1. health and fitness
2. disease
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CHEST
Original Research
INTERVENTIONAL PULMONOLOGY
Real-time Endobronchial
Ultrasound-Guided Transbronchial
Needle Aspiration in Mediastinal Staging
of Non-Small Cell Lung Cancer*
How Many Aspirations Per Target Lymph Node
Station?
Hee Seok Lee, MD†; Geon Kook Lee, MD, PhD†; Hyun-Sung Lee, MD, PhD;
Moon Soo Kim, MD; Jong Mog Lee, MD; Hyae Young Kim, MD, PhD;
Byung-Ho Nam, PhD; Jae Ill Zo, MD, PhD; and Bin Hwangbo, MD
Objective: The goal of this study was to determine the optimal number of aspirations per lymph
node (LN) station during endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) for maximum diagnostic yield in mediastinal staging of non-small cell lung cancer
(NSCLC) in the absence of rapid on-site cytopathologic examination.
Methods: EBUS-TBNA was performed in potentially operable NSCLC patients with mediastinal
LNs accessible by EBUS-TBNA (5 to 20 mm). Every target LN station was punctured four times.
Results: We performed EBUS-TBNA in 163 mediastinal LN stations in 102 NSCLC patients.
EBUS-TBNA confirmed malignancy in 41 LN stations in 30 patients. Two malignant LN stations
were missed in two patients. The sensitivity, specificity, positive predictive value, negative
predictive value (NPV), and accuracy of EBUS-TBNA in predicting mediastinal metastasis were
93.8%, 100%, 100%, 96.9%, and 97.9%, respectively. Sample adequacy was 90.1% for one
aspiration, and it reached 100% for three aspirations. The sensitivity for differentiating malignant
from benign LN stations was 69.8%, 83.7%, 95.3%, and 95.3% for one, two, three, and four
aspirations, respectively. The NPV was 86.5%, 92.2%, 97.6%, and 97.6% for one, two, three, and
four aspirations, respectively. Maximum diagnostic values were achieved in three aspirations.
When at least one tissue core was obtained by the first or second aspiration, the sensitivity and NPV
of the first two aspirations were 91.9% and 96.0%, respectively.
Conclusions: Optimal results can be obtained in three aspirations per LN station in EBUS-TBNA
for mediastinal staging of potentially operable NSCLC. When at least one tissue core specimen
is obtained by the first or second aspiration, two aspirations per LN station can be acceptable.
(CHEST 2008; 134:368 –374)
Key words: endobronchial ultrasound; lung cancer; staging
Abbreviations: EBUS ⫽ endobronchial ultrasound; LN ⫽ lymph node; NPV ⫽ negative predictive value; NSCLC ⫽ nonsmall cell lung cancer; PET ⫽ positron emission tomography; PPV ⫽ positive predictive value; ROSE ⫽ rapid on-site
cytopathologic examination; TBNA ⫽ transbronchial needle aspiration
ndobronchial ultrasound (EBUS)-guided transE bronchial
needle aspiration (TBNA) is a new
bronchoscopic method that enables real-time aspiration of peribronchial or peritracheal lesions. Evidence of the usefulness of EBUS-TBNA in the
diagnosis of mediastinal lymph nodes (LNs) is increasing.1–9 EBUS-TBNA has a high sensitivity and a
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high negative predictive value (NPV) in the mediastinal staging of lung cancer.3,8
EBUS-TBNA is a recently introduced technique.
Details of EBUS-TBNA methodology, such as the
number of aspirations per target needed and the
need for on-site cytopathologic support, have not
been determined. According to Japanese reports2,3,8
Original Research
about EBUS-TBNA, aspirates were evaluated by an
on-site cytopathologist, and the median number of
needle passes was two for each site. In some studies1,4,5 not using rapid on-site cytopathologic examination (ROSE), one to three aspirates were obtained
from the target lesion; judgment concerning the
number of aspirates required was made according to
the macroscopic appearance of the aspirate or arbitrarily by a bronchoscopist. In other studies6,7 not
using ROSE, two needle passes were made at every
site. Some authors10 suggest that three to four needle
passes are associated with 90% sensitivity.
The goal of this study was to determine the optimal
number of aspirations per LN station required during EBUS-TBNA for maximum diagnostic yield in
the mediastinal staging of non-small cell lung cancer
(NSCLC) when ROSE is not available.
Materials and Methods
Patients
This study was conducted between July 2006 and April 2007
at the Center for Lung Cancer, National Cancer Center, South
Korea. Patients with strongly suspected or histologically confirmed potentially operable NSCLC were enrolled. To be included in the study, patients were required to have a mediastinal LN accessible by EBUS-TBNA with a short diameter of
5 to 20 mm on axial chest CT. LN status was classified according
to the international staging system reported by Mountain and
Dressler.11 Tumor resectability was evaluated after an imagebased staging workup for NSCLC, including CT of the chest and
upper abdomen, brain MRI, whole-body positron emission tomography (PET)-CT, and/or bone scan. We excluded patients
with M1 disease, inoperable T4 disease, evident N3 disease with
spread to supraclavicular LNs, bulky mediastinal LN (short
diameter ⬎ 2 cm on axial image of chest CT), or extranodal
invasion of the mediastinal LN visible on chest CT. Patients with
unresectable tumors diagnosed by white light bronchoscopy or
patients with a Pancoast tumor were also excluded. Medical
operability was assessed, and patients who were not physically
suitable for surgery were excluded.
The ethical committee of our institute approved this study.
Informed consent was obtained from all patients included in this
study.
*From the Center for Lung Cancer (Drs. H. S. Lee, G. K. Lee,
H-S Lee, M. S. Kim, J. M. Lee, H. Y. Kim, Zo, and Hwangbo),
Research Institute and Hospital; and Cancer Biostatistics Branch
(Dr. Nam), Research Institute for National Cancer Control and
Evaluation, National Cancer Center, Gyeonggi, Korea.
†These authors contributed equally to this work.
This work was supported by the National Cancer Center grant
710620.
The authors have no conflicts of interest to disclose.
Manuscript received August 20, 2007; revision accepted January
12, 2008.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Bin Hwangbo, MD, Center for Lung Cancer,
National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang,
Gyeonggi, 411–764, Korea; e-mail: [email protected]
DOI: 10.1378/chest.07-2105
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EBUS-TBNA
EBUS-TBNA was performed with a flexible ultrasonic puncture bronchoscope with a linear scanning transducer (CP-EBUS,
XBF-UC260F-OL8; Olympus; Tokyo, Japan). All EBUS-TBNA
procedures were performed by the same bronchoscopist (B.H.).
Local anesthesia (lidocaine) was applied. The procedure was
performed under conscious sedation (midazolam). After full
inspection of the mediastinal LNs accessible by EBUS-TBNA,
target nodal stations considered to be necessary in mediastinal
staging were selected by the judgment of a bronchoscopist. In
selecting, we considered the likelihood of metastasis of the
target nodal stations based on imaging studies and the potential pathway of lymphatic metastasis. We also considered the
impact of metastasis of the target nodal station in deciding on
treatment. Each target nodal station was aspirated four times
with a dedicated 22-gauge needle (NA-201SX-4022; Olympus).
We tried to target different areas of each nodal station for each
aspiration to cover large parts of a nodal station (Fig 1). Different
needles were used for different nodal stations to avoid contamination. N3 nodes were sampled first, and then N2 nodes were
punctured. Procedure time was calculated from the insertion of
the bronchoscope through mouth to the retrieval of the bronchoscope after the procedure.
The aspirate was expelled onto glass slides, smeared, and immediately fixed with 95% alcohol. We made three pairs of smear slides
for each aspiration, if possible. Tissue cores (the solid substances in
the aspiration needle obtained by EBUS-TBNA) were put into a
solution of 10% neutral-buffered formalin. All specimens were
numbered with respect to the order of aspiration. The remnants of
each aspirate from the same nodal station were collected in one
bottle filled with 95% alcohol for cell block. Smeared cytology slides
were stained with hematoxylin-eosin and Papanicolaou. Tissue cores
and cell blocks were stained with hematoxylin-eosin. Cytopathologic
specimens were categorized as positive (presence of tumor cells),
negative (lymphocytes or lymphoid tissue only), or inadequate (no
cellular component, blood only, or cartilage or bronchial epithelial
cells only). A pathologist (G.K. Lee), blinded to the details of the
patients performed the cytopathologic examinations.
Treatment
Based on the EBUS-TBNA results, we recommended surgery
for patients without mediastinal metastasis (open thoracotomy or
video-assisted thoracic surgery including systematic LN dissection). Mediastinoscopy was not performed. We recommended
chemotherapy (with or without radiotherapy) for patients with
mediastinal metastasis with curative or neoadjuvant intent.
Statistical Analysis
The sensitivity, specificity, positive predictive value (PPV), NPV,
and diagnostic accuracy of EBUS-TBNA were determined. The
diagnostic consistency according to the number of aspirations was
analyzed using the McNemar test. Differences in diagnostic values
with respect to the presence of tissue core samples were examined
with ␹2 or Fisher exact test; p values ⬍ 0.05 were considered
statistically significant. All statistical analyses were performed using
statistical software (STATA9, Stata Statistical Software Release 9;
StataCorp; College Station, TX).
Results
Characteristics of Patients and LNs
We enrolled 105 patients in the study (Fig 2).
Small cell lung cancer was diagnosed in three paCHEST / 134 / 2 / AUGUST, 2008
369
Figure 1. Each LN station was aspirated four times. A representative 4R LN station is shown.
SVC ⫽ superior vena cava.
tients. We evaluated 102 NSCLC patients (Table 1).
In 102 patients, we encountered 234 mediastinal
nodal stations accessible by EBUS-TBNA that contained at least one LN ⱖ 5 mm on axial chest CT.
We obtained cytopathologic samples from 163 nodal
stations according to the judgment of a bronchoscopist. We successfully aspirated each of the 162 nodal
stations four times. In a 74-year-old man with COPD
(FEV1, 1.29 L; 61% of expected), EBUS-TBNA was
stopped after two aspirations of the 4R station due to
hypoxemia during the procedure. He recovered from
hypoxemia after EBUS-TBNA. Otherwise, there
were no procedure-related complications.
Diagnostic Values of EBUS-TBNA for the
Diagnosis of Mediastinal Metastasis
Among the 102 NSCLC patients studied, mediastinal metastasis was confirmed by EBUS-TBNA in
41 nodal stations in 30 patients (N2, n ⫽ 25; N3,
n ⫽ 5). A positive EBUS-TBNA result was considered a true positive because the chance of contamination is rare.8 Seventy-two patients were found to
have benign mediastinal LNs based on EBUSTBNA. Five patients chose not to have surgery in our
hospital. Moreover, we found unexpected pleural
EBUS-TBNA
N=105
NSCLC
N=102 (163 LNS*)
SC L C
N=3
N2/N3 negative
N=72
N2/N3 positive
N=30 (41LNS)
Refused surgery
N=5
Surgery
N=67
N2 positive
N= 2 (2LNS)
N2/N3 negative
N=63
No LN dissection#
N=2
Figure 2. The clinical course of 105 patients who enrolled in this
study. *Mediastinal LN stations (LNS). #Due to pleural metastasis. SCLC ⫽ small cell lung cancer.
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metastasis in two patients; thus, LN dissection was
not performed for those patients. Of 65 patients who
underwent surgery and mediastinal LN dissection
(open thoracotomy, n ⫽ 43; VATS, n ⫽ 22), we surgically confirmed two metastatic N2 nodal stations
that were benign by EBUS-TBNA in 2 patients
(Fig 2). One patient had a 5-mm metastasis in the
subcarinal station of which the long axis was 39 mm
on coronal chest CT. The other patient had two
metastatic foci (7 mm and 6 mm) in the subcarinal
station; the long axis of the nodal station was 51
Table 1—Characteristics of Patients and LNs*
Characteristics
Data
Patients, No.
Male/female gender, No.
Median age (range), yr
Histologic type of lung cancer
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Sarcomatoid carcinoma
Adenocarcinoma/squamous cell carcinoma,
double primary
LN stations per patient†
One LN station
Two LN stations
Three LN stations
Location of LN station
2R
2L
4R
4L
7
Median LN size on CT image (range), mm‡
Short axis
Long axis
Mean time of EBUS-TBNA (range), min§
One LN station
Two LN stations
Three LN stations
102
82/20
64.3 (35.0–81.1)
46 (45.1)
45 (44.1)
9 (8.8)
1 (1.0)
1 (1.0)
49 (48.0)
45 (44.2)
8 (7.8)
163
7 (4.3)
1 (0.6)
59 (36.2)
31 (19.0)
65 (39.9)
8.6 (5.1–19.3)
15.2 (7.2–39.9)
33.4 (12–70)
21.6 (12–50)
41.2 (27–70)
60.3 (53–70)
*Data are presented as No. (%) unless otherwise indicated.
†Data are presented as No. of patients (%).
‡Size of biggest LN in each LN station.
§One patient who underwent two aspirations for the 4R station was
excluded in this calculation.
Original Research
Cytologic samples
Tissue-core samples
Overall
52
(8.0%)
99
(15.2%)
158
(24.3%)
117
(18.0%)
434
(66.8%)
No sample
130
(20.0%)
468
(72.0%)
359
(55.2%)
31(4.8%)
102
(15.7%)
Inadequate
Positive
Negative
Figure 3. Cytopathologic results of 650 aspirates from 163 mediastinal LN stations.
mm on coronal chest CT. Among LN stations not
sampled by EBUS-TBNA, LN dissection did not
reveal any metastatic nodes. Considering surgicalpathologic staging as the “gold standard,” the sensitivity, specificity, PPV, NPV, and accuracy of EBUSTBNA in the prediction of mediastinal LN metastasis
were 93.8% (30 of 32 patients), 100% (63 of 63
patients), 100% (30 of 30 patients), 96.9% (63 of 65
patients), and 97.9% (93 of 95 patients), respectively.
stations, cell block specimens were obtained from 13
stations. Eight specimens contained malignant cells.
Cell blocks from the two LN stations for which
diagnosis of malignancy was missed were inadequate
or negative.
Diagnostic Values of EBUS-TBNA According to the
Number of Aspiration
The cumulative sensitivity, specificity, PPV, NPV,
and diagnostic accuracy of EBUS-TBNA according
to the number of aspirations used are presented in
Table 2. Diagnostic values were calculated based on
126 LN stations from 91 patients. We excluded one
benign nodal station that was not aspirated four
times and 36 benign nodal stations that were not
surgically dissected (in 9 LN stations due to refusing
surgery in our hospital; in 3 LN stations due to
pleural metastasis found by thorocotomy; in 8 LN
stations due to confirmed N2 or N3 disease by
EBUS-TBNA; and in 16 LN stations due to contralateral locations of the LN stations by the surgical
site). The sensitivity for differentiating malignant
and benign nodal station increased to 95.3% when
three aspirations were performed. NPV increased to
97.6% when three aspirations were performed. Likewise, the cumulative diagnostic accuracy increased to
98.4% with three aspirations. The fourth aspiration
did not confer an additional diagnostic yield. There
was a significant difference in the EBUS-TBNA
Characteristics of Aspirates by EBUS-TBNA
We obtained 650 aspirates from 163 mediastinal
nodal stations (Fig 3). On average, 5.9 smear slides
(range, 3 to 6 smear slides) were made for each
aspiration. We obtained tissue cores in 75.7% of aspirates. However, 6.3% (n ⫽ 31) of tissue core samples
were inadequate for evaluation (cartilage only,
n ⫽ 4; blood clot only, n ⫽ 27). Considering the
cytologic and histologic results combined, 92.0% of
aspirates were adequate for evaluation. We evaluated cumulative sample adequacy in 101 patients
(162 LN stations) who had four successful aspirations per site. Sample adequacy was 90.1% (146 of
162 LN stations) for one aspiration, 98.1% (159 of
162 LN stations) for two aspirations, and reached
100% (162 of 162 LN stations) in three aspirations.
We could make only 55 cell block specimens
(33.7% of 163 LN stations) due to the poor cellularity of the collected remnants. Of 43 malignant nodal
Table 2—Cumulative Diagnostic Values of EBUS-TBNA Shown by the Number of Aspirations*
Aspirations, No.
Variables
1
2
3
4
Sensitivity
Specificity
PPV
NPV
Accuracy
69.8 (30/43)
100 (83/83)
100 (30/30)
86.5 (83/96)
89.7 (113/126)
83.7 (36/43)
100 (83/83)
100 (36/36)
92.2 (83/90)
94.4 (119/126)
95.3 (41/43)
100 (83/83)
100 (41/41)
97.6 (83/85)
98.4 (124/126)
95.3 (41/43)
100 (83/83)
100 (41/41)
97.6 (83/85)
98.4 (124/126)
*Data are presented as % (No./total). We considered inadequate samples as negative results.
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CHEST / 134 / 2 / AUGUST, 2008
371
Table 3—Diagnostic Values of EBUS-TBNA According to the Presence of a Tissue Core Sample and the Number of
Aspirations*
Aspirations, No.
1
2
3
4
Variables
Tissue Core
No
Tissue Core
Tissue Core
No
Tissue Core
Tissue Core
No
Tissue Core
Tissue Core
No
Tissue Core
Sensitivity
NPV
Accuracy
75.9 (22/29)
89.9 (62/69)
92.3 (84/91)
57.1 (8/14)
77.8 (21/27)
82.9 (29/35)
91.9 (34/37)
96.0 (72/75)
97.2 (106/109)
33.3 (2/6)
73.3 (11/15)
76.5 (13/17)
95.1 (39/41)
97.5 (79/81)
98.3 (118/120)
100 (2/2)
100 (4/4)
100 (6/6)
95.2 (40/42)
97.6 (81/83)
98.4 (121/123)
100 (1/1)
100 (2/2)
100 (3/3)
*Data are presented as % (No./total). We considered inadequate samples as negative results.
diagnostic results after one vs two aspirations
(p ⫽ 0.031, McNemar test). There was a borderline
difference in diagnostic results after two vs three
aspirations (p ⫽ 0.063, McNemar test).
Analysis of Diagnostic Values According to the
Presence of Tissue Core Sample
Of 650 aspirates, aspirates with tissue cores were
more likely to be adequate for evaluation than
aspirates without tissue cores: 96.1% (473 of 492
aspirates) vs 78.5% (124 of 158 aspirates) [p ⬍ 0.001,
␹2 test]. We evaluated diagnostic values with respect
to the presence of tissue core samples and the number
of aspirations (Table 3). The 126 nodal stations mentioned above were analyzed. When at least one tissue
core was obtained by the first or second aspiration,
the sensitivity of the first two aspirations was significantly higher compared to the two aspirations without tissue core samples (91.9%, vs 33.3%, p ⫽ 0.004;
Fisher exact test). Significant differences in NPV
(96.0%, vs 73.3%, p ⫽ 0.014, Fisher exact test) and
diagnostic accuracy (97.2%, vs 76.5%, p ⫽ 0.006,
Fisher exact test) were also found to be dependent
on the presence of the tissue core in the first or
second aspiration.
Discussion
EBUS-TBNA has been reported to be an accurate
and safe diagnostic method for the mediastinal staging of lung cancer.3,8 In this study, we performed
EBUS-TBNA safely under local anesthesia, with
only one COPD patient experiencing hypoxemia,
which led us to discontinue the EBUS-TBNA procedure. Overall, our diagnostic accuracy was consistent with previous studies.3,8
In this study, maximal diagnostic values of EBUSTBNA were obtained in three aspirations. Sample
adequacy reached 100% in three aspirations. We
missed two metastatic mediastinal LN stations that
contained tumor cells in small parts of the node
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station, even though we aspirated four times per site.
Practically, it is not easy to aspirate more than four
times per site due to the duration of the procedure.
In our study, median procedure time was 1 h when
three nodal stations were punctured. Our results
suggest that a fourth aspiration is not necessary in
EBUS-TBNA for the mediastinal staging of NSCLC.
The sensitivity of the first aspiration was 68.9%.
The sensitivity increased to 83.7% after two aspirations and to 95.3% after three aspirations. This
suggests that one needle pass per nodal station is
insufficient for staging of NSCLC, while three aspirations is optimal. However, the macroscopic appearance of aspirates may influence the decision to
perform further aspirations. Aspirates that contained
a tissue core were more likely to be adequate in this
study compared to aspirates lacking tissue core.
Even though 6.3% of tissue core samples that we
obtained were inadequate for evaluation, the sensitivity (91.7%), NPV (96.0%), and accuracy (97.2%)
were high when a tissue core sample was obtained in
the first two aspirations. These data suggest that two
aspirations per LN station can be acceptable when at
least one tissue core specimen is obtained by the first
two aspirations.
As well as the macroscopic appearance of aspirated samples, the adequacy of targeting can also
affect the number of aspirations performed during
EBUS-TBNA. If a bronchoscopist thinks that the
targeting is inadequate or insufficient, an additional
aspiration would be performed. It is common for an
LN station to contain many LNs. Some nodes may
be too large to be sufficiently sampled with only one
or two aspirations. Therefore, bronchoscopists
should select LNs or areas even in a single nodal
station. The size of the LN, the appearance of the
LN on chest CT, result of PET or PET-CT, sonographic features of the LN, and proximity of the LN
to the tumor in the potential pathway of lymphatic
metastasis would influence the decision of a bronchoscopist in the selection of LNs. Larger LNs are
more likely to be malignant, but this is not always the
Original Research
case.12,13 PET is more accurate than CT in mediastinal staging14 and PET can guide invasive mediastinal staging.15,16 The common path of LN metastasis
of lung cancer is known.17 Some echo features of
LNs are associated with metastasis in endoscopic
ultrasound18,19 and remain to be evaluated by EBUS.
Depending on the subjective decision of a bronchoscopist considering the factors mentioned above, we
performed EBUS-TBNA by first attempting to target the most promising area in each nodal station.
However, the targeting was not always successful.
Adequate targeting can reduce the number of aspirations needed. Targeting issues were not evaluated
in this study.
The number of aspirations needed in conventional
TBNA has also been studied, and the maximum
diagnostic yield was obtained in five to seven needle
passes.20,21 Conventional TBNA is a technique that
does not employ direct visualization. It is guided by
endobronchial landmarks and a mental reconstruction of CT images. There are greater limitations in
the size and location of accessible LNs that can be
aspirated using TBNA vs EBUS-TBNA. In a metaanalysis,22 the pooled sensitivity of conventional
TBNA in the mediastinal staging of NSCLC was
reported to be 39 to 78%.
The benefit of ROSE was evaluated in conventional TBNA.23–25 ROSE was cost-effective and improved diagnostic yield.23,24 ROSE also improved the
diagnostic yield of in endoscopic ultrasound-guided
fine needle aspiration.26 If ROSE were available in
our institution, our cytologic results suggest that we
could have stopped EBUS-TBNA in 68.3% of malignant nodal stations after the first aspiration and
after the second aspiration in an additional 14.6% of
stations. In one study8 using ROSE, the mean examination time of EBUS-TBNA was approximately 15
min. In our study, the mean procedure time was 33.4
min when we punctured four times per nodal station
(average, 1.6 stations per patient). The procedure
time would be shorter if two to three aspirations per
site were performed. The benefits of ROSE with
respect to procedure time, cost-effectiveness, and diagnostic yield remain to be studied in EBUS-TBNA.
This study has several limitations. We selected the
target LN stations considered to be necessary in mediastinal staging. Another limitation is that all negative
LN stations by EBUS-TBNA were not surgically
confirmed. We could not surgically confirm the
negative LN stations sampled in patients with mediastinal metastasis proved by EBUS-TBNA. We also
could not get surgical samples from 16 contralateral
nodal stations from 15 surgical patients with surgical
stage I or II disease because LN dissection of the
contralateral side was considered not to be beneficial
for those patients. The selection of LNs and the
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limitations of surgical confirmation would have affected the diagnostic values, especially NPV.
In our study, we collected the remnants of all
aspirates from each nodal station for a cell block,
rather than making a cell block for each aspiration.
After three pairs of slides were made, the cellularity
of the remnants was often scant. The cytologic
results of cell blocks did not influence the overall
diagnostic values of EBUS-TBNA. We think it is
unlikely that collecting the remnants would influence the interpretation of our data.
In conclusion, our results suggest that optimal
diagnostic results of EBUS-TBNA can be obtained
with three aspirations per LN station in the mediastinal staging of potentially operable NSCLC. When
at least one tissue core specimen is obtained by the
first or second aspiration, two aspirations per LN
station can be acceptable.
ACKNOWLEDGMENT: The authors thank Dr. K. Yasufuku
and Dr. T. Fujisawa (Chiba University, Japan) for their instruction and advice concerning EBUS-TBNA.
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