Cardiopulmonar y Imaging • Original Research
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Choi et al. Outcomes of Biopsies of Small Pulmonary Nodules Cardiopulmonary Imaging Original Research
Percutaneous CT-Guided Aspiration and Core Biopsy of Pulmonary Nodules Smaller Than 1 cm: Analysis of Outcomes of 305 Procedures From a Tertiary Referral Center
Sang Hyun Choi1 Eun Jin Chae Ji-Eun Kim Eun Young Kim Sang Young Oh Hye Jeon Hwang Hyun Joo Lee
OBJECTIVE. We conducted a retrospective analysis to evaluate the diagnostic outcomes of CT-guided aspiration and core biopsy of 305 pulmonary nodules measuring less than 1 cm. MATERIALS AND METHODS. We determined the diagnostic yield of using CT-guided aspiration and core biopsy to analyze 305 lesions in 290 patients. Diagnostic performance was evaluated according to the biopsy method, including aspiration alone, core biopsy alone, and combination use, and the consistency of the nodule, including solid, partly solid groundglass opacity (GGO), and pure GGO. Final diagnoses were established in 268 of the 305 lesions (87.9%). Nondiagnostic biopsy results were obtained for 27 of the 268 lesions (10.1%). RESULTS. The overall sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignancy were 93.1% (148 of 159 lesions), 98.8% (81/82), 99.3% (148/149), and 88.0% (81/92), respectively; diagnostic accuracy was 95.0% (229/241). Using multivariate logistic regression analysis, we found that aspiration alone was a significant independent risk factor associated with diagnostic failure (odds ratio, 3.199; p = 0.001). CONCLUSION. The use of CT-guided aspiration and core biopsy resulted in a high diagnostic yield for pulmonary nodules smaller than 1 cm. The use of the aspiration method alone was an independent risk factor associated with diagnostic failure.
Choi SH, Chae EJ, Kim JE, Kim EY, et al.
L
Keywords: CT-guided core needle biopsy, CT-guided fine-needle aspiration, lung biopsy, lung cancer DOI:10.2214/AJR.12.10156 Received October 16, 2012; accepted after revision March 9, 2013. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (grant 2010-0023610). 1
All authors: Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Korea. Address correspondence to E. J. Chae ([email protected]).
AJR 2013; 201:964–970 0361–803X/13/2015–964 © American Roentgen Ray Society
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ung 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 tak-
ing 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,
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Outcomes of Biopsies of Small Pulmonary Nodules
A
B
Fig. 1—CT-guided core biopsy of ground-glass opacity (GGO) nodule in right upper lobe of 53-year-old woman. A, CT scan shows 8.5-mm GGO nodule in right upper lobe. B, CT scan obtained during core biopsy shows needle targeting GGO nodule. Aspiration biopsy result was mostly blood. Final diagnosis after surgical resection was interstitial fibrosis with nodular smooth-muscle proliferation.
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 short-
A
est 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).
B
Fig. 2—CT-guided core biopsy of solid nodule in right lower lobe of 44-year-old woman. A, CT scan shows 8-mm solid nodule in right lower lobe. B, CT scan obtained during core biopsy shows needle targeting solid nodule. Core biopsy result was adenocarcinoma, which was final diagnosis after surgical resection.
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Choi et al. 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 proce-
TABLE 1: Characteristics of Patients, Nodules, and Procedures Characteristic
Aspiration
Core Biopsy
Combination Use
All
94 (35.1)
153 (57.1)
21 (7.8)
268 (100)
Mean ± SD
9.2 ± 1.0
9.3 ± 1.1
9.6 ± 0.8
9.3 ± 1.0
Range
7.0–9.9
5.0–9.9
8.0–9.9
5.0–9.9
No. (%) of patients Nodule size (mm)
Location of nodule Upper lobe
51 (34.7)
84 (57.1)
12 (8.2)
147 (100)
Middle lobe
3 (20.0)
10 (66.7)
2 (13.3)
15 (100)
Lower lobe
40 (37.7)
59 (55.7)
7 (6.6)
106 (100) 205 (100)
Consistency of nodule on CT Solid
82 (40.0)
107 (52.2)
16 (7.8)
Pure GGO
4 (15.4)
22 (84.6)
0 (0)
26 (100)
Partly solid GGO
8 (21.6)
24 (64.9)
5 (13.5)
37 (100)
21.1 ± 17.7
25.6 ± 18.0
17.9 ± 9.5
23.4 ± 17.6
1.1 ± 0.3
2.6 ± 0.8
2.4 ± 0.9
2.0 ± 1.0
Pneumothorax, no. (%) of patients
13 (28.9)
31 (68.9)
1 (2.2)
45 (100)
Nondiagnostic results, no. (%) of nodules
18 (66.7)
7 (25.9)
2 (7.4)
27 (100)
Benign
41 (39.8)
55 (53.4)
7 (6.8)
103 (100)
Malignant
112 (67.9)
39 (23.6)
14 (8.5)
165 (100)
Length of aerated lung traversed by needle (mm) Mean ± SD No. of specimens Mean ± SD
Final diagnosis, no. (%) of nodules
Note—GGO indicates ground-glass opacity.
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Outcomes of Biopsies of Small Pulmonary Nodules dural 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 diagnosticsuccess 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 falsepositive 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 falsenegative 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 fre-
TABLE 2: Diagnostic Yields According to Biopsy Method No. (%) of Pulmonary Nodules Aspiration
Core Biopsy
Combination Use
All
True-positive
Result
33 (22.3)
103 (69.6)
12 (8.1)
148 (100)
True-negative
38 (46.9)
36 (44.4)
7 (8.6)
81 (100)
False-positive
1 (100)
0 (0)
0 (0)
1 (100)
False-negative
4 (36.4)
7 (63.6)
0 (0)
11 (100)
Nondiagnostic
18 (66.7)
7 (25.9)
2 (7.4)
27 (100)
Note—Percentages may not add up to 100% because of rounding.
TABLE 3: Diagnostic Yields According to Nodular Consistency No. (%) of Pulmonary Nodules Result
Solid
Partly Solid GGO
Pure GGO
All
True-positive
105 (70.9)
22 (14.9)
21 (14.2)
148 (100)
True-negative
73 (90.1)
7 (8.6)
1 (1.2)
81 (100)
False-positive
1 (100)
0 (0)
0 (0)
1 (100)
False-negative
5 (45.5)
5 (45.5)
1 (9.1)
11 (100)
Nondiagnostic
21 (77.8)
3 (11.1)
3 (11.1)
27 (100)
Note— Percentages may not add up to 100% because of rounding GGO = ground-glass opacity.
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Choi et al. TABLE 4: Results of the Univariate Analysis Used to Determine the Risk Factors Associated With Diagnostic Failure Characteristic
Diagnostic Successa
Diagnostic Failureb
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Mean ± SD
62.0 ± 11.3
59.3 ± 9.4
Male
123 (45.9)
22 (8.2)
Female
106 (39.6)
17 (6.3)
Sex, no. (%) of patients
0.755
Size of nodule (mm) Mean ± SD
0.060 9.4 ± 1.0
9.0 ± 1.1
Location of nodule, no. (%) of nodules
0.144
Upper lobe
131 (48.9)
16 (6.0)
Middle lobe
13 (4.9)
2 (0.7)
Lower lobe
85 (31.7)
21 (7.8)
178 (66.4)
27 (10.1)
Consistency of nodule on CT, no. (%) of nodules Solid
0.411
Pure GGO
22 (8.2)
4 (1.5)
Partly solid GGO
29 (10.8)
8 (3.0)
23.6 ± 17.7
22.0 ± 16.7
Length of aerated lung traversed by needle (mm) Mean ± SD
0.585 0.005c
No. of specimens Mean ± SD
2.1 ± 1.0
1.6 ± 0.9 0.005c
Biopsy method, no. (%) of nodules Aspiration
71 (26.5)
23 (8.6)
Core biopsy
139 (51.9)
14 (5.2)
19 (7.1)
2 (0.7)
Combination use
p 0.164
0.014c
Final diagnosis, no. (%) of nodules Benign
81 (30.2)
22 (8.2)
Malignant
148 (55.2)
17 (6.3)
Pneumothorax, no. (%) of patients
40 (88.9)
5 (11.1)
0.475
Note— Percentages may not add up to 100% because of rounding. GGO = ground-glass opacity. aTrue-positive and true-negative results. bNondiagnostic, false-positive, and false-negative results. cStatistically significant p value.
quently 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 nod-
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ules 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
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Outcomes of Biopsies of Small Pulmonary Nodules TABLE 5: Diagnostic Performance of CT-Guided Biopsy Reported in Previously Published Studies First Author [Reference No.]
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Sensitivity (%)
Specificity (%)
Accuracy (%)
Laurent [20]
7
No. of Nodules
Combination use
Biopsy Method
66.7
100.0
85.7
Wallace [11]
57
Aspiration
82.1
100.0
87.7
Yamagami [14]
32
Aspiration
86.7
100.0
71.9
Core biopsy
93.3
100.0
84.4
Combination use
94.1
100.0
93.8
Shimizu [10]
33
Aspiration
48.5
Ng [12]
55
Aspiration
67.7
100.0
78.8
Hur [17]
10 (GGO nodules)
Aspiration
67.0
100.0
80.0
Hiraki [13]
151
Core biopsy
91.7
100.0
92.7
Yamauchi [18]
8 (GGO nodules)
Core biopsy
85.7
100.0
87.5
Choi [present study]
268
93.4
Aspiration
89.2
97.4
Core biopsy
93.6
100.0
95.2
100.0
100.0
100.0
93.1
98.8
95.0
Combination use Overall Note—GGO = ground-glass opacity.
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 falsenegative 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
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Choi et al. 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. References 1. World Health Organization website. Cancer: fact sheet no. 297. www.who.int/mediacentre/factsheets/fs297/en/. Accessed August 14, 2012 2. National Lung Screening Trial Research Team; Aberle DR, Adams AM, Berg CD, et al. Reduced lungcancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365:395–409 3. Saghir Z, Dirksen A, Ashraf H, et al. CT screening for lung cancer brings forward early disease: the randomised Danish Lung Cancer Screening
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Trial—status after five annual screening rounds with low-dose CT. Thorax 2012; 67:296–301 4. Khouri NF, Stitik FP, Erozan YS, et al. Transthoracic needle aspiration biopsy of benign and malignant lung lesions. AJR 1985; 144:281–288 5. Stanley JH, Fish GD, Andriole JG, et al. Lung lesions: cytologic diagnosis by fine-needle biopsy. Radiology 1987; 162:389–391 6. Westcott JL. Percutaneous transthoracic needle biopsy. Radiology 1988; 169:593–601 7. Yankelevitz DF, Henschke CI, Koizumi JH, Altorki NK, Libby D. CT-guided transthoracic needle biopsy of small solitary pulmonary nodules. Clin Imaging 1997; 21:107–110 8. Larscheid RC, Thorpe PE, Scott WJ. Percutaneous transthoracic needle aspiration biopsy: a comprehensive review of its current role in the diagnosis and treatment of lung tumors. Chest 1998; 114:704–709 9. Tsukada H, Satou T, Iwashima A, Souma T. Diagnostic accuracy of CT-guided automated needle biopsy of lung nodules. AJR 2000; 175:239–243 10. Shimizu K, Ikeda N, Tsuboi M, Hirano T, Kato H. Percutaneous CT-guided fine needle aspiration for lung cancer smaller than 2 cm and revealed by ground-glass opacity at CT. Lung Cancer 2006; 51:173–179 11. Wallace MJ, Krishnamurthy S, Broemeling LD, et al. CT-guided percutaneous fine-needle aspiration biopsy of small (< or = 1-cm) pulmonary lesions. Radiology 2002; 225:823–828 12. Ng YL, Patsios D, Roberts H, et al. CT-guided percutaneous fine-needle aspiration biopsy of pulmonary nodules measuring 10 mm or less. Clin Radiol 2008; 63:272–277
13. Hiraki T, Mimura H, Gobara H, et al. CT fluoroscopy–guided biopsy of 1,000 pulmonary lesions performed with 20-gauge coaxial cutting needles: diagnostic yield and risk factors for diagnostic failure. Chest 2009; 136:1612–1617 14. Yamagami T, Iida S, Kato T, Tanaka O, Nishimura T. Combining fine-needle aspiration and core biopsy under CT fluoroscopy guidance: a better way to treat patients with lung nodules? AJR 2003; 180:811–815 15. Ohno Y, Hatabu H, Takenaka D, et al. CT-guided transthoracic needle aspiration biopsy of small (≤ 20 mm) solitary pulmonary nodules. AJR 2003; 180:1665–1669 16. Klein JS, Salomon G, Stewart EA. Transthoracic needle biopsy with a coaxially placed 20-gauge automated cutting needle: results in 122 patients. Radiology 1996; 198:715–720 17. Hur J, Lee HJ, Nam JE, et al. Diagnostic accuracy of CT fluoroscopy–guided needle aspiration biopsy of ground-glass opacity pulmonary lesions. AJR 2009; 192:629–634 18. Yamauchi Y, Izumi Y, Nakatsuka S, et al. Diagnostic performance of percutaneous core needle lung biopsy under multi-CT fluoroscopic guidance for ground-glass opacity pulmonary lesions. Eur J Radiol 2011; 79:e85–e89 19. Kim TJ, Lee JH, Lee CT, et al. Diagnostic accuracy of CT-guided core biopsy of ground-glass opacity pulmonary lesions. AJR 2008; 190:234–239 20. Laurent F, Latrabe V, Vergier B, et al. CT-guided transthoracic needle biopsy of pulmonary nodules smaller than 20 mm: results with an automated 20-gauge coaxial cutting needle. Clin Radiol 2000; 5S:281–287
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Choi et al. Outcomes of Biopsies of Small Pulmonary Nodules Cardiopulmonary Imaging Original Research
Percutaneous CT-Guided Aspiration and Core Biopsy of Pulmonary Nodules Smaller Than 1 cm: Analysis of Outcomes of 305 Procedures From a Tertiary Referral Center
Sang Hyun Choi1 Eun Jin Chae Ji-Eun Kim Eun Young Kim Sang Young Oh Hye Jeon Hwang Hyun Joo Lee
OBJECTIVE. We conducted a retrospective analysis to evaluate the diagnostic outcomes of CT-guided aspiration and core biopsy of 305 pulmonary nodules measuring less than 1 cm. MATERIALS AND METHODS. We determined the diagnostic yield of using CT-guided aspiration and core biopsy to analyze 305 lesions in 290 patients. Diagnostic performance was evaluated according to the biopsy method, including aspiration alone, core biopsy alone, and combination use, and the consistency of the nodule, including solid, partly solid groundglass opacity (GGO), and pure GGO. Final diagnoses were established in 268 of the 305 lesions (87.9%). Nondiagnostic biopsy results were obtained for 27 of the 268 lesions (10.1%). RESULTS. The overall sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignancy were 93.1% (148 of 159 lesions), 98.8% (81/82), 99.3% (148/149), and 88.0% (81/92), respectively; diagnostic accuracy was 95.0% (229/241). Using multivariate logistic regression analysis, we found that aspiration alone was a significant independent risk factor associated with diagnostic failure (odds ratio, 3.199; p = 0.001). CONCLUSION. The use of CT-guided aspiration and core biopsy resulted in a high diagnostic yield for pulmonary nodules smaller than 1 cm. The use of the aspiration method alone was an independent risk factor associated with diagnostic failure.
Choi SH, Chae EJ, Kim JE, Kim EY, et al.
L
Keywords: CT-guided core needle biopsy, CT-guided fine-needle aspiration, lung biopsy, lung cancer DOI:10.2214/AJR.12.10156 Received October 16, 2012; accepted after revision March 9, 2013. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (grant 2010-0023610). 1
All authors: Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Korea. Address correspondence to E. J. Chae ([email protected]).
AJR 2013; 201:964–970 0361–803X/13/2015–964 © American Roentgen Ray Society
964
ung 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 tak-
ing 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,
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Outcomes of Biopsies of Small Pulmonary Nodules
A
B
Fig. 1—CT-guided core biopsy of ground-glass opacity (GGO) nodule in right upper lobe of 53-year-old woman. A, CT scan shows 8.5-mm GGO nodule in right upper lobe. B, CT scan obtained during core biopsy shows needle targeting GGO nodule. Aspiration biopsy result was mostly blood. Final diagnosis after surgical resection was interstitial fibrosis with nodular smooth-muscle proliferation.
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 short-
A
est 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).
B
Fig. 2—CT-guided core biopsy of solid nodule in right lower lobe of 44-year-old woman. A, CT scan shows 8-mm solid nodule in right lower lobe. B, CT scan obtained during core biopsy shows needle targeting solid nodule. Core biopsy result was adenocarcinoma, which was final diagnosis after surgical resection.
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Choi et al. 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 proce-
TABLE 1: Characteristics of Patients, Nodules, and Procedures Characteristic
Aspiration
Core Biopsy
Combination Use
All
94 (35.1)
153 (57.1)
21 (7.8)
268 (100)
Mean ± SD
9.2 ± 1.0
9.3 ± 1.1
9.6 ± 0.8
9.3 ± 1.0
Range
7.0–9.9
5.0–9.9
8.0–9.9
5.0–9.9
No. (%) of patients Nodule size (mm)
Location of nodule Upper lobe
51 (34.7)
84 (57.1)
12 (8.2)
147 (100)
Middle lobe
3 (20.0)
10 (66.7)
2 (13.3)
15 (100)
Lower lobe
40 (37.7)
59 (55.7)
7 (6.6)
106 (100) 205 (100)
Consistency of nodule on CT Solid
82 (40.0)
107 (52.2)
16 (7.8)
Pure GGO
4 (15.4)
22 (84.6)
0 (0)
26 (100)
Partly solid GGO
8 (21.6)
24 (64.9)
5 (13.5)
37 (100)
21.1 ± 17.7
25.6 ± 18.0
17.9 ± 9.5
23.4 ± 17.6
1.1 ± 0.3
2.6 ± 0.8
2.4 ± 0.9
2.0 ± 1.0
Pneumothorax, no. (%) of patients
13 (28.9)
31 (68.9)
1 (2.2)
45 (100)
Nondiagnostic results, no. (%) of nodules
18 (66.7)
7 (25.9)
2 (7.4)
27 (100)
Benign
41 (39.8)
55 (53.4)
7 (6.8)
103 (100)
Malignant
112 (67.9)
39 (23.6)
14 (8.5)
165 (100)
Length of aerated lung traversed by needle (mm) Mean ± SD No. of specimens Mean ± SD
Final diagnosis, no. (%) of nodules
Note—GGO indicates ground-glass opacity.
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Outcomes of Biopsies of Small Pulmonary Nodules dural 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 diagnosticsuccess 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 falsepositive 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 falsenegative 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 fre-
TABLE 2: Diagnostic Yields According to Biopsy Method No. (%) of Pulmonary Nodules Aspiration
Core Biopsy
Combination Use
All
True-positive
Result
33 (22.3)
103 (69.6)
12 (8.1)
148 (100)
True-negative
38 (46.9)
36 (44.4)
7 (8.6)
81 (100)
False-positive
1 (100)
0 (0)
0 (0)
1 (100)
False-negative
4 (36.4)
7 (63.6)
0 (0)
11 (100)
Nondiagnostic
18 (66.7)
7 (25.9)
2 (7.4)
27 (100)
Note—Percentages may not add up to 100% because of rounding.
TABLE 3: Diagnostic Yields According to Nodular Consistency No. (%) of Pulmonary Nodules Result
Solid
Partly Solid GGO
Pure GGO
All
True-positive
105 (70.9)
22 (14.9)
21 (14.2)
148 (100)
True-negative
73 (90.1)
7 (8.6)
1 (1.2)
81 (100)
False-positive
1 (100)
0 (0)
0 (0)
1 (100)
False-negative
5 (45.5)
5 (45.5)
1 (9.1)
11 (100)
Nondiagnostic
21 (77.8)
3 (11.1)
3 (11.1)
27 (100)
Note— Percentages may not add up to 100% because of rounding GGO = ground-glass opacity.
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Choi et al. TABLE 4: Results of the Univariate Analysis Used to Determine the Risk Factors Associated With Diagnostic Failure Characteristic
Diagnostic Successa
Diagnostic Failureb
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Mean ± SD
62.0 ± 11.3
59.3 ± 9.4
Male
123 (45.9)
22 (8.2)
Female
106 (39.6)
17 (6.3)
Sex, no. (%) of patients
0.755
Size of nodule (mm) Mean ± SD
0.060 9.4 ± 1.0
9.0 ± 1.1
Location of nodule, no. (%) of nodules
0.144
Upper lobe
131 (48.9)
16 (6.0)
Middle lobe
13 (4.9)
2 (0.7)
Lower lobe
85 (31.7)
21 (7.8)
178 (66.4)
27 (10.1)
Consistency of nodule on CT, no. (%) of nodules Solid
0.411
Pure GGO
22 (8.2)
4 (1.5)
Partly solid GGO
29 (10.8)
8 (3.0)
23.6 ± 17.7
22.0 ± 16.7
Length of aerated lung traversed by needle (mm) Mean ± SD
0.585 0.005c
No. of specimens Mean ± SD
2.1 ± 1.0
1.6 ± 0.9 0.005c
Biopsy method, no. (%) of nodules Aspiration
71 (26.5)
23 (8.6)
Core biopsy
139 (51.9)
14 (5.2)
19 (7.1)
2 (0.7)
Combination use
p 0.164
0.014c
Final diagnosis, no. (%) of nodules Benign
81 (30.2)
22 (8.2)
Malignant
148 (55.2)
17 (6.3)
Pneumothorax, no. (%) of patients
40 (88.9)
5 (11.1)
0.475
Note— Percentages may not add up to 100% because of rounding. GGO = ground-glass opacity. aTrue-positive and true-negative results. bNondiagnostic, false-positive, and false-negative results. cStatistically significant p value.
quently 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 nod-
968
ules 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
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Outcomes of Biopsies of Small Pulmonary Nodules TABLE 5: Diagnostic Performance of CT-Guided Biopsy Reported in Previously Published Studies First Author [Reference No.]
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Sensitivity (%)
Specificity (%)
Accuracy (%)
Laurent [20]
7
No. of Nodules
Combination use
Biopsy Method
66.7
100.0
85.7
Wallace [11]
57
Aspiration
82.1
100.0
87.7
Yamagami [14]
32
Aspiration
86.7
100.0
71.9
Core biopsy
93.3
100.0
84.4
Combination use
94.1
100.0
93.8
Shimizu [10]
33
Aspiration
48.5
Ng [12]
55
Aspiration
67.7
100.0
78.8
Hur [17]
10 (GGO nodules)
Aspiration
67.0
100.0
80.0
Hiraki [13]
151
Core biopsy
91.7
100.0
92.7
Yamauchi [18]
8 (GGO nodules)
Core biopsy
85.7
100.0
87.5
Choi [present study]
268
93.4
Aspiration
89.2
97.4
Core biopsy
93.6
100.0
95.2
100.0
100.0
100.0
93.1
98.8
95.0
Combination use Overall Note—GGO = ground-glass opacity.
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 falsenegative 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
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Choi et al. 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. References 1. World Health Organization website. Cancer: fact sheet no. 297. www.who.int/mediacentre/factsheets/fs297/en/. Accessed August 14, 2012 2. National Lung Screening Trial Research Team; Aberle DR, Adams AM, Berg CD, et al. Reduced lungcancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365:395–409 3. Saghir Z, Dirksen A, Ashraf H, et al. CT screening for lung cancer brings forward early disease: the randomised Danish Lung Cancer Screening
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