| Keywords
Lung Cancer, EUS, Fine Needle Aspiration,
Review
Introduction
Lung cancer is the most common cause of
cancer death in the United States (1). Approximately 72% of
all lung cancers are classified histologically as non-small
cell lung carcinoma (NSCLC), 25% as small cell carcinoma,
and the remaining 2-3% is comprised of miscellaneous tumors.
There will be approximately 170,000 new cases of lung cancer
diagnosed in 2002, with an overall 5-year survival of less
than 15% (2). In patients with suspected lung cancer, accurate
diagnosis and staging are critical for determining optimal
treatment modalities and prognosis. Treatment is based first
on distinguishing between small cell and NSCLC, then determining
the stage of disease. Greater than 70% of small cell carcinoma
is widespread and unresectable at the time of diagnosis, whereas
20% of patients with NSCLC have local disease and 25% have
disease spread to regional lymph nodes, both of which may
be amenable to surgical resection.
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Figure
1A |
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Figure
1B |
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Figure
1C |
NSCLC is staged using TNM classification
(3). A standardized lymph node mapping system has recently
been proposed that demarcates the anatomic boundaries between
lymph node stations in metastatic NSCLC (4-6) (Figure 1A-1C).
This mapping system is often used in the literature to document
location of malignant lymph nodes when comparing staging modalities.
Lymph node involvement is characterized as N1 (peri-bronchial
or ipsilateral hilar), N2 (ipsilateral mediastinal or subcarinal),
or N3 (contralateral mediastinal or hilar nodes, or supraclavicular
nodes) (3). Patients with ipsilateral malignant mediastinal
lymph nodes (N2) have Stage IIIa disease, and are usually
not surgical candidates, although may be considered for surgery
after preoperative chemoradiation. Patients with contralateral
malignant mediastinal lymph nodes (N3) are Stage IIIb, and
are not considered surgical candidates.
Staging is performed initially with thoracic
computed tomography (CT) scanning, and has a reported sensitivity
and specificity of 60-70% for detecting N2 or N3 (i.e. advanced)
disease (1). Mediastinal adenopathy detected on CT can be
further investigated either nonsurgically or with cervical
mediastinoscopy to determine which nodes contain malignant
foci. Non-surgical means include transbronchial and CT-guided
fine-needle aspiration (FNA), which have sensitivities ranging
from 50-98% (7-11). CT-guided transthoracic needle biopsies
are associated with a 37% risk of pneumothorax, with up to
15% of patients requiring a chest tube (8,12). Despite the
ability of transbronchial FNA to diagnosis subcarinal lymph
nodes, only 12% of bronchoscopists were performing transbronchial
FNA in 1991 (13). Fluorodeoxyglucose-positron emission tomography
(FDG-PET) scanning is emerging as a new non-surgical method
for staging, with reported sensitivity of 73%, specificity
of 94%, and accuracy of 87% for detecting malignant mediastinal
lymph nodes in patients with NSCLC (14). However, it is very
expensive, has limited availability, and its definitive role
has yet to be determined (15).
Cervical mediastinoscopy is performed under
general anesthesia and involves making an incision in the
suprasternal notch and placing a rigid scope into the mediastinum.
There is access to lymph nodes at the tracheobronchial angle
(levels 10L and 10R), but dissection is needed to reach upper
(levels 2L and 2R) and lower (levels 4L and 4R) nodes. Subcarinal
(level 7) and aorticopulmonary (AP) window (level 5) lymph
nodes can be reached with some difficulty. Mediastinoscopy
is generally safe and usually performed as an outpatient procedure,
but has the potential complications of incisional discomfort
and scarring, transient hoarseness, bleeding, esophageal perforation,
pneumothorax, and arrythmia (16). In a review of 2137 mediastinoscopies,
the peri-operative mortality rate was 0.2%, and the complication
rate 0.6% (17). Mediastinoscopy has a sensitivity of 70-95%
and a specificity of 100% (17).
Endoscopic ultrasound (EUS)-guided transesophageal
FNA has become a useful non-surgical adjunct in the evaluation
of mediastinal adenopathy in patients with NSCLC, especially
in the imaging and sampling of inferior and posterior (levels
8 and 9), AP window (levels 5), subcarinal (level 7), and
para-tracheal (level 4) lymph nodes (15). The technique usually
involves using a radial array echoendoscope to identify the
size and precise location of the nodes to be biopsied (Figures
2-4), followed by a linear array echoendoscope to direct the
placement of a 22-guage FNA needle directly into the node
under EUS guidance (Figures 5,6). Aspiration is performed
with an "in-and-out" motion, either with or without
the use of a suction syringe (18). A cytologist is typically
present to determine if diagnostic material has been obtained
(Figure 7), which helps in deciding the number of passes needed,
and whether material needs to be sent for flow cytometry or
microbiology. A review of EUS-guided FNA of several different
anatomic sites revealed it to be a safe and cost-effective
procedure, with a reported complication rate of less than
1% for solid lesions (i.e. lymph nodes and masses) (18-27).
Several series have described EUS or EUS-guided
FNA of the mediastinum in the evaluation of patients with
known or suspected lung cancer who had mediastinal adenopathy.
Table 1 summarizes those studies that utilized EUS/FNA (19,20,22,24,26,28,29,30,32,33).
Pedersen et al. reported on nine patients with CT scans showing
posterior mediastinal masses or lymphadenopathy. Of the 6
patients with primary lung cancer, EUS-guided FNA correctly
made the diagnosis in all six (22). Silvestri et al. reported
that in 27 patients with known or suspected lung cancer, EUS
found malignant appearing posterior mediastinal lymph nodes
in 15 patients, and FNA was positive for malignancy in all
nodes. The lymph nodes were assessed in levels 5, 7, and 10R.
Sensitivity was 89%, specificity 100%, and accuracy 100%,
all of which were better than CT scanning (24).
Gress et al. performed EUS on all patients
with potentially resectable NSCLC who on CT were found to
have mediastinal adenopathy greater than 1 cm in diameter
(30). Among 130 patients with NSCLC, 52 (40%) were found to
have mediastinal nodes on CT greater than 1 cm. Seventeen
of the 52 patients had EUS before the advent of FNA, and 35
had EUS with the possibility of simultaneous FNA. Among the
35 patients, 24 (69%) underwent FNA, and 14 (40%) had a positive
FNA which upstaged the patient to unresectable status. The
accuracy of EUS/FNA in diagnosing malignant mediastinal lymph
nodes was 96%, with sensitivity 95% and specificity 81%. Potepan
et al. studied 71 patients with a histologic diagnosis of
lung cancer (31). All patients underwent both EUS (without
FNA) and chest CT after nodal involvement was excluded by
chest x-ray. They found that on a per-station basis, CT had
sensitivity 74% and specificity 83%, while EUS without FNA
had sensitivity 56% and specificity 93% for the detection
of malignant mediastinal adenopathy. The accuracy rates of
the two techniques were similar (CT 81%, EUS 83%).
Fritscher-Ravens et al. first described
16 patients with intrapulmonary lesions on chest X-ray or
CT but negative bronchoscopic biopsy and/or cytology (19).
All patients underwent transesophageal EUS-guided FNA, with
cytology conclusive for cancer in 9 out of 10 patients. Sensitivity
for EUS-guided FNA was 90%, specificity was 100%, and diagnostic
accuracy was 94%. Her group later described 35 patients with
posterior mediastinal adenopathy suspicious for malignancy,
who had non-diagnostic bronchoscopic evaluation, including
trans-bronchial FNA (20). They diagnosed malignant lymph nodes
in 71% of patients, and had a final sensitivity, specificity,
and accuracy of 96%, 100%, and 97%, respectively. The same
group also described their experience with 153 patients who
underwent EUS/FNA for mediastinal lymphadenopathy, and reported
a sensitivity, specificity, and accuracy of 92%, 100%, and
95%, respectively (34).
Wiersema et al. performed EUS/FNA on 86
patients with posterior mediastinal adenopathy. His accuracy
rate in distinguishing benign from malignant lymph nodes was
98%, with sensitivity 96% and specificity 100%. In 29 patients
with NSCLC, staging accuracy, sensitivity, and specificity
for EUS/FNA were each 100%. In comparison, staging accuracy,
sensitivity, and specificity for EUS alone and CT alone were
each 79%, 86%, and 57%, respectively (p=0.01) (26). Wallace
et al. found that in 85 of 121 patients with lung cancer,
EUS/FNA detected mediastinal spread of tumor, with overall
sensitivity for the detection of mediastinal lymph node metastases
alone of 87% and specificity of 100% (33).
We recently described our experience with
the role of EUS/FNA in the diagnosis of lung cancer in a managed
care setting (32). Of 44 patients referred with mediastinal
adenopathy on CT scan, a new cancer diagnosis was made in
25/44 (57%). Of 25 patients with a final diagnosis of NSCLC,
60% were upstaged to N2 disease by EUS/FNA. The overall accuracy
for EUS/FNA in diagnosing malignant adenopathy was 98%, with
sensitivity 96% and specificity 100%. Only 20% of the patients
underwent any subsequent thoracic surgery, compared to an
expected 100% prior to the EUS/FNA.
There are also several reports that show
that other etiologies for unexplained mediastinal adenopathy
can be determined. Conditions such as sarcoidosis and histoplasmosis
have been diagnosed with EUS/FNA, (26; 35-37) and metastases
from non-pulmonary tumors can also be diagnosed (26). The
utility in diagnosing lymphoma, however, is limited compared
to NSCLC. Wiersema has shown that sensitivity is only 71%
for diagnosing lymphoma compared to 100% for NSCLC. (26).
Therefore, patients with suspected lymphoma and negative EUS/FNA
might need to undergo mediastinoscopy for diagnosis.
Summary
In conclusion, EUS-guided FNA has high sensitivity,
specificity, and diagnostic accuracy that are comparable to
that of mediastinoscopy and trans-bronchial FNA, and allows
sampling of nodes that cannot be easily obtained with the
other methods. When mediastinal adenopathy due to lung cancer
is suspected from imaging studies, it can serve as a first-line
means to obtain a definitive tissue diagnosis, and can safely
and efficaciously provide the staging information that is
so critical in guiding therapy. Compared to EUS/FNA of the
pancreas, transesophageal EUS/FNA of mediastinal lymph nodes
is technically much easier, and should allow physicians new
to EUS/FNA to still maintain a high diagnostic accuracy despite
a relative lack of expertise.
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