this was a multicenter , community - based , retrospective observational study of patients with pns , ranging from 8 to 20 mm in diameter , presenting to 18 geographically representative outpatient pulmonary clinics across the united states .
the study was approved at 15 sites by a central institutional review board and at three sites by local institutional review board approval .
four hundred forty sites were identified based on investigator databases and claims data from a large insurance carrier whose coverage population was representative of the overall us population . of these
, 77 sites expressed interest in participating , and 48 sites went on to sign confidentiality agreements .
of these , 17 did not request additional information , leaving 31 sites undergoing qualification review .
eighteen outpatient pulmonary clinics were chosen to participate based on the following criteria : ( 1 ) management of patients with pns , ( 2 ) availability of medical records , and ( 3 ) ability to perform data abstraction .
in addition , investigators targeted enrollment of geographically diverse patients to limit the potential bias associated with differences in practice patterns and to account for variation in disease prevalence ( eg , endemic mycoses ) that could alter management decisions .
patients were identified by querying databases ( eg , billing and scheduling systems ) using five international classification of diseases , ninth revision , clinical modification codes for pn ( 793.1 , 786.6 , 518.89 , 519.8 , 519.9 ) to ensure homogeneity in patient identification and inclusion .
manual chart abstraction was then used to identify those who met the criteria . to minimize selection bias , the sites were not permitted to use additional codes during database query to identify patients . to ensure a systematic sample ,
inclusion criteria included age  40 years and  89 years at the time of nodule finding , presentation to a pulmonologist , nodule size 8 to 20 mm , and definitive diagnosis ascertained by tissue diagnosis or radiographic follow - up for 2 years .
exclusion criteria included chest ct scan performed > 60 days prior to the initial visit , prior diagnosis of any cancer within 2 years of nodule detection , or incomplete chart data .
patients were categorized into three groups by the most invasive procedure performed during management , as follows : surveillance ( serial imaging ) , biopsy ( ct scan - guided transthoracic needle aspiration [ ttna ] or bronchoscopy ) , or surgery ( including mediastinoscopy , video - assisted thorascopic surgery , and/or thoracotomy ) .
clinical data were abstracted retrospectively by designated study staff into an electronic data capture system from initial consultation through establishment of a definitive diagnosis ( ie , pathology results ) or a minimum 2-year follow - up .
data included patient demographic and clinical characteristics , pn characteristics , imaging tests , invasive testing , and surgery .
pet scan reports were reviewed and abstracted where available for a subset of patients . to adjudicate a pet scan report as positive or negative , an algorithm was developed that prioritized the following components of the report from highest to lowest : final radiology impression , description of findings , and standard uptake values ( suvs ) ( e - fig 1 ) .
pet scanning was defined as negative if the report included any of the following statements : no evidence of malignancy , no 18f - fluorodeoxyglucose uptake or hypermetabolic activity , or an suv of < 2.5 .
a positive pet scan was defined as a report that included any of the following statements : concern or suggestion of malignancy , findings that described increased 18f - fluorodeoxyglucose uptake or hypermetabolic activity , or an suv  2.5 . in the 27 cases in which the findings were discordant with the final impression ,
programmed edit checks were built into the electronic data capture system and at the conclusion of chart abstraction , each site provided access to a random 10% sample of deidentified patient records for review .
two previously developed and validated models were used to estimate the pca in each patient .
receiver operating characteristic curves and the area under the curve were generated with 95% cis .
the pca was calculated for each patient and categorized into three groups ( < 5% , 5% to < 65% , and  65% ) .
 or analysis of variance tests were used to compare subgroups , and p values < .05 were considered significant .
a nodule was classified as benign based on confirmed benign pathology or the absence of radiographic change as determined by the managing physician during surveillance for at least 2 years .
multivariate logistic regression was performed to identify factors associated with the use of an invasive diagnostic procedure .
all statistical analyses were performed using sas / stat , version 9.3 ( sas institute inc ) .
four hundred forty sites were identified based on investigator databases and claims data from a large insurance carrier whose coverage population was representative of the overall us population . of these
, 77 sites expressed interest in participating , and 48 sites went on to sign confidentiality agreements . of these , 17 did not request additional information , leaving 31 sites undergoing qualification review .
eighteen outpatient pulmonary clinics were chosen to participate based on the following criteria : ( 1 ) management of patients with pns , ( 2 ) availability of medical records , and ( 3 ) ability to perform data abstraction .
in addition , investigators targeted enrollment of geographically diverse patients to limit the potential bias associated with differences in practice patterns and to account for variation in disease prevalence ( eg , endemic mycoses ) that could alter management decisions .
patients were identified by querying databases ( eg , billing and scheduling systems ) using five international classification of diseases , ninth revision , clinical modification codes for pn ( 793.1 , 786.6 , 518.89 , 519.8 , 519.9 ) to ensure homogeneity in patient identification and inclusion .
manual chart abstraction was then used to identify those who met the criteria . to minimize selection bias , the sites were not permitted to use additional codes during database query to identify patients . to ensure a systematic sample ,
inclusion criteria included age  40 years and  89 years at the time of nodule finding , presentation to a pulmonologist , nodule size 8 to 20 mm , and definitive diagnosis ascertained by tissue diagnosis or radiographic follow - up for 2 years .
exclusion criteria included chest ct scan performed > 60 days prior to the initial visit , prior diagnosis of any cancer within 2 years of nodule detection , or incomplete chart data .
patients were categorized into three groups by the most invasive procedure performed during management , as follows : surveillance ( serial imaging ) , biopsy ( ct scan - guided transthoracic needle aspiration [ ttna ] or bronchoscopy ) , or surgery ( including mediastinoscopy , video - assisted thorascopic surgery , and/or thoracotomy ) .
clinical data were abstracted retrospectively by designated study staff into an electronic data capture system from initial consultation through establishment of a definitive diagnosis ( ie , pathology results ) or a minimum 2-year follow - up .
data included patient demographic and clinical characteristics , pn characteristics , imaging tests , invasive testing , and surgery .
pet scan reports were reviewed and abstracted where available for a subset of patients . to adjudicate a pet scan report as positive or negative , an algorithm was developed that prioritized the following components of the report from highest to lowest : final radiology impression , description of findings , and standard uptake values ( suvs ) ( e - fig 1 ) .
pet scanning was defined as negative if the report included any of the following statements : no evidence of malignancy , no 18f - fluorodeoxyglucose uptake or hypermetabolic activity , or an suv of < 2.5 .
a positive pet scan was defined as a report that included any of the following statements : concern or suggestion of malignancy , findings that described increased 18f - fluorodeoxyglucose uptake or hypermetabolic activity , or an suv  2.5 . in the 27 cases in which the findings were discordant with the final impression , adjudication was performed by two independent pulmonologists and agreement was reached in all cases .
programmed edit checks were built into the electronic data capture system and at the conclusion of chart abstraction , each site provided access to a random 10% sample of deidentified patient records for review .
two previously developed and validated models were used to estimate the pca in each patient . model accuracy was determined by comparing the pca with the final diagnosis .
receiver operating characteristic curves and the area under the curve were generated with 95% cis .
the pca was calculated for each patient and categorized into three groups ( < 5% , 5% to < 65% , and  65% ) .
 or analysis of variance tests were used to compare subgroups , and p values < .05 were considered significant .
a nodule was classified as benign based on confirmed benign pathology or the absence of radiographic change as determined by the managing physician during surveillance for at least 2 years .
multivariate logistic regression was performed to identify factors associated with the use of an invasive diagnostic procedure .
all statistical analyses were performed using sas / stat , version 9.3 ( sas institute inc ) .
eighteen sites were chosen based on geographic location and ability to meet the inclusion criteria ( e - fig 2 ) .
most of the exclusions were based on nodule size ( < 8 mm or > 20 mm ) ( n = 1,314 ) , missing clinical information ( n = 424 ) , or insufficient follow - up time ( n = 303 ) .
there was some variation at both the site level and regionally in the numbers of patients excluded because of missing data ( e - tables 1 , 2 ) . inclusion and exclusion .
eval = evaluation . of the 377 patients included , 283 ( 75% ) had a nodule that was benign , and 94 ( 25% ) had a malignant nodule ( table 1 ) .
the average age was 64.5 years , although patients with malignancy were slightly older ( p < .02 ) .
those with cancer were more likely to be current or former smokers ( p < .0001 ) . although the number of pack - years smoked was significantly higher in those with malignancy ( 45 vs 27 , p < .0001 ) , a substantial proportion of those with benign nodules smoked ( 67% ) .
malignant nodules were larger than benign nodules ( p < .0001 ) , although there did not appear to be a reliable cutoff above which malignancy could be predicted .
twelve percent of nodules  11 mm in size were malignant , whereas 40% of nodules between 16 and 20 mm were malignant .
other cancer diagnoses include spindle cell , mesothelioma , and metastatic cancer . diagnostic outcome by nodule size ( n = 377 ) .
current smokers ( or = 3.29 ; 95% ci , 1.36 - 7.98 ) and patients with larger nodules ( 16 - 20 mm ) were more likely ( or = 4.77 ; 95% ci , 2.95 - 7.72 ) to have a procedure ( biopsy or surgery ) performed .
there was no difference in receipt of procedure based on age , family history of cancer , or geographic location ( table 2 ) .
factors associated with the decision to pursue invasive procedures in the management of pns pn = pulmonary nodule . to further understand nodule management decisions , we used two prediction models to determine the pca for each individual in the study .
these models had very good accuracy in this cohort of patients , with an area under the curve of 0.77 ( 95% ci , 0.72 - 0.81 ) and 0.74 ( 95% ci , 0.69 - 0.80 ) , respectively ( e - fig 3 ) .
because the results did not vary significantly between models , we report the results from the veteran affairs model here and results from the mayo model in e - table 3 .
table 3 lists the pretest probability for cancer by three ranges as defined by the chest guidelines for pn management : low risk ( pca < 0.05 ) , intermediate risk ( pca 0.05 to < 0.65 ) , and high risk ( > 0.65 ) .
the average pca for all patients as calculated by the model was 0.33 , which is only slightly higher than the cancer prevalence of 25% in this population .
thirty - six patients had nodules that had a low risk of malignancy , and all were benign .
slightly more than one - half were followed by serial imaging alone ( n = 20 , 56% ) .
however , despite a pca of < 0.05 , 10 ( 28% ) underwent biopsy , and six ( 17% ) had surgical resection .
the majority of nodules ( n = 300 ) fell into the intermediate - risk category , and 75% of these were benign .
forty - one patients ( 11% ) had high - risk nodules , and 23 ( 58% ) were benign .
the rate of surgical resection was similar among the three groups ( 17% , 21% , 17% , respectively ; p = .69 ) .
alternative cut points for the low - risk category were investigated . all nodules with a pca of < 0.10
were found to be benign , whereas 98% of those with a pca of < 0.15 were benign ( table 4 ) .
( % ) or mean  sd . see table 3 for expansion of abbreviations .
nearly one - half of all patients ( 46% , n = 175 ) were followed with serial imaging only .
the median number of scans performed was three ( range , one to seven ) .
although the majority ( 62% ) had three to five follow - up imaging studies , 4% underwent seven repeat scans .
all nodules in this group were benign by resolution or 2 years of radiographic stability .
biopsy ( ttna or bronchoscopy ) was performed as the most invasive procedure in 125 patients ( 33% ) and was positive for malignancy in 44 ( 35% ) . in more than one - half ( n = 71 , 57% ) ,
a specific benign diagnosis was obtained , whereas 10 ( 8% ) were nondiagnostic and subsequently followed for 2 years .
a total of 77 patients ( 20% ) had surgery as their most invasive test .
prior to surgery , 19 patients ( 25% ) underwent a ttna or bronchoscopy ; 11 had a nondiagnostic biopsy ( seven malignant , four benign at surgery ) , and eight had a benign biopsy result ( three malignant , five benign at surgery )
. overall , malignancy was diagnosed in 65% ( n = 50 ; 95% ci , 53.2%-75.5% ) of those who received surgery , whereas 35% ( n = 27 ; 95% ci , 24.5%-46.8% ) underwent surgery for benign disease . a pet scan was performed in 141 patients ( 37% ) .
overall , pet scan use increased with the intensity of testing ( surveillance 24% , biopsy 42% , surgery 60% , p < .0001 ) .
results were available for 78% ( n = 110 ) of those who underwent pet scanning ( fig 3 ) .
the overall accuracy of pet scanning was 74% , with a false - positive ( fp ) rate of 39% and a false - negative ( fn ) rate of 9% . in 8- to 11-mm
nodules with pet scan data ( n = 38 ) , the fn rate was 10% and the fp rate was 36% . nodules measuring > 11 to 15 mm ( n = 48 ) had fn and fp rates of 9% and 36% , respectively .
the fn rate for pet scans in nodules > 15 mm ( n = 24 ) was 8% , and the fp rate was 55% . pet scan use grouped based on most invasive procedure . a , surveillance .
( n = 175 ) , 42 ( 24% ) underwent pet scanning , for whom 31 reports were available .
seven ( 23% ) had pet scan positive results and were followed with serial imaging . among the 125 patients who underwent biopsy as the most invasive procedure , 53 ( 42% ) underwent pet scan prior to the biopsy .
twenty - nine ( 69% ) were pet scan positive and 13 ( 31% ) were negative , yet all went on to biopsy .
in the 77 patients who underwent surgery , 46 ( 60% ) underwent a preoperative pet scan , for which 37 reports were available .
thirty - one ( 84% ) had pet scan positive results . among the 19 patients who underwent preoperative biopsy ,
this study describing the management of intermediate pns referred to community pulmonologists has several important findings .
first , a quarter of patients referred for intermediate - sized pn evaluation were found to have cancer , emphasizing the importance of the diagnostic evaluation .
third , despite guideline recommendations for surveillance of pns with < 5% pca , 44% of low - risk patients underwent one or more invasive procedures for a benign nodule .
finally , the rate of surgical resection for nodules with various pretest probabilities of malignancy was similar .
this suggests that pulmonologists do not routinely consider pca , are unaware that guidelines exist for nodule management , or do not to follow them . to our knowledge
, this is the first study that documents the prevalence of cancer ( 25% ) in patients with intermediate - sized nodules who are referred to community - based pulmonologists .
this finding has implications for managing pns in the community ; because the risk of cancer is substantial , patients should be managed based on their individualized risk of malignancy .
we found that a high proportion of patients who underwent surgery had benign disease without variation when stratified by the pretest probability of cancer in the nodule .
the rates of resection for benign disease varied from 9% to 23% in screening trials and surgical series .
guidelines recommend surgery if the pretest probability of cancer is high ( pca > 65% ) because a negative biopsy result would not dissuade the physician from pursuing a definitive diagnosis and a positive biopsy result would lead to surgery anyway .
the risk models we evaluated were very good at identifying those patients who did not have cancer ( 100% nodules with < 5% pca were benign ) , yet surgical resection was performed at rates similar to those with a high probability of cancer .
similarly , there was no difference in the proportion of patients undergoing surveillance when stratified by pca .
this suggests that pulmonologists did not readily follow the guidelines because they were unaware of them , did not believe them useful , or overestimated the pca .
this study does not allow us to explore the reasons why pulmonologists aggressively manage some nodules that turn out to be benign .
there are several possible explanations as to what may have led to biopsy or surgery , and they include being misled by pet scan results , patient preferences for diagnostic certainty , an overestimation of the pca , or incentives for procedure referral .
further research is needed to determine the exact drivers of physician decision - making in pn management .
although physicians did not appear to use pca in making decisions about surgery or surveillance , there was a trend toward an increasing use of biopsy as the pca increased ( p = .07 ) .
this finding suggests that pulmonologists may use clinical intuition and experience to distinguish benign from malignant disease , although , admittedly , data on provider years in practice and the proportion who were board certified were not available .
a significant proportion of patients in this study with benign nodules were older and had significant smoking histories and larger nodules , all which typically suggest malignancy and may have led physicians to overestimate pca . in the setting of a positive or ambiguous pet scan interpretation , it is possible that the pulmonologists felt compelled to confirm the abnormal findings with a definitive tissue diagnosis .
the fp rate for pet scans in this study was 39% , as compared with the 5% to 28% rate reported in the literature .
conversely , in some instances , pet scan results did not seem to be taken into account when making management decisions .
for instance , in the surveillance - only group , eight patients with positive pet scans did not undergo further diagnostic procedures .
similarly , in the biopsy group , 13 patients with negative pet scan results still underwent an invasive procedure .
the guidelines advocate a patient - centered approach to decision - making after patients are informed of the pca .
thus , some patients may request surgery despite a low pca because of anxiety about the unknown and an unwillingness to continue with surveillance .
the cornerstone of management for pns has been calculating pca and acting on those calculations .
this study provides evidence that physicians may not use pca to guide decision - making and also suggests that an alternative low - risk - category pca higher than the current chest guidelines would shift more patients into the surveillance management strategy without missing malignancy . although the exact reason for management decisions can not be elicited , it is clear that there is wide variation in the management of pns by pulmonologists .
the goal for nodule management is to efficiently detect lung cancer while decreasing the number of unnecessary invasive procedures .
a number of radiographic improvements , novel tests , and biomarkers have been developed with the potential to help determine the likelihood of malignancy in a nodule .
the use of semiautomated volumetric software to measure the diameter and volume doubling time of a nodule between scans has been used successfully in screening trials to improve the sensitivity , specificity , and negative predictive value of ct scans .
similarly , volumetric measurements added to traditional nodule malignancy prediction models have also been shown to improve the classification of malignancy from 60% to 80% , with better performance than that of the traditional model .
identification of aberrations in airway epithelial cell gene expression , circulating tumor antibodies , plasma proteomics , exhaled breath analysis , and microrna are all being studied actively for use in diagnosing lung cancer .
these novel tests have the potential to further refine nodule management and alleviate the ambiguity of current management strategies .
first , the retrospective design precluded a complete understanding of the rationale for test ordering .
however this design did allow for a definitive final diagnosis to be established with biopsy , surgery , or 2 years of radiographic surveillance .
second , incomplete pet scan data coupled with difficulties in scan interpretation resulted in variations in the definition of a  positive  pet scan . to overcome this limitation
finally , excluding patients who had had a ct scan > 60 days prior to initial consultation may have selectively excluded some patients with low probability nodules .
the findings are generalizable because of the large sample size , geographic distribution , and multicenter design .
the study also focuses on a size range of nodules ( 8 - 20 mm ) that most often presents a diagnostic dilemma for physicians .
nodules smaller than 8 mm are followed with surveillance because the pca is low , pet scans do not reliably characterize small nodules , and biopsy of small nodules is difficult ; by contrast , nodules > 20 mm are likely to undergo biopsy or surgery because the pca is high .
as opposed to other published series , this study allowed for all three management strategies to be studied in detail .
in conclusion , one in four patients referred with a nodule to a community pulmonologist has cancer , making management decisions critical to patient outcomes . to spare patients unnecessary testing , use of a higher pca to define a nodule as low risk seems reasonable .
there is a wide variation in how nodules are managed and the choice of management may be influenced by a variety of factors in addition to pretest probability .
future research should focus on what influences decision - making in pn management so that interventions may be developed to promote proper guideline adherence and avoidance of unnecessary invasive procedures .
 background : pulmonary nodules ( pns ) are a common reason for referral to pulmonologists . 
 the majority of data for the evaluation and management of pns is derived from studies performed in academic medical centers . 
 little is known about the prevalence and diagnosis of pns , the use of diagnostic testing , or the management of pns by community pulmonologists.methods:this multicenter observational record review evaluated 377 patients aged 40 to 89 years referred to 18 geographically diverse community pulmonary practices for intermediate pns ( 8 - 20 mm ) . study measures included the prevalence of malignancy , procedure / test use , and nodule pretest probability of malignancy as calculated by two previously validated models . 
 the relationship between calculated pretest probability and management decisions was evaluated.results:the prevalence of malignancy was 25% ( n = 94 ) . nearly one - half of the patients ( 46% , n = 175 ) had surveillance alone . 
 biopsy was performed on 125 patients ( 33.2% ) . 
 a total of 77 patients ( 20.4% ) underwent surgery , of whom 35% ( n = 27 ) had benign disease . 
 pet scan was used in 141 patients ( 37% ) . 
 the false - positive rate for pet scan was 39% ( 95% ci , 27.1%-52.1% ) . 
 pretest probability of malignancy calculations showed that 9.5% ( n = 36 ) were at a low risk , 79.6% ( n = 300 ) were at a moderate risk , and 10.8% ( n = 41 ) were at a high risk of malignancy . 
 the rate of surgical resection was similar among the three groups ( 17% , 21% , 17% , respectively ; p = .69).conclusions : a substantial fraction of intermediate - sized nodules referred to pulmonologists ultimately prove to be lung cancer . despite advances in imaging and nonsurgical biopsy techniques , invasive sampling of low - risk nodules and surgical resection of benign nodules remain common , suggesting a lack of adherence to guidelines for the management of pns . 