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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 sen- INTRODUCTION
sitivity, cytological diagnoses, endoscopic ultrasound (EUS)
features, complications, clinical impact, and long term fol- Identification of hepatic metastases from systemic malig-
low-up of a large single-center experience with endoscopic nancy usually implies inoperable disease and a poor prog-
ultrasound– guided fine needle aspiration (EUS-FNA) of nosis. Furthermore, the diagnosis of unresectable malig-
benign and malignant solid liver lesions. nancy may obviate the need for surgery along with its
inherent morbidity and mortality. The diagnosis of liver
METHODS: A database of cytologic specimens from EUS- masses is traditionally accomplished by percutaneous fine
FNA was reviewed to identify all hepatic lesions aspirated needle aspiration (P-FNA) under fluoroscopic, computed
between January, 1997, and July, 2002. Procedural indica- tomographic, or ultrasonographic guidance (1–3). Although
tions, prior radiographic data, patient demographics, EUS rare, complications from P-FNA may include severe bleed-
examination results, complications, and follow-up data were ing and implantation metastases in up to 3% of patients
obtained and recorded. (3– 8).
RESULTS: EUS-FNA of 77 liver lesions in 77 patients was Endoscopic ultrasound (EUS)– guided fine needle aspira-
performed without complications. Of these 77 lesions, 45 tion (EUS-FNA) has been established as a safe and accurate
(58%) were diagnostic for malignancy, 25 (33%) were be- method for the diagnosis of benign or malignant lymphad-
nign, and seven (9%) were nondiagnostic. A total of 22 enopathy and for intramural and extramural neoplasms (9,
lesions were confirmed as negative for malignancy by fol- 10). The role of EUS-FNA in the diagnosis and staging of
low-up (mean 762 days, range 512–1556 days) or intraop- liver metastases or masses, however, is limited to a small
single-center series (11), a large retrospective international
erative examination; however, seven lesions could not be
survey (12), and several case series (13, 14). Furthermore,
classified as benign or malignant. Depending on the status of
the sensitivity of EUS-FNA and endosonographic features
the seven unclassified lesions, sensitivity of EUS-FNA for
of benign and malignant hepatic lesions have not been
the diagnosis of malignancy ranged from 82 to 94%. When
described. The aim of this study was to report the sensitivity,
compared with benign lesions, EUS features predictive of
cytological diagnoses, EUS features, complications, and
malignant hepatic masses were the presence of regular outer
clinical impact of a large single-center experience with
margins (60% vs 27%; p ⫽ 0.02) and the detection of two
EUS-FNA of solid liver lesions.
or more lesions (38% vs 9%; p ⫽ 0.03). Of the 42 patients
with malignancy identified by EUS-FNA and other avail-
able imaging records, EUS detected the malignancy in 41% MATERIALS AND METHODS
of patients with previously negative examinations. For the
From an existing EUS-FNA cytology database, we identi-
45 subjects with cytology positive for malignancy, EUS-
fied all patients between January, 1997, and July, 2002, in
FNA changed management in 86% of subjects.
whom EUS-FNA of the liver was performed. The database
CONCLUSION: EUS-FNA of the liver is a safe and sensitive used had been maintained and prospectively updated by one
procedure that can have a significant impact on patient cytotechnologist (J.C.). Patients with hilar cholangiocarci-
management. Prospective studies comparing the accuracy nomas or cystic hepatic lesions were excluded from the
and complication rate of EUS-FNA and percutaneous fine analysis.
needle aspiration (P-FNA) for the diagnosis of liver tumors Staging EUS examinations for known or suspected ma-
are needed. (Am J Gastroenterol 2003;98:1976 –1981. © lignancy were performed initially with an Olympus GF-
2003 by Am. Coll. of Gastroenterology) UM20 or GFUM-130 radial echoendoscope (Olympus,
AJG – September, 2003 EUS-FNA Cytology of Solid Liver Lesions 1977

Melville NY). The right lobe of the liver was surveyed from Table 1. Indications for EUS Examinations by Cytology Results of
the duodenum and distal stomach, whereas the left lobe was EUS-FNA of the Liver
imaged from the proximal and mid-stomach. Endoscope Cytology Result
rotation was used as necessary to visualize as much of the All Malignant Benign/ND
liver parenchyma as possible. EUS-FNA was performed Indication (n ⫽ 77) (n ⫽ 45) (n ⫽ 32)
using the Pentax 32-UA, Pentax 36-UX (Pentax Precision Abnormal ERCP 21 (27) 11 (24) 10 (31)
Instruments, Orangeburg, NY), Olympus GF-UC30P, or Pancreatic mass on CT 19 (25) 12 (27) 7 (22)
Olympus GF-UC140P curvilinear array echoendoscope. Staging of known cancer 10 (13) 7 (16) 3 (9)
EUS-FNA was performed using a 22-gauge, 8-cm Wilson- Liver mass on CT 9 (12) 9 (20) 0 (0)
Other abnormal CT findings 4 (5) 1 (2) 3 (9)
Cook EUSN-1, EUSN-2, or EUSN-3 needle (Wilson-Cook Suspected recurrent cancer 2 (3) 1 (2) 1 (3)
Medical, Winston-Salem, NC) by one of four physicians Chronic abdominal pain 2 (3) 0 (0) 2 (7)
(J.D., D.C., L.M., or J.L.). Doppler color angiography was Other 10 (12) 4 (9) 6 (19)
used to ensure the absence of intervening vascular structures Total 77 45 32
along the anticipated needle path. Depending on the amount ND ⫽ nondiagnostic
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 staged primary malignancy); 4) incurred no change in man-
cytopathologist was available on-site for preliminary inter- agement (results did not change patient treatment). This
pretations on all procedures. Samples aspirated were ex- study was approved by the Institutional Review Board at our
pressed onto a glass slide and two smear preparations were institution.
made. One slide was air-dried and stained with a modified
Giemsa stain for rapid on-site interpretation. The other slide Statistical Analysis
was alcohol-fixed and stained by the Papanicolaou method. Assuming that the EUS-FNA diagnosis of malignancy is a
EUS-FNA was repeated until a definitive diagnosis was true positive, sensitivity was calculated as the proportion of
made or the endoscopist believed that further sampling patients with cancer in whom EUS-FNA was positive for
would not likely increase yield. Within several days of each malignancy. For analysis, continuous variables were de-
EUS examination, a final cytological diagnosis was ren- scribed as means and standard deviations, and dichotomous
dered by a staff cytopathologist. variables were expressed as simple proportions with or
A true positive EUS-FNA for malignancy is defined as without 95% confidence limits. Student’s t test and ␹2 or
unequivocal cytological evidence of malignancy. A false Fisher’s exact tests were used to test for differences in
negative aspirate is a nondiagnostic or benign specimen, comparisons between continuous and dichotomous vari-
which is subsequently found to be malignant by percutane- ables, respectively.
ous FNA or intraoperative findings. A true negative EUS-
FNA for malignancy is defined as benign or nondiagnostic RESULTS
samples that are either confirmed as benign by alternative
sampling, intraoperative examination, or appropriate clini- In total, EUS-FNA was performed on 77 different liver
cal follow-up. Specimens with benign hepatocytes without lesions in 77 patients (42 male and 35 female, 69 white and
evidence of atypical cells are categorized as benign aspi- eight African American, with a mean age of 63 ⫾ 11 yr).
rates. Aspirates from EUS-FNA that are interpreted as non- Follow-up was available in all patients.
diagnostic, highly suspicious, suspicious, or atypical for Indications for EUS Examinations
malignancy are considered as negative for malignancy. The indications for the 77 EUS procedures are recorded in
Medical records of enrolled subjects were reviewed and Table 1. The two most common indications were abnormal
procedural indications, prior radiographic data, patient de- ERCP findings, the majority of which were strictures, and a
mographics, EUS test results, clinical outcomes, procedural pancreatic mass on CT scan, which accounted for 27% and
complications, and follow-up data were abstracted. When 25% of the procedures performed, respectively. Ten (13%)
multiple liver lesions were noted, the endosonographic de- of 77 procedures were done for staging of a recently diag-
scription of only the aspirated lesion was recorded. When nosed malignancy (pancreas in five, esophageal in four, and
charts were incomplete, written informed consent was sent lung in one). Of the 45 malignancies diagnosed by EUS-
and follow-up telephone calls were made to the subject, FNA, the most common indications for the EUS were a CT
closest relative of the deceased, or referring physician for finding of a pancreatic mass (27%) and abnormal ERCP
clarification or any required further information. The poten- findings (24%).
tial clinical impact of EUS-FNA of a liver metastasis or
malignancy is defined as results that met the following Characteristics of EUS Examination
criteria: 1) avoided surgery (results precluded resectable EUS-FNA was performed in 77 patients (mean 3.4 ⫾ 1.8
malignancy); 2) made diagnosis (results provided initial passes, range 1– 8) into the left lobe (n ⫽ 66; 86%) and right
diagnosis of malignancy); 3) upstaged tumor (results up- 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* Malignant† Benign‡
(n ⫽ 77) (n ⫽ 48) (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.
Figure 1. Sensitivity of EUS-FNA of the liver for the diagnosis of
malignancy.
cations (upper 95% CI ⫽ 4.7%; see Table 2). A total of 45
(58%) aspirates were diagnostic for malignancy. Three false or echotexture (p ⫽ 0.36). Malignant masses, however,
negatives were later discovered by intraoperative findings (n were more often accompanied by the presence of multiple
⫽ 2) or P-FNA (n ⫽ 1). One patient with pancreatic ade- hepatic lesions detected on EUS (38% vs 9%; p ⫽ 0.03; ␹2
nocarcinoma (as confirmed by EUS-FNA of the pancreas) analysis) and to have regular margins (60% vs 27%; p ⫽
had benign cytology of a 6-mm left lobe mass that intraop- 0.02; ␹2 analysis).
eratively was confirmed as metastatic adenocarcinoma. A
second patient with pancreatic adenocarcinoma (as con- Diagnoses from EUS-FNA of the Liver
firmed by EUS-FNA of the pancreas) had benign cytology The final diagnoses for the 45 malignant liver aspirates are
of a 6-mm right lobe mass, which was later confirmed by recorded in Table 3. Of these, 44 (98%) were metastatic and
percutaneous ultrasound-guided biopsy as metastatic adeno- one (2%) was a hepatocellular carcinoma. The most com-
carcinoma. The third patient with a false negative EUS-FNA mon diagnosis was metastatic adenocarcinoma from the
had a 29-mm left lobe mass that was benign by EUS-FNA. pancreas, which accounted for 34 of 45 (76%). The next
Intraoperative examination, however, confirmed hepatocel- most frequent diagnosis was metastatic neuroendocrine tu-
lular carcinoma. Overall, 48 of 77 (62%) of the liver masses mor from the pancreas (n ⫽ 5; 11%). Of the 32 nonmalig-
were malignant. Among the remaining 29 subjects with nant aspirates, 25 (33%) were cytologically benign and
nonmalignant aspirates, in 22 (76%) the masses were con- seven (9%) were nondiagnostic. One (4%) benign aspirate
sidered benign by clinical follow-up (n ⫽ 18; mean 762 demonstrated cytological features consistent with an
days; range: 512–1556 days) or intraoperative evaluation (n abscess.
⫽ 4). Seven (24%) of the subjects with nonmalignant Previous Imaging of Malignancy Diagnosed by
masses with pancreatic adenocarcinoma (as confirmed by EUS-FNA
EUS-FNA of the pancreas; n ⫽ 6) or lung cancer (n ⫽ 1) Prior radiographic imaging reports were available for 42 of
died (mean 154 days, range 14 – 424 days) without fol- 45 (93%) malignant hepatic masses diagnosed by EUS-
low-up imaging, biopsy of the liver, or autopsy and there-
fore cannot be classified as benign or malignant. The 45 Table 3. Diagnoses of Malignant Aspirates of the Liver
diagnostic aspirates for malignancy are considered true pos-
Diagnosis No. (%)
itives (Fig. 1). Assuming that the test results for these seven
patients were all true negatives or all false negatives, the Pancreatic adenocarcinoma 34 (76)
Pancreatic neuroendocrine tumor 5 (11)
sensitivity of EUS-FNA for the diagnosis of malignancy
Renal cell carcinoma 2 (5)
would range from 82 to 94%. Gallbladder adenocarcinoma 1 (2)
In comparison between benign and malignant lesions Colon cancer 1 (2)
detected by EUS-FNA (Table 2), no statistically significant Hepatocellular carcinoma 1 (2)
difference was found between the liver lobe aspirated (p ⫽ Esophageal adenocarcinoma 1 (2)
Total 45
0.57), number of passes (p ⫽ 0.44), lesion size (p ⫽ 0.70),
AJG – September, 2003 EUS-FNA Cytology of Solid Liver Lesions 1979

FNA. All imaging had been performed within 45 days of the itive results when testing aspirates, the inability to histolog-
EUS examination. Of these 42 lesions, EUS-FNA detected ically corroborate this does not allow for calculation of
malignancy in 17 (41%) when prior imaging of the liver by specificity. A previous report of 14 patients that underwent
CT alone (n ⫽ 13), transabdominal ultrasound (US) alone (n EUS-FNA of liver metastases described a sensitivity and
⫽ 1), or both (n ⫽ 3) were normal. For the 32 patients in specificity of 100% and 100% for the diagnosis of malig-
whom CT alone was performed, EUS-FNA initially de- nancy (11). To our knowledge, however, our study is the
tected a malignancy in 13 (41%). For the nine patients in first report of the test characteristics of EUS-FNA of the
whom CT and US were both performed, EUS-FNA initially liver that includes both malignant and benign hepatic le-
detected malignancy in three (33%). The mean size of the 17 sions. The sensitivity of the EUS-FNA of the liver we report
malignant liver lesions detected initially by EUS-FNA was is similar to previous series that describe the sensitivity of
12.6 mm (range 3–26 mm). Of these 17, six (35%) were ⬍1 EUS-FNA of pancreatic malignancy (9, 15–17) and P-FNA
cm in diameter. of liver tumors (2, 18 –20). Despite the good sensitivity of
EUS-FNA of liver tumors, we obtained three false negative
Clinical Impact of EUS-FNA of the Liver results. Therefore, follow-up percutaneous biopsy or intra-
For the 45 patients with malignant cytology, EUS-FNA had operative evaluation is warranted when the diagnosis of
(by protocol definition) a clinical impact in all patients. malignancy in the liver is strongly suspected and would
EUS-FNA changed management, however, in only 38 significantly affect patient management.
(84%) of these patients, because in seven cases (16%) tumor The mean number of overall passes performed for the
was upstaged but did not change overall patient manage- diagnosis of hepatic lesions (n ⫽ 3.2; range 1– 8) is slightly
ment. EUS-FNA provided the initial diagnosis of malig- higher in our series than has been previously reported (11).
nancy in 35 patients (78%) and avoided surgery in 12 The exact reason for this difference is not clear, although it
(27%). Of the 35 patients in whom EUS-FNA made the is not significantly different from the number required for
initial diagnosis of malignancy, 34 (97%) had metastases ultrasound-guided P-FNA of small hepatic masses (21). In a
and one (3%) had a hepatocellular carcinoma. In 25 patients series of 14 patients with EUS-FNA of a malignant liver
(55%), the FNA provided both the primary diagnosis and lesion, Nguyen et al. reported a mean of 2.0 (range 1–5)
upstaged the malignancy. In nine subjects (20%), EUS-FNA passes for the diagnosis of malignancy (11). The presence of
made the initial diagnosis, upstaged the tumor, and pre- a cytopathologist on-site was implied, as interpretation of
vented surgery. Three EUS-FNAs (7%) were diagnostic in specimens was performed before making repeated passes.
which previous CT-FNA was benign (two of three) or We also have a cytotechnologist or cytopathologist avail-
nondiagnostic (one of three). In three patients with nonma- able on site to assess the adequacy of obtained specimens.
lignant EUS-FNA aspirates, malignancy was later con- Because the diagnosis of metastatic disease is clinically
firmed by surgery (n ⫽ 2) or percutaneous biopsy (n ⫽ 1). relevant and initial air-dried preparations are sometimes
difficult to interpret, we will often repeat another pass to
Follow-Up After EUS-FNA ensure that cytology is sufficient to render a diagnosis if the
Of the 45 patients with malignant cytology from EUS-FNA, adequacy of a specimen is initially interpreted as “suspi-
40 have died, with a mean time to death after EUS-FNA of cious” but not diagnostic of malignancy. We found no
135 days (range 7–754 days). The patient who died 7 days statistically significant difference between the numbers of
after EUS-FNA expired in his sleep outside the hospital passes required for the diagnosis of benign (n ⫽ 3.2; range
without any apparent adverse consequence from EUS-FNA; 1– 8) or malignant (n ⫽ 3.5; range 1– 8) lesions. In addition,
however, no autopsy was performed. The patient who lived no difference existed between the number of passes required
754 days had metastatic pancreatic cancer and enrolled in an during the first or second half of the study. This implies that
experimental chemotherapy protocol at another institution. increased experience with this technique may not decrease
The longest survival otherwise was 298 days. Five patients the number of passes needed to obtain an accurate cytolog-
remain alive with a mean follow-up of 64 days (range ical diagnosis.
30 –140 days). The mean time to death from metastatic Despite the relatively higher number of passes performed
pancreatic adenocarcinoma to the liver was 113 days (n ⫽ in this study, we observed no complications after EUS-FNA
31; range 7–754 days). of the liver. In a large international survey of 167 cases
describing EUS-FNA of the liver, however, six complica-
DISCUSSION tions (4%) were described (12). These complications in-
cluded one death in a patient who underwent EUS-FNA of
The results of this study demonstrate that EUS-guided FNA the liver despite a suspected obstructed biliary stent. Other
of solid hepatic masses is sensitive, safe, and has a signif- complications noted were bleeding, abdominal pain, and
icant impact on patient management when malignancy is fever. Although it is standard practice for gastroenterolo-
diagnosed. In our series, the sensitivity of EUS-FNA for the gists to observe patients in the right lateral decubitus posi-
diagnosis of malignancy ranged from 82% to 94%. Al- tion for several hours after percutaneous biopsy of the liver,
though it may be presumed that we obtained no false pos- 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 significant difference was found with regard to site of biopsy
patients on their right side during recovery before discharge. (p ⫽ 0.57), size (p ⫽ 0.70), echogenicity (p ⫽ 0.36), or
A recent series (5) describing the use of P-FNA in the number of passes performed (p ⫽ 0.44) for these lesions.
diagnosis of 216 liver tumors reported the occurrence of Although EUS features of malignant lymphadenopathy have
implantation metastases in seven patients (3%) a median 4 been described (31), to our knowledge the endosonographic
months (range 2– 49 months) after P-FNA of liver masses features for malignant liver lesions have not been previously
from colorectal cancer (n ⫽ 5), gallbladder carcinoma (n ⫽ reported. These findings may help to guide decision making
1), and a hepatoma (n ⫽ 1). In addition, the implantation and assessment of the risk/benefit ratio of EUS-FNA of
metastases caused major problems locally and were fatal in hepatic masses.
four patients. This complication has not been described after In conclusion, the results of our study show that the
EUS-FNA of the liver. The true incidence of implantation sensitivity of EUS-FNA of the liver for the diagnosis of
metastases after EUS-FNA of the liver, however, is difficult malignancy ranges from 82% to 94% and that, contrary to
to estimate, inasmuch as hepatic metastases from pancreatic previous reports, it is a safe procedure. When malignancy is
malignancy (which comprise 87% of malignancies in our diagnosed, EUS-FNA of the liver significantly affects pa-
study) usually carry a dismal prognosis and are managed tient management and implies a poor overall prognosis.
nonoperatively. Therefore, as the overwhelming majority of EUS features predictive of malignant hepatic masses are the
patients diagnosed with of hepatic metastases after EUS- presence of regular outer margins and the detection of two
FNA of the liver do not undergo intended curative resection, or more lesions. In this series, EUS and EUS-FNA detected
the true incidence of this complication is not known. The malignant liver tumors that were not seen by CT or US (or
most common malignancies diagnosed by P-FNA (colorec- both) in 41% of subjects. Therefore, surveillance of the
tal metastases and primary hepatomas) are often managed entire liver is indicated during evaluation of known or
surgically with curative intent. We believe that these fun- suspected malignancy. Prospective studies are needed to
damental differences partially explain the disparity in re- compare the accuracy and complication rate of EUS-FNA
ported incidence of implantation metastases between EUS- and P-FNA for the diagnosis of liver tumors.
FNA and P-FNA of liver masses. Studies comparing the
diagnostic accuracy and complications EUS-FNA and P-
Reprint requests and correspondence: John M. DeWitt, M.D.,
FNA of all types of suspected liver tumors are needed to Department of Medicine, Division of Gastroenterology, Indiana
resolve these issues. University Medical Center, 550 N. University Boulevard, UH
The overall sensitivity of transabominal US for the de- 4100, Indianapolis, IN 46202-5121.
tection of liver metastases is reportedly between 80% and Received Nov. 11, 2002; accepted Jan. 30, 2003.
90% (22, 23). Recent studies using helical CT and magnetic
resonance imaging, however, show that noninvasive imag-
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