat curve , and the m - ct value was calculated to be 760  hu ( a ) .
the profile of mixed ggo revealed that the ct value of the solid portion was higher than the ggo portion , and the m - ct value was calculated to be 440  hu ( b ) the ct image with a profile of the density across the tumor .
the profile of pure ggo revealed an almost flat curve , and the m - ct value was calculated to be 760  hu ( a ) .
the profile of mixed ggo revealed that the ct value of the solid portion was higher than the ggo portion , and the m - ct value was calculated to be 440  hu ( b ) histologic findings of adenocarcinomas were classified according to the criteria of the world health organization   and the criteria of noguchi et al . .
is as follows : type a ( localized bronchioloalveolar carcinoma lbac ) , type b ( lbac with foci of collapse of alveolar structure ) , type c ( lbac with foci of active fibroblastic proliferation ) , type d ( poorly differentiated adenocarcinoma ) , type e ( tubular adenocarcinoma ) , type f ( papillary adenocarcinoma with compressive and destructive growth ) .
aah was defined as a proliferation of minimally atypical cuboidal type ii pneumocytes with gaps between the cells .
we classified aah and type a and b as to pre - invasive lesions , and type c , d , e , and f as invasive lesions .
the differences in mean and sd values were analyzed between groups using a two - tailed student s t test .
patients ranged in age from 39 to 83  years ( median 62  years ) .
the maximum tumor dimension was 10  mm in 19 nodules , 1115  mm in 11 nodules , and 1620  mm in 14 nodules .
the m - ct values were 559    133  hu for pure ggo and 355    144  hu for mixed ggo .
the mean interval from first detection of focal ggo to pulmonary resection was 11.9  months ( range 348  months ) .
surgical procedures included lobectomy in 19 patients , segmentectomy in 6 patients , and partial resection in 19 patients .
the pathologic specimens demonstrated adenocarcinoma in 22 nodules , bronchioloalveolar carcinoma ( bac ) in 18 nodules , and aah in 4 nodules .
pure ggos consisted of 16 pre - invasive lesions ( type a , type b , and aah ) and 6 invasive lesions ( types c , d , e , and f ) , while mixed ggos consisted of 6 pre - invasive lesions and 16 invasive lesions .
none of the 27 patients who underwent lymph node dissection or sampling had lymph node involvement .
all patients , except for 1 died from other disease , remain alive with no evidence of tumor recurrence to date , with a median follow - up of 41  months .
figure  2 illustrates the distributions of m - ct value of maximum diameters for pre - invasive lesions ( aah , type a , and type b ) and invasive lesions ( types c , d , e , and f ) .
the m - ct value was 682    64  hu ( range ) for aah lesions , 544 
  179 ( range ) for type a lesions , 496    147 ( range ) for type b lesions , and 371    142 ( range ) for invasive lesions .
aah had a significantly lower m - ct value than type b. aah , type a , and type b lesions had significantly lower m - ct values than invasive lesions ( p  <  0.05 ) .
no significant differences in m - ct values were observed between aah and type a lesions or between type a and type b lesions .
the m - ct values of aah lesions were all 600  hu ; in contrast , most of the m - ct values for invasive lesions were > 600  hu . based on these findings , a ct value of 600  hu appears to represent a cutoff value between aah and invasive lesions.fig . 
2the m - ct values were 682    64  hu ( range ) for aah lesions , 544 
  179 ( range ) for type a lesions , 496    147 ( range ) for type b lesions , and 371    142 ( range ) for invasive lesions .
aah , type a , and type b lesions had a significantly lower m - ct values than invasive lesions ( p  <  0.05 ) . no significant differences in m - ct values were observed between aah and type a lesions or between type a and type b lesions .
the m - ct value of aah lesions were all 600  hu , while most of the m - ct values of invasive lesions were > 600  hu the m - ct values were 682    64  hu ( range ) for aah lesions , 544 
  179 ( range ) for type a lesions , 496    147 ( range ) for type b lesions , and 371    142 ( range ) for invasive lesions .
aah , type a , and type b lesions had a significantly lower m - ct values than invasive lesions ( p  <  0.05 ) .
no significant differences in m - ct values were observed between aah and type a lesions or between type a and type b lesions .
the m - ct value of aah lesions were all 600  hu , while most of the m - ct values of invasive lesions were > 600  hu figure  3 illustrates the relationship between m - ct value and maximum diameter of all ggo lesions .
all seven ggo lesions with a maximum diameter 1  cm and m - ct value 600  hu were pre - invasive lesions , while 16 of 22 ( 73  % ) cases with a maximum diameter > 1  cm and m - ct value > 600  hu were invasive lesions ( a).fig . 
3a , b relationship between m - ct value and maximum diameter of all ggo lesions .
all seven ggo lesions with a maximum diameter 1  cm in the maximum diameter and m - ct value 600  hu were pre - invasive lesions , while 16 of 22 ( 73  % ) with a maximum diameter > 1  cm and m - ct value > 600  hu in m - ct were invasive lesions a , b relationship between m - ct value and maximum diameter of all ggo lesions .
all seven ggo lesions with a maximum diameter 1  cm in the maximum diameter and m - ct value 600  hu were pre - invasive lesions , while 16 of 22 ( 73  % ) with a maximum diameter > 1  cm and m - ct value > 600  hu in m - ct were invasive lesions m - ct value and maximum diameter of ggo lesions are significant predictive factors of invasiveness of the tumor . ggo lesions with a maximum diameter > 1  cm and m - ct value > 600  hu are highly diagnosed as invasive lesions .
the diagnostic accuracy is 73  % ( 32/44 ) ( sensitivity 73  % , specificity 73  % , positive predictive value 73  % , negative predictive value 73  % ) ( b ) .
figure  4 illustrates the relationship between m - ct value and maximum diameter of pure ggo and mixed ggo .
all ggo lesions with a maximal diameter 1  cm and 600  hu are pure type ( a ) .
although , ggo lesions of both categories with a maximum diameter > 1  cm and m - ct value > 600  hu are highly diagnosed as invasive lesions , specificity of pure ggo were significantly better than that of mixed ggo ( b).fig . 
4a , b relationship between m - ct value and maximum diameter of pure and mixed type ggo lesions .
cm in maximum diameter and 600  hu in m - ct value are all pure type .
although , ggo lesions of both categories with a maximum diameter > 1  cm and m - ct value > 600  hu are highly diagnosed as invasive lesions , specificity of pure ggo were significantly better than that of mixed ggo a , b relationship between m - ct value and maximum diameter of pure and mixed type ggo lesions .
cm in maximum diameter and 600  hu in m - ct value are all pure type .
although , ggo lesions of both categories with a maximum diameter > 1  cm and m - ct value > 600  hu are highly diagnosed as invasive lesions , specificity of pure ggo were significantly better than that of mixed ggo
ggo is defined as a shadow completely occupied by a hazy increased attenuation of the lung , with reservation of the bronchial and vascular margins in the lesion on hrct .
although ggo is a nonspecific finding that may be caused by various disorders , including inflammatory disease , fibrosis , and neoplastic disease , the pathologic diagnoses of ggo in this study , adenocarcinoma in 47 patients ( 90  % ) and aah in 4 patients ( 8  % ) , were shown to be neoplastic lesions , and all patients with adenocarcinoma had t1n0m0 disease .
these results suggest that persistent focal ggo is a significant sign of early - stage adenocarcinoma .
many radiologic studies of small lung adenocarcinomas have demonstrated a strong correlation between ct findings and pathologic features .
several authors have classified small lung lesions into nonsolid ( pure ) ggo type , partly solid ( mixed ) ggo type , and solid type , and have suggested that pure type and mixed type with small solid components are almost always non - invasive carcinomas [ 710 ] .
however , it is sometimes difficult to differentiate between pure and mixed ggo , and between high - density ggo and solid tumor .
classified homogeneous ( so - called  pure  ) ggo into pure ggo and semiconsolidation to evaluate the differences in density within the tumor , and stated that pathologically , semiconsolidation tends to be adenocarcinoma with invasive foci .
although the differentiation between pure ggo and semiconsolidation is unclear in their report , density within homogeneous ggo appears to be an important factor for predicting tumor invasiveness .
ikeda et al . reported that the 75th percentile ct value analyzed by three - dimensional computerized quantification of ggo lesions was the optimal ct value for differentiating between aah , bac and adenocarcinoma .
these investigators noted that ct cutoff value of 584  hu was optimal for differentiation between aah and bac , and 472  hu was optimal for differentiation between bac and adenocarcinoma .
used histograms of ct pixel numbers for aah and nonmucinous adenocarcinoma to quantify peaks and mean numbers of ct pixels , and found the mean value of mean ct values to be 697    56  hu for aah lesions and 541    73 for bac lesions .
these investigators noted that the peak ct value on the histogram is the most frequent value observed in the tumor , and that the effect of vessels and bronchi within the tumor can be ignored .
although the one - dimensional quantitative m - ct value can be slightly affected by the densities of vessels or bronchi within the tumor , this calculation method is straightforward , and can similarly estimate pure ggo and mixed ggo .
the present study demonstrates that an m - ct value of 600  hu may represent a cutoff value demarcating aah versus invasive lesions .
we believe that this finding could significantly impact the selection of therapeutic strategies for ggo lesions .
although aah is usually discovered incidentally during microscopic examination of surgically resected lung specimens , a recent increase in the detection of aah as pure ggo has occurred .
pathologically , aah was classified as a premalignant lesion in the 1999 world health organization classification .
thus , while the clinical and pathological features of aah have become clearer , therapeutic strategy for aah lesions have not .
aah is considered to be a precursor of bac or adenocarcinoma [ 1719 ] ; however , no reports of progression of aah to bac or adenocarcinoma have been published .
we believe that at time , pure ggo lesions that are suspected to be aah based on m - ct values are now possible to follow - up .
whether ggo lesions that are suspected to be bac should be resected or followed up also remains controversial .
recently , several researchers reported that for noninvasive lesions identified on hrct , careful observation without surgical intervention represents a valid treatment options [ 2022 ] . according to the interim guidelines suggested by godoy and nadich , isolated lesions with pure ggo that are 5  mm
do not necessarily require ct follow - up , since they almost always represent foci of aah , but for lesions between 5 and 10  mm , follow - up is requisite pending better definition of their true nature ; lesions > 1  cm should be assumed to be bac or invasive adenocarcinoma , but surgery should be considered particularly if the nodule is growing or if an increase in attenuation or development of a solid component is observed .
diligent long - term follow - up is the natural history of pure ggo , and should be conducted to determine whether surgical intervention is acceptable or unnecessary .
however , we believe that early detection and early therapy of some primary lung cancers with ggo is important for improving individual prognoses for the following reasons . first , pure ggo lesions are not all histologically pre - invasive lesions , as some have an invasive adenocarcinoma component , such as noguchi s type c. second , some researchers have reported the concept of a multi - step progression from aah through localized bac ( type a and b ) to advanced adenocarcinoma with a replacement growth pattern ( type c ) [ 1719 ] .
third , patients with noguchi s type c lesions have a worse 5-year survival rate ( 75  % ) than patients with type a or b lesions ( 100  % ) . ggo lesions with a maximum diameter > 1  cm and m - ct value > 600  hu are absolute indication of operation , because those lesions were highly diagnosed as invasive lesions .
ggo lesions with a maximum diameter 1  cm and m - ct 600  hu should be observed , because all seven lesions were preinvasive lesions .
although , ggo lesions with a maximum diameter > 1  cm or m - ct value > 600 
hu are possible to be observed , we think these lesions should be resected because it is more important to avoid observation for invasive lesions than resection for preinvasive lesions .
it is noteworthy that pure ggo are not all preinvasive lesions , and specificity of pure ggo correlated between invasiveness and maximum diameter and m - ct value is significantly higher than that of mixed ggo .
evaluation of m - ct value is useful for determining  follow up or resection  for ggo , especially pure type .
the usefulness of m - ct value for benign ggo including inflammatory disease , fibrosis , and so on is unclear , because 98  % of removed ggo in this study is malignant neoplasm including aah .
we think persistent ggo is almost all neoplasms , so differentiating benign and malignant is more important solid lesions than ggo lesions .
evaluation of m - ct value is useful for determining  follow up or resection  for ggo , especially pure type .
although the number of cases is small , all lesions with a maximum diameter 1  cm and m - ct 600  hu are pre - invasive lesions . therefore , observation may be indicated for this type of ggo lesion .
 objectivedifferentiation of atypical adenomatous hyperplasia ( aah ) , bronchioloalveolar carcinoma ( bac ) , and invasive carcinoma on computed tomography ( ct ) is useful for determining  follow - up or resection  strategies for lesions displaying ground - glass opacity ( ggo ) . 
 the purpose of this study is to evaluate one - dimensional quantitative ct values of ggo on high - resolution ct ( hrct ) images using computer - aided diagnosis.methodsbetween april 2001 and march 2010 , a total of 44 nodules in 42 patients with pure or mixed ggos 2  cm were retrospectively evaluated . 
 maximum diameter and one - dimensional mean ct ( m - ct ) value of the diameter were measured using a computer graphics support system ( hope / drable - ex , fujitsu , tokyo , japan ) that displays a ct density profile across the tumor.resultsm-ct values were 682    64  hu ( range ) for aah lesions , 544  
   179 ( range ) for type a lesions , 496    147 ( range ) for type b lesions , and 371    142 ( range ) for invasive lesions . 
 aah lesions had a significantly lower m - ct value than type b lesions . 
 aah , type a , and type b lesions had significantly lower m - ct values than invasive lesions ( p  <  0.05 ) . 
 all seven ggo lesions with a maximum diameter 1  cm and m - ct value 600  hu were pre - invasive lesions , while 16 of 22 ( 73 % ) cases with maximum diameter > 1  cm and m - ct value > 600  hu were invasive lesions.conclusionobservation may be indicated for ggo lesions with a maximum diameter 1  cm and m - ct value 600  hu . 
Introduction
Patients and methods
Results
Discussion
Conclusion