Endoscopic Ultrasound–Guided Fine Needle Aspiration Cytology of ...

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 9, 2003
© 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00
Published by Elsevier Inc.
doi:10.1016/S0002-9270(03)00549-5
Endoscopic Ultrasound–Guided Fine Needle
Aspiration Cytology of Solid Liver Lesions:
A Large Single-Center Experience
John DeWitt, M.D., Julia LeBlanc, M.D., Lee McHenry, M.D., Dan Ciaccia, M.D., Tom Imperiale, M.D.,
John Chappo, B.S., C.T., Harvey Cramer, M.D., Kathy McGreevy, R.N., Melissa Chriswell, R.N., and
Stuart Sherman, M.D.
Department of Gastroenterology and Hepatology and Department of Pathology and Laboratory Medicine,
Indiana University Medical Center, Indianapolis, Indiana
OBJECTIVES: The aim of this study was to report the sensitivity,
cytological diagnoses, endoscopic ultrasound (EUS)
features, complications, clinical impact, and long term follow-up
of a large single-center experience with endoscopic
ultrasound–guided fine needle aspiration (EUS-FNA) of
benign and malignant solid liver lesions.
METHODS: A database of cytologic specimens from EUS-
FNA was reviewed to identify all hepatic lesions aspirated
between January, 1997, and July, 2002. Procedural indications,
prior radiographic data, patient demographics, EUS
examination results, complications, and follow-up data were
obtained and recorded.
RESULTS: EUS-FNA of 77 liver lesions in 77 patients was
performed without complications. Of these 77 lesions, 45
(58%) were diagnostic for malignancy, 25 (33%) were benign,
and seven (9%) were nondiagnostic. A total of 22
lesions were confirmed as negative for malignancy by follow-up
(mean 762 days, range 512–1556 days) or intraoperative
examination; however, seven lesions could not be
classified as benign or malignant. Depending on the status of
the seven unclassified lesions, sensitivity of EUS-FNA for
the diagnosis of malignancy ranged from 82 to 94%. When
compared with benign lesions, EUS features predictive of
malignant hepatic masses were the presence of regular outer
margins (60% vs 27%; p 0.02) and the detection of two
or more lesions (38% vs 9%; p 0.03). Of the 42 patients
with malignancy identified by EUS-FNA and other available
imaging records, EUS detected the malignancy in 41%
of patients with previously negative examinations. For the
45 subjects with cytology positive for malignancy, EUS-
FNA changed management in 86% of subjects.
CONCLUSION: EUS-FNA of the liver is a safe and sensitive
procedure that can have a significant impact on patient
management. Prospective studies comparing the accuracy
and complication rate of EUS-FNA and percutaneous fine
needle aspiration (P-FNA) for the diagnosis of liver tumors
are needed. (Am J Gastroenterol 2003;98:1976–1981. ©
2003 by Am. Coll. of Gastroenterology)
INTRODUCTION
Identification of hepatic metastases from systemic malignancy
usually implies inoperable disease and a poor prognosis.
Furthermore, the diagnosis of unresectable malignancy
may obviate the need for surgery along with its
inherent morbidity and mortality. The diagnosis of liver
masses is traditionally accomplished by percutaneous fine
needle aspiration (P-FNA) under fluoroscopic, computed
tomographic, or ultrasonographic guidance (1–3). Although
rare, complications from P-FNA may include severe bleeding
and implantation metastases in up to 3% of patients
(3–8).
Endoscopic ultrasound (EUS)–guided fine needle aspiration
(EUS-FNA) has been established as a safe and accurate
method for the diagnosis of benign or malignant lymphadenopathy
and for intramural and extramural neoplasms (9,
10). The role of EUS-FNA in the diagnosis and staging of
liver metastases or masses, however, is limited to a small
single-center series (11), a large retrospective international
survey (12), and several case series (13, 14). Furthermore,
the sensitivity of EUS-FNA and endosonographic features
of benign and malignant hepatic lesions have not been
described. The aim of this study was to report the sensitivity,
cytological diagnoses, EUS features, complications, and
clinical impact of a large single-center experience with
EUS-FNA of solid liver lesions.
MATERIALS AND METHODS
From an existing EUS-FNA cytology database, we identified
all patients between January, 1997, and July, 2002, in
whom EUS-FNA of the liver was performed. The database
used had been maintained and prospectively updated by one
cytotechnologist (J.C.). Patients with hilar cholangiocarcinomas
or cystic hepatic lesions were excluded from the
analysis.
Staging EUS examinations for known or suspected malignancy
were performed initially with an Olympus GF-
UM20 or GFUM-130 radial echoendoscope (Olympus,

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EUS-FNA Cytology of Solid Liver Lesions
1977
Table 1. Indications for EUS Examinations by Cytology Results of
EUS-FNA of the Liver
Melville NY). The right lobe of the liver was surveyed from
the duodenum and distal stomach, whereas the left lobe was
imaged from the proximal and mid-stomach. Endoscope
rotation was used as necessary to visualize as much of the
liver parenchyma as possible. EUS-FNA was performed
using the Pentax 32-UA, Pentax 36-UX (Pentax Precision
Instruments, Orangeburg, NY), Olympus GF-UC30P, or
Olympus GF-UC140P curvilinear array echoendoscope.
EUS-FNA was performed using a 22-gauge, 8-cm Wilson-
Cook EUSN-1, EUSN-2, or EUSN-3 needle (Wilson-Cook
Medical, Winston-Salem, NC) by one of four physicians
(J.D., D.C., L.M., or J.L.). Doppler color angiography was
used to ensure the absence of intervening vascular structures
along the anticipated needle path. Depending on the amount
of blood anticipated during tissue sampling, full, partial, or
no suction was applied at the discretion of the endoscopist,
cytotechnologist, or cytopathologist. A cytotechnologist or
cytopathologist was available on-site for preliminary interpretations
on all procedures. Samples aspirated were expressed
onto a glass slide and two smear preparations were
made. One slide was air-dried and stained with a modified
Giemsa stain for rapid on-site interpretation. The other slide
was alcohol-fixed and stained by the Papanicolaou method.
EUS-FNA was repeated until a definitive diagnosis was
made or the endoscopist believed that further sampling
would not likely increase yield. Within several days of each
EUS examination, a final cytological diagnosis was rendered
by a staff cytopathologist.
A true positive EUS-FNA for malignancy is defined as
unequivocal cytological evidence of malignancy. A false
negative aspirate is a nondiagnostic or benign specimen,
which is subsequently found to be malignant by percutaneous
FNA or intraoperative findings. A true negative EUS-
FNA for malignancy is defined as benign or nondiagnostic
samples that are either confirmed as benign by alternative
sampling, intraoperative examination, or appropriate clinical
follow-up. Specimens with benign hepatocytes without
evidence of atypical cells are categorized as benign aspirates.
Aspirates from EUS-FNA that are interpreted as nondiagnostic,
highly suspicious, suspicious, or atypical for
malignancy are considered as negative for malignancy.
Medical records of enrolled subjects were reviewed and
procedural indications, prior radiographic data, patient demographics,
EUS test results, clinical outcomes, procedural
complications, and follow-up data were abstracted. When
multiple liver lesions were noted, the endosonographic description
of only the aspirated lesion was recorded. When
charts were incomplete, written informed consent was sent
and follow-up telephone calls were made to the subject,
closest relative of the deceased, or referring physician for
clarification or any required further information. The potential
clinical impact of EUS-FNA of a liver metastasis or
malignancy is defined as results that met the following
criteria: 1) avoided surgery (results precluded resectable
malignancy); 2) made diagnosis (results provided initial
diagnosis of malignancy); 3) upstaged tumor (results upstaged
primary malignancy); 4) incurred no change in management
(results did not change patient treatment). This
study was approved by the Institutional Review Board at our
institution.
Statistical Analysis
Assuming that the EUS-FNA diagnosis of malignancy is a
true positive, sensitivity was calculated as the proportion of
patients with cancer in whom EUS-FNA was positive for
malignancy. For analysis, continuous variables were described
as means and standard deviations, and dichotomous
variables were expressed as simple proportions with or
without 95% confidence limits. Student’s t test and 2 or
Fisher’s exact tests were used to test for differences in
comparisons between continuous and dichotomous variables,
respectively.
RESULTS
Indication
All
(n 77)
Cytology Result
Malignant
(n 45)
Benign/ND
(n 32)
Abnormal ERCP 21 (27) 11 (24) 10 (31)
Pancreatic mass on CT 19 (25) 12 (27) 7 (22)
Staging of known cancer 10 (13) 7 (16) 3 (9)
Liver mass on CT 9 (12) 9 (20) 0 (0)
Other abnormal CT findings 4 (5) 1 (2) 3 (9)
Suspected recurrent cancer 2 (3) 1 (2) 1 (3)
Chronic abdominal pain 2 (3) 0 (0) 2 (7)
Other 10 (12) 4 (9) 6 (19)
Total 77 45 32
ND nondiagnostic
In total, EUS-FNA was performed on 77 different liver
lesions in 77 patients (42 male and 35 female, 69 white and
eight African American, with a mean age of 63 11 yr).
Follow-up was available in all patients.
Indications for EUS Examinations
The indications for the 77 EUS procedures are recorded in
Table 1. The two most common indications were abnormal
ERCP findings, the majority of which were strictures, and a
pancreatic mass on CT scan, which accounted for 27% and
25% of the procedures performed, respectively. Ten (13%)
of 77 procedures were done for staging of a recently diagnosed
malignancy (pancreas in five, esophageal in four, and
lung in one). Of the 45 malignancies diagnosed by EUS-
FNA, the most common indications for the EUS were a CT
finding of a pancreatic mass (27%) and abnormal ERCP
findings (24%).
Characteristics of EUS Examination
EUS-FNA was performed in 77 patients (mean 3.4 1.8
passes, range 1–8) into the left lobe (n 66; 86%) and right
lobe (n 11; 14%) of the liver without procedural compli-

1978 DeWitt et al. AJG – Vol. 98, No. 9, 2003
Table 2. Characteristics of EUS Examination
All*
(n 77)
Malignant†
(n 48)
Benign‡
(n 22) p-value§
Site of FNA
Left lobe 66 (86) 41 (85) 20 (91) 0.57
Right lobe 11 (14) 7 (15) 2 (9)
No. of passes 3.4 1.8 3.5 1.5 3.2 1.5 0.44
Range 1–8 1–8 1–8
Echogenicity
Hypoechoic 52 (68) 33 (69) 13 (59) 0.36
Hyperechoic 23 (30) 13 (27) 9 (41)
Both 2 (2) 2 (4) 0 (0)
Margins
Regular 39 (51) 29 (60) 6 (27) 0.02
Irregular 38 (49) 19 (40) 16 (73)
Size (mm) 16.0 10.8 15.6 7.7 16.7 12.0 0.70
Range 3–40 3–35 4–40
No. of lesions seen
1 57 (74) 30 (62) 20 (91) 0.03
1 20 (26) 18 (38) 2 (9)
* Includes seven patients unable to be classified as benign or malignant.
† Includes 45 positive and three false negative EUS-FNA results.
‡ By follow-up or intraoperative findings.
§ Between malignant and benign lesions.
cations (upper 95% CI 4.7%; see Table 2). A total of 45
(58%) aspirates were diagnostic for malignancy. Three false
negatives were later discovered by intraoperative findings (n
2) or P-FNA (n 1). One patient with pancreatic adenocarcinoma
(as confirmed by EUS-FNA of the pancreas)
had benign cytology of a 6-mm left lobe mass that intraoperatively
was confirmed as metastatic adenocarcinoma. A
second patient with pancreatic adenocarcinoma (as confirmed
by EUS-FNA of the pancreas) had benign cytology
of a 6-mm right lobe mass, which was later confirmed by
percutaneous ultrasound-guided biopsy as metastatic adenocarcinoma.
The third patient with a false negative EUS-FNA
had a 29-mm left lobe mass that was benign by EUS-FNA.
Intraoperative examination, however, confirmed hepatocellular
carcinoma. Overall, 48 of 77 (62%) of the liver masses
were malignant. Among the remaining 29 subjects with
nonmalignant aspirates, in 22 (76%) the masses were considered
benign by clinical follow-up (n 18; mean 762
days; range: 512–1556 days) or intraoperative evaluation (n
4). Seven (24%) of the subjects with nonmalignant
masses with pancreatic adenocarcinoma (as confirmed by
EUS-FNA of the pancreas; n 6) or lung cancer (n 1)
died (mean 154 days, range 14–424 days) without follow-up
imaging, biopsy of the liver, or autopsy and therefore
cannot be classified as benign or malignant. The 45
diagnostic aspirates for malignancy are considered true positives
(Fig. 1). Assuming that the test results for these seven
patients were all true negatives or all false negatives, the
sensitivity of EUS-FNA for the diagnosis of malignancy
would range from 82 to 94%.
In comparison between benign and malignant lesions
detected by EUS-FNA (Table 2), no statistically significant
difference was found between the liver lobe aspirated (p
0.57), number of passes (p 0.44), lesion size (p 0.70),
Figure 1. Sensitivity of EUS-FNA of the liver for the diagnosis of
malignancy.
or echotexture (p 0.36). Malignant masses, however,
were more often accompanied by the presence of multiple
hepatic lesions detected on EUS (38% vs 9%; p 0.03; 2
analysis) and to have regular margins (60% vs 27%; p
0.02; 2 analysis).
Diagnoses from EUS-FNA of the Liver
The final diagnoses for the 45 malignant liver aspirates are
recorded in Table 3. Of these, 44 (98%) were metastatic and
one (2%) was a hepatocellular carcinoma. The most common
diagnosis was metastatic adenocarcinoma from the
pancreas, which accounted for 34 of 45 (76%). The next
most frequent diagnosis was metastatic neuroendocrine tumor
from the pancreas (n 5; 11%). Of the 32 nonmalignant
aspirates, 25 (33%) were cytologically benign and
seven (9%) were nondiagnostic. One (4%) benign aspirate
demonstrated cytological features consistent with an
abscess.
Previous Imaging of Malignancy Diagnosed by
EUS-FNA
Prior radiographic imaging reports were available for 42 of
45 (93%) malignant hepatic masses diagnosed by EUS-
Table 3. Diagnoses of Malignant Aspirates of the Liver
Diagnosis No. (%)
Pancreatic adenocarcinoma 34 (76)
Pancreatic neuroendocrine tumor 5 (11)
Renal cell carcinoma 2 (5)
Gallbladder adenocarcinoma 1 (2)
Colon cancer 1 (2)
Hepatocellular carcinoma 1 (2)
Esophageal adenocarcinoma 1 (2)
Total 45

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EUS-FNA Cytology of Solid Liver Lesions
1979
FNA. All imaging had been performed within 45 days of the
EUS examination. Of these 42 lesions, EUS-FNA detected
malignancy in 17 (41%) when prior imaging of the liver by
CT alone (n 13), transabdominal ultrasound (US) alone (n
1), or both (n 3) were normal. For the 32 patients in
whom CT alone was performed, EUS-FNA initially detected
a malignancy in 13 (41%). For the nine patients in
whom CT and US were both performed, EUS-FNA initially
detected malignancy in three (33%). The mean size of the 17
malignant liver lesions detected initially by EUS-FNA was
12.6 mm (range 3–26 mm). Of these 17, six (35%) were 1
cm in diameter.
Clinical Impact of EUS-FNA of the Liver
For the 45 patients with malignant cytology, EUS-FNA had
(by protocol definition) a clinical impact in all patients.
EUS-FNA changed management, however, in only 38
(84%) of these patients, because in seven cases (16%) tumor
was upstaged but did not change overall patient management.
EUS-FNA provided the initial diagnosis of malignancy
in 35 patients (78%) and avoided surgery in 12
(27%). Of the 35 patients in whom EUS-FNA made the
initial diagnosis of malignancy, 34 (97%) had metastases
and one (3%) had a hepatocellular carcinoma. In 25 patients
(55%), the FNA provided both the primary diagnosis and
upstaged the malignancy. In nine subjects (20%), EUS-FNA
made the initial diagnosis, upstaged the tumor, and prevented
surgery. Three EUS-FNAs (7%) were diagnostic in
which previous CT-FNA was benign (two of three) or
nondiagnostic (one of three). In three patients with nonmalignant
EUS-FNA aspirates, malignancy was later confirmed
by surgery (n 2) or percutaneous biopsy (n 1).
Follow-Up After EUS-FNA
Of the 45 patients with malignant cytology from EUS-FNA,
40 have died, with a mean time to death after EUS-FNA of
135 days (range 7–754 days). The patient who died 7 days
after EUS-FNA expired in his sleep outside the hospital
without any apparent adverse consequence from EUS-FNA;
however, no autopsy was performed. The patient who lived
754 days had metastatic pancreatic cancer and enrolled in an
experimental chemotherapy protocol at another institution.
The longest survival otherwise was 298 days. Five patients
remain alive with a mean follow-up of 64 days (range
30–140 days). The mean time to death from metastatic
pancreatic adenocarcinoma to the liver was 113 days (n
31; range 7–754 days).
DISCUSSION
The results of this study demonstrate that EUS-guided FNA
of solid hepatic masses is sensitive, safe, and has a significant
impact on patient management when malignancy is
diagnosed. In our series, the sensitivity of EUS-FNA for the
diagnosis of malignancy ranged from 82% to 94%. Although
it may be presumed that we obtained no false positive
results when testing aspirates, the inability to histologically
corroborate this does not allow for calculation of
specificity. A previous report of 14 patients that underwent
EUS-FNA of liver metastases described a sensitivity and
specificity of 100% and 100% for the diagnosis of malignancy
(11). To our knowledge, however, our study is the
first report of the test characteristics of EUS-FNA of the
liver that includes both malignant and benign hepatic lesions.
The sensitivity of the EUS-FNA of the liver we report
is similar to previous series that describe the sensitivity of
EUS-FNA of pancreatic malignancy (9, 15–17) and P-FNA
of liver tumors (2, 18–20). Despite the good sensitivity of
EUS-FNA of liver tumors, we obtained three false negative
results. Therefore, follow-up percutaneous biopsy or intraoperative
evaluation is warranted when the diagnosis of
malignancy in the liver is strongly suspected and would
significantly affect patient management.
The mean number of overall passes performed for the
diagnosis of hepatic lesions (n 3.2; range 1–8) is slightly
higher in our series than has been previously reported (11).
The exact reason for this difference is not clear, although it
is not significantly different from the number required for
ultrasound-guided P-FNA of small hepatic masses (21). In a
series of 14 patients with EUS-FNA of a malignant liver
lesion, Nguyen et al. reported a mean of 2.0 (range 1–5)
passes for the diagnosis of malignancy (11). The presence of
a cytopathologist on-site was implied, as interpretation of
specimens was performed before making repeated passes.
We also have a cytotechnologist or cytopathologist available
on site to assess the adequacy of obtained specimens.
Because the diagnosis of metastatic disease is clinically
relevant and initial air-dried preparations are sometimes
difficult to interpret, we will often repeat another pass to
ensure that cytology is sufficient to render a diagnosis if the
adequacy of a specimen is initially interpreted as “suspicious”
but not diagnostic of malignancy. We found no
statistically significant difference between the numbers of
passes required for the diagnosis of benign (n 3.2; range
1–8) or malignant (n 3.5; range 1–8) lesions. In addition,
no difference existed between the number of passes required
during the first or second half of the study. This implies that
increased experience with this technique may not decrease
the number of passes needed to obtain an accurate cytological
diagnosis.
Despite the relatively higher number of passes performed
in this study, we observed no complications after EUS-FNA
of the liver. In a large international survey of 167 cases
describing EUS-FNA of the liver, however, six complications
(4%) were described (12). These complications included
one death in a patient who underwent EUS-FNA of
the liver despite a suspected obstructed biliary stent. Other
complications noted were bleeding, abdominal pain, and
fever. Although it is standard practice for gastroenterologists
to observe patients in the right lateral decubitus position
for several hours after percutaneous biopsy of the liver,
we discharge stable patients within 60–75 min after EUS-

1980 DeWitt et al. AJG – Vol. 98, No. 9, 2003
FNA of the liver. Furthermore, we do not routinely place
patients on their right side during recovery before discharge.
A recent series (5) describing the use of P-FNA in the
diagnosis of 216 liver tumors reported the occurrence of
implantation metastases in seven patients (3%) a median 4
months (range 2–49 months) after P-FNA of liver masses
from colorectal cancer (n 5), gallbladder carcinoma (n
1), and a hepatoma (n 1). In addition, the implantation
metastases caused major problems locally and were fatal in
four patients. This complication has not been described after
EUS-FNA of the liver. The true incidence of implantation
metastases after EUS-FNA of the liver, however, is difficult
to estimate, inasmuch as hepatic metastases from pancreatic
malignancy (which comprise 87% of malignancies in our
study) usually carry a dismal prognosis and are managed
nonoperatively. Therefore, as the overwhelming majority of
patients diagnosed with of hepatic metastases after EUS-
FNA of the liver do not undergo intended curative resection,
the true incidence of this complication is not known. The
most common malignancies diagnosed by P-FNA (colorectal
metastases and primary hepatomas) are often managed
surgically with curative intent. We believe that these fundamental
differences partially explain the disparity in reported
incidence of implantation metastases between EUS-
FNA and P-FNA of liver masses. Studies comparing the
diagnostic accuracy and complications EUS-FNA and P-
FNA of all types of suspected liver tumors are needed to
resolve these issues.
The overall sensitivity of transabominal US for the detection
of liver metastases is reportedly between 80% and
90% (22, 23). Recent studies using helical CT and magnetic
resonance imaging, however, show that noninvasive imaging
is relatively insensitive for lesions 1 cm(24–26). By
EUS and EUS-FNA, we detected 17 malignant hepatic
lesions (mean 12.6 mm, range 3–26 mm) with a previously
normal CT alone (n 13), CT and US (n 3), or US alone
(n 1). Of these, six (35%) were 1 cm in diameter. These
17 lesions were found in 41% of the 42 patients with
available radiographic imaging information performed before
EUS. Nguyen et al. (11) reported that CT performed
before EUS-FNA of the liver failed to detect liver lesions in
11 of 14 patients (79%). Collectively, these results demonstrate
the utility of EUS-FNA for the detection of malignant
liver lesions that have been missed by prior radiographic
imaging. Further comparative studies are needed to determine
whether other imaging modalities such as fluorine-18
fluorodeoxyglucose positron emission tomography (27),
magnetic resonance imaging (28), harmonic ultrasound imaging
(29), or ultrasound contrast agents (30) offer any
advantages over EUS for detection of occult or subcentimeter
liver metastases.
When compared with benign lesions, we found that malignant
lesions detected by EUS-FNA of the liver were more
likely to have regular margins (60% vs 27%; p 0.02) and
to be accompanied by at least one other lesion detected on
EUS (38% vs 9%; p 0.03). Furthermore, no statistically
significant difference was found with regard to site of biopsy
(p 0.57), size (p 0.70), echogenicity (p 0.36), or
number of passes performed (p 0.44) for these lesions.
Although EUS features of malignant lymphadenopathy have
been described (31), to our knowledge the endosonographic
features for malignant liver lesions have not been previously
reported. These findings may help to guide decision making
and assessment of the risk/benefit ratio of EUS-FNA of
hepatic masses.
In conclusion, the results of our study show that the
sensitivity of EUS-FNA of the liver for the diagnosis of
malignancy ranges from 82% to 94% and that, contrary to
previous reports, it is a safe procedure. When malignancy is
diagnosed, EUS-FNA of the liver significantly affects patient
management and implies a poor overall prognosis.
EUS features predictive of malignant hepatic masses are the
presence of regular outer margins and the detection of two
or more lesions. In this series, EUS and EUS-FNA detected
malignant liver tumors that were not seen by CT or US (or
both) in 41% of subjects. Therefore, surveillance of the
entire liver is indicated during evaluation of known or
suspected malignancy. Prospective studies are needed to
compare the accuracy and complication rate of EUS-FNA
and P-FNA for the diagnosis of liver tumors.
Reprint requests and correspondence: John M. DeWitt, M.D.,
Department of Medicine, Division of Gastroenterology, Indiana
University Medical Center, 550 N. University Boulevard, UH
4100, Indianapolis, IN 46202-5121.
Received Nov. 11, 2002; accepted Jan. 30, 2003.
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