Lung cancer was the leading cause of cancer mortality worldwide in 2008 according to the World Health Organization [
1]. Recently, the results of various randomized controlled trials, such as the National Lung Screening Trial [
2] and the Danish Lung Cancer Screening Trial [
3], have been reported. Although the results of those two randomized trials are controversial (one reported that screening with CT reduces mortality, whereas the other reported the opposite), the usefulness of CT screening is an important public health issue. The detection of indeterminate nodules on CT scans indicates the need for further clinical evaluations, including follow-up CT, percutaneous biopsy, and even thoracotomy. Percutaneous biopsy of lung nodules has been established as a safe diagnostic procedure, with high diagnostic performance and a diagnostic accuracy as high as 90% [
4–
9]. However, the diagnostic performance of percutaneous biopsy of indeterminate small nodules, which are usually detected on CT, has not been fully investigated. In a few previously reported studies, the diagnostic performance of biopsy was analyzed after taking nodule size into account, including nodules smaller than 1 cm [
10,
11].
To determine the clinical usefulness of percutaneous biopsy for the diagnosis of small lung nodules, we investigated the diagnostic outcomes of percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm performed at our tertiary referral center over a study period of approximately 13 years. We analyzed diagnostic performance according to the biopsy method and nodule consistency with the goal of determining the risk factors associated with diagnostic failure.
Materials and Methods
This retrospective study was approved by the institutional review board of our institution. The acquisition of informed consent was waived because we retrospectively used data available in electronic medical records.
Patients
From January 1999 through November 2011, 305 CT-guided lung biopsies were performed of pulmonary nodules smaller than 1 cm in 290 patients. Of these 305 procedures, 108 aspirations, 164 core biopsies, and 33 combination uses of aspiration and core biopsy were performed. For 37 of the 305 procedures, a final diagnosis could not be established for one of the following reasons: The lesion was diagnosed as benign by the biopsy and remained stable in size, but the follow-up period was less than 2 years (n = 10); the lesion showed imaging-pathology discordance, but no additional biopsies were performed (n = 26); or pulmonary tuberculosis was suspected, but no additional biopsies were performed (n = 1). These lesions were excluded from this study because a final diagnosis could not be determined despite the fact that the aspirations and core biopsies were successfully performed. The remaining 268 procedures that were performed in 253 patients were included in our study. Because of nondiagnostic biopsy results, a second rebiopsy was performed in nine patients and a third rebiopsy was performed in three patients.
Biopsy Procedures
One of nine attending chest radiologists or a fellow under their supervision performed all of the biopsies. Commercially available MDCT scanners (1999–2010, HiSpeed iPro, GEHealthcare; 2011, Somatom Definition AS, Siemens Healthcare) were used to guide biopsies. All patients underwent unenhanced CT in either the prone or supine position depending on the location of the nodule. In most situations, the nodule was approached via the shortest route but individual variations were accepted to avoid adjacent large pulmonary vessels, visible airways, or fissures. Images through the region of interest were obtained at a slice thickness of 3 mm and viewed under a combination of lung and soft-tissue window settings. Localization was determined using the CT gantry lights and the grid on the patient's skin. The chosen entry site was prepared and draped in a sterile fashion.
After the administration of a local anesthetic, a needle was advanced until its tip was positioned within the lesion. After needle insertion, CT was used to confirm the position of the needle. A 20-gauge needle (Westcott needle, Becton Dickinson) was used for all aspirations (
Figs 1 and
2). Aspirated specimens were transferred to microscopy slides without verifying the adequacy of the cytologic specimen by a pathologist on-site. For core biopsies a 20-gauge needle (Franseen biopsy needle, Allegiance Healthcare) was used in 53 patients and a 20-gauge automated biopsy gun (Pro-Mag 2.2, Manan Medical Products) was used in 113 patients. The coaxial technique was used in all cases that were performed using the automated biopsy gun. When the coaxial technique was used, the automated biopsy gun was advanced through the introducer needle into the lesion to obtain a specimen. If the operator considered the specimen inadequate for diagnosis, the gun was fired several times without additional pleural puncture. Core specimens were immersed in 10% formalin for pathologic examination.
Upright chest radiographs of all patients were obtained immediately after these procedures. In the absence of pneumothorax, a 3-hour follow-up radiograph was obtained. If pneumothorax was apparent on the initial radiograph or on CT scans obtained during the procedure, a 1-hour follow-up radiograph was obtained. A thoracostomy tube was inserted if tension pneumothorax developed or there was collapse of more than 20% of the lung.
Specimens obtained by aspiration were cytologically evaluated, and those obtained by core biopsy were histologically evaluated. All specimens were classified as positive or negative for malignancy and specific cell types were identified when possible.
Assessment of Diagnostic Performance
The diagnostic results of the biopsies were classified as malignant, benign, or nondiagnostic. The results were considered nondiagnostic if the specimen was insufficient for diagnosis on the pathologic report.
A final diagnosis of malignant disease was made when malignancy was confirmed in the surgical specimen (n = 119), the histology of the lesion was similar to that of the primary malignancy (n = 15), malignancy was proven in additional biopsies (n = 2), or the postprocedural clinical course was consistent with an obvious malignant process such as increased lesion size (n = 29). A final diagnosis of benign disease was made when the specimen showed specific benign pathologic findings (n = 20), such as chronic granulomatous inflammation with caseous necrosis consistent and tuberculosis, hamartoma, or sclerosing hemangioma, or the histologic findings correlated with the laboratory findings (n = 12), such as positive staining for acid-fast bacilli, Mycobacterium tuberculosis, or nontuberculous Mycobacterium culture. Benign disease was confirmed in the surgical specimen (n = 12) if the lesion regressed with conservative medical therapy (n = 52) or if the lesion was stable in size for at least 2 years (n = 7).
Positive biopsy results were categorized as true-positive or false-positive if the final diagnosis was malignant or benign disease, respectively. Negative biopsy results were categorized as true-negative or false-negative if the final diagnosis was benign or malignant disease, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the diagnosis of malignancy and the overall diagnostic accuracy were then calculated.
Assessment of Independent Risk Factors Associated With Diagnostic Failure
The characteristics of patients, lesions, and biopsy procedures were gathered for statistical analysis. The patient characteristics included age and sex. The lesion characteristics included the size of the nodule (diameter across the longest axis), lobar location of the nodule (upper, middle, or lower lobe) referring to anatomic lobes, consistency of the nodule (solid, partly solid ground-glass opacity [GGO], or pure GGO), and the final diagnosis of the biopsy (benign or malignant). The procedural characteristics included the length of aerated lung traversed by the needle, number of pleural punctures, number of specimens obtained, biopsy method (aspiration alone, core biopsy alone, or combination), occurrence of pneumothorax, and drainage of pneumothorax.
To determine the independent risk factors associated with diagnostic failure, we divided the results of the 268 lesions into two groups: the diagnostic-success group (i.e., true-positive and true-negative results) and the diagnostic-failure group (nondiagnostic, false-positive, and false-negative results). The characteristics of the two groups were compared by univariate analysis with Student t tests used for numeric values and Fisher exact tests for categoric values. Subsequently, the characteristics that were found to be significantly different were evaluated using multivariate logistic regression analysis to determine any independent risk factors. The category with the lowest risk associated with diagnostic failure, as indicated by the univariate analysis, was used as the reference. An odds ratio (OR) > 1.00 indicated a greater likelihood of diagnostic failure. A p value < 0.05 was considered statistically significant. Statistical analysis was performed using statistics software (SPSS, version 11.0, SPSS).
Results
Diagnostic Performance
The characteristics of the patients, nodules, and procedures are summarized in
Table 1. Nondiagnostic results were obtained for 27 of the 268 lesions (10.1%). Insufficient samples were obtained from 18 patients (66.7%) using aspiration alone, seven patients (25.9%) using core biopsy alone, and two patients (7.4%) using combination use. Of the 27 lesions with a nondiagnostic biopsy result, the final diagnosis was benign disease in 21 patients (77.8%) and malignant disease in six patients (22.2%).
No procedures were terminated before specimen acquisition because of pneumothorax or other significant complications. The incidence of pneumothorax was 16.8%. Pneumothorax was present in 19.3% (33/171) of patients who underwent core biopsy, 15.6% (17/109) of patients who underwent only aspiration, and 4.0% (1/25) who underwent the combination procedure. A thoracostomy tube was inserted in five patients because of moderate pneumothorax.
The specimens obtained from the remaining 241 lesions (89.9%) were adequate for diagnosis. Biopsy was used to diagnose malignant or benign disease in 149 and 92 lesions, respectively. A final diagnosis of malignancy was made for 159 lesions. These diagnoses were based on confirmation of malignancy in the surgical specimen (n = 113) or in additional biopsies (n = 2) or were made because the histology of the lesion was similar to that of the primary malignancy (n = 15) or because there were obvious postprocedural malignant processes (n = 29). A final diagnosis of benign disease was made for 82 lesions and was based on the confirmation of benignity in the surgical specimen (n = 6), specific benign pathologic findings (n = 20), isolation of a microbial cause (n = 9), lesion regression with conservative medical therapy (n = 43), or stability of lesion size for at least 2 years (n = 4).
The overall sensitivity, specificity, PPV, and NPV for the diagnosis of malignancy were 93.1%, 98.8%, 99.3%, and 88.0%, respectively; diagnostic accuracy was 95.0%.
Diagnostic yields according to biopsy method and nodule consistency are shown in
Tables 2 and
3, respectively. For cases of aspiration alone (
n = 94), sensitivity, specificity, and accuracy were 89.2%, 97.4%, and 93.4%. For cases of core biopsy alone (
n = 153), sensitivity, specificity, and accuracy were 93.6%, 100.0%, and 95.2%. For cases of combination use (
n = 21), sensitivity, specificity, and accuracy were 100.0%, 100.0%, and 100.0%.
For solid nodules (n = 205), sensitivity, specificity, and accuracy were 95.5%, 98.6%, and 96.7%, respectively. For partly solid GGO nodules (n = 37), sensitivity, specificity, and accuracy were 91.3%, 100.0%, and 95.8%. For pure GGO nodules (n = 26), sensitivity, specificity, and accuracy were 81.5%, 100.0%, and 85.3%.
Biopsy diagnoses of the 11 lesions with false-negative biopsy results were anthracofibrosis in three cases, inflammation in six cases, and reactive epithelial cells in two cases. The final diagnoses of the false-negative biopsies were adenocarcinoma in nine cases and squamous cell carcinoma in two cases. Among these 11 cases, additional biopsy was performed in three cases at 6-month intervals, and true-positive results were finally obtained in two of these cases. In one case with a false-positive result, the biopsy diagnosis was carcinoid tumor, whereas the final diagnosis of the surgical specimen was chondroid hamartoma.
Risk Factors Associated With Diagnostic Failure
The diagnostic-success group (n = 229) consisted of 148 true-positive results and 81 true-negative results; the diagnostic-failure group (n = 39) consisted of 27 nondiagnostic results, one false-positive result, and 11 false-negative results.
The results of the univariate analyses are shown in
Table 4. The mean size of the lesions in the diagnostic-failure group (9.0 mm) was smaller than that of the lesions in the diagnostic-success group (9.4 mm), although this difference was not statistically significant (
p = 0.060). The number of specimens obtained from the diagnostic-failure group (mean, 1.6 specimens) was less than that obtained from the diagnostic-success group (mean, 2.1 specimens) (
p = 0.005). Core biopsies was more frequently performed in the diagnostic-success group (69.0%, 158/229) than in the diagnostic-failure group (41.0%, 16/39) (
p = 0.013).
Age, sex, nodule lobar location, nodular consistency, length of aerated lung traversed by the needle, and occurrence of pneumothorax did not show any significant differences between the two groups.
According to the multivariate logistic regression analysis, applying only aspiration was an independent risk factor associated with diagnostic failure (OR, 3.199; p = 0.001) compared with core biopsy and combination use.
Discussion
We assessed the diagnostic outcomes of 305 percutaneous biopsies of pulmonary nodules smaller than 1 cm that were performed at our tertiary referral center over a study period of approximately 13 years. Although the use of percutaneous biopsy for lung nodules has been established as a safe diagnostic procedure, few studies have reported the diagnostic outcomes in a large number of pulmonary nodules smaller than 1 cm. To our knowledge, our current consecutive case series comprises the largest number of percutaneous biopsies performed on small nodules (
Table 5). Because of the frequent detection of small lung nodules on CT screening examinations, the demand for CT-guided biopsy of small indeterminate nodules may increase. In this clinical context, the results of our study could be used to make clinical decisions about indeterminate lung nodules.
We found that the overall sensitivity, specificity, PPV, and NPV for the diagnosis of malignancy by this method were 93.1%, 98.8%, 99.3%, and 88.0%, respectively, with an overall diagnostic accuracy of 95.0%. Wallace et al. [
11] reported that the diagnostic accuracy of CT-guided aspiration was 87.7% for 57 pulmonary nodules smaller than 1 cm. Ng et al. [
12] reported that the diagnostic accuracy of CT-guided aspiration was 78.8% for 55 nodules smaller than 1 cm. Hiraki et al. [
13] reported that the diagnostic accuracy of CT fluoroscopy–guided core biopsy was 92.7% for 151 pulmonary nodules smaller than 1 cm that were chosen from among 1000 nodules of various sizes. The overall diagnostic accuracy of 95.0% for the 268 pulmonary nodules smaller than 1 cm in our study is higher than the accuracies reported in previous studies. When we assess our results according to the biopsy method, the diagnostic accuracy of aspiration is also higher than the accuracies reported in previous studies. In addition, we found that the accuracies of core biopsy, combination use, and aspiration in our present cohort were higher than those reported by Yamagami et al. [
14]. Because the number of pulmonary nodules was small in most previous studies, it is difficult to compare their diagnostic accuracy with ours. Differences in lesion characteristics—for example, the length of aerated lung or the proportion of experienced operators—may affect diagnostic accuracy.
The number of specimens obtained and the biopsy methods were significantly different between the diagnostic-success and diagnostic-failure groups in our present study. Hiraki et al. [
13] reported that the acquisition of a larger number of specimens significantly increases diagnostic accuracy because the sampling error decreases. However, the rate of pneumothorax among patients with a single puncture is significantly less compared with patients with three punctures [
15]. When we used the coaxial technique, core biopsy could be performed without additional pleural punctures; therefore, the risk of pneumothorax could be reduced. When we consider the increased time needed for the acquisition of a larger number of specimens, complications such as pneumothorax and hemoptysis could increase. A higher rate of complications was reported when using the combination use compared with a single method in a study by Klein et al. [
16]. Therefore, it is important to decide the number of specimens to be obtained during biopsy and to choose the method while simultaneously considering the risks and benefits.
Regarding the biopsy method, the diagnostic accuracies of aspiration, core biopsy, and combination use were 93.4%, 95.2%, and 100.0%, respectively. Cases of aspiration alone made up a large portion (66.7%) of our nondiagnostic results. Moreover, the biopsy method turned out to be a significant independent risk factor associated with diagnostic failure. Yamagami et al. [
14] investigated the efficacy of the combination use of core biopsy and aspiration compared with each method alone. The difference in the rates of diagnosis was particularly significant in this earlier report among the 32 lesions that ranged in size from 3 to 10 mm, with rates of 71.9%, 84.4%, and 93.8% obtained for aspiration, core biopsy, and combination use, respectively [
14]. Therefore, we see similar results in two studies that indicate that combination use and core biopsy are more accurate than aspiration alone.
Lung biopsy is needed to determine the specific cell type of lung cancer. Moreover, the current trend of using receptor antagonists as chemotherapeutic agents requires more tissue to determine the presence of specific receptors and perform various kinds of immunohistochemical staining. Also, when a lesion is shown to be benign, clarification of the specific cell type may be necessary [
16]. Core biopsy or a combination of core and aspiration biopsy is required for higher diagnostic accuracy and more pathologic information.
It is not obvious whether the consistency of the nodule is a significant factor associated with diagnostic accuracy. Hur et al. [
17] reported that the diagnostic accuracy of aspiration is significantly lower for evaluating pure GGO nodules (
n = 7) than mixed GGO nodules (
n = 21). On the other hand, the sensitivity, specificity, and accuracy of CT fluoroscopy–guided core biopsy were not significantly different between pure GGO nodules (
n = 31) and mixed GGO nodules (
n = 36) according to Yamauchi et al. [
18]. Kim et al. [
19] also showed that results for pure GGO nodules (
n = 21; sensitivity, 93%; accuracy, 91%) were not significantly different from those for mixed GGO nodules (
n = 25; sensitivity, 91%; accuracy, 92%). In our study, the results for pure GGO nodules showed a tendency toward lower sensitivity, higher specificity, and lower diagnostic accuracy than those for partly solid GGO or solid nodules. Considering that a diagnosis of adenocarcinoma made up most (81.8%) of our false-negative biopsy results, we can assume that adenocarcinomas presenting as pure GGO nodules may also show low diagnostic yield on CT-guided biopsy.
There are several limitations in our study. Its retrospective design could be a limitation. The results of this study could have been affected by how the operators selected among the biopsy methods of aspiration, core biopsy, or combination use. In addition, because our institution is a tertiary referral center, the prevalence of benign and malignant disease in our study population could be different from that in the general population. Because our study cohort included all percutaneous CT-guided biopsies over a study period of approximately 13 years, the clinical settings, including indications, operator experience, and techniques of the operators, may have varied over time. However, these limitations could have been minimized and may not have substantially affected the outcome of the analysis because a relatively large number of procedures were included in this study.
In conclusion, we found that percutaneous CT-guided aspiration and core biopsy can be useful diagnostic procedures for evaluating indeterminate pulmonary nodules smaller than 1 cm and show high diagnostic performance. Diagnostic accuracy is influenced by the biopsy method. The use of core biopsy alone or the combination use of core biopsy and aspiration showed enhanced diagnostic performance over aspiration alone.