Introduction
In the past few decades, there has been relatively little change in the epidemiology,
therapy, or over-all survival of pancreatico-biliary tumors. However, we are now in
an era where diagnostic and therapeutic paradigms are finally going beyond traditional
approaches (cytology/pathology for diagnosis and cytotoxic agents for therapy) with
the potential of changing the natural history of these tumors. Many of these new approaches
are made possible with emerging diagnostic and interventional EUS techniques. This
state-of-the-art paper will review the role of EUS-guided FNA in the diagnosis of
pancreaticobiliary lesions such as pancreatic tumors, cystic and neuroendocrine tumors
of the pancreas, as well as the less appreciated applications to biliary and ampullary
cancers. I will also discuss the specific role of EUS-guided FNA in the staging of
various pancreaticobiliary cancers. The role of EUS-guided therapies, including celiac
neurolysis, cyst-gastrostomy, and delivery of anti-tumor agents via EUS-guided fine
needle aspiration (FNI) will be covered in the accompanying article ”FNI and Anti-tumor
therapy”.
EUS-guided FNA in the diagnosis of pancreatic tumors
Pancreatic cancer
Adenocarcinoma is the fifth leading cause for cancer-related death in the United States.
Despite improvements in medical and surgical therapy, the overall 5-year survival
still remains at 4 %. The most favorable outcome is among surgical patients with small
tumors without nodal, vascular, or systemic metastasis. These patients have 5-year
survivals that range up to 25 %. Optimally, earlier detection and precise pre-operative
staging would best stratify patients who would most likely benefit from surgery while
sparing the remaining patients from exploratory or palliative-only surgery. Endoscopic
ultrasound is considered as one of the most useful diagnostic procedures among the
body imaging tools for detecting pancreatic cancer. EUS was shown to be superior (sensitivity
98 %) to other imaging modalities, including CT, in 146 patients with pancreatic cancer
[1]. With the more recent introduction of spiral CT with dual phase contrast, the detection
rate for CT is improving. However, recent comparisons between dual-phase spiral CT
and endoscopic ultrasound still favor EUS. The ability to obtain cytological specimen
by EUS-guided FNA has overcome the difficulty in differentiating between benign vs
malignant lesion seen on EUS alone. The application of EUS-guided FNA to the pancreas
in particular has great clinical utility. CT or US guided percutaneous FNA are the
more common methods for diagnosing pancreatic cancer. The sensitivity of percutaneous
FNA ranges from 45 % to 100 %, with a specificity of up to 100 %. However, obtaining
a tissue diagnosis with CT or US guidance is limited by the ability to visualize the
lesion. In a previous multi-center trial, 56 % of patients with pancreatic carcinoma
had CT scans which did not demonstrate a mass or revealed nonspecific enlargement
of the pancreas [2]. ERCP with cytologic brushing also has a relatively low yield, with sensitivities
between 30 % and 56 %. The over-all sensitivity, specificity, diagnostic accuracy,
NPV and PPV of EUS-guided FNA for pancreatic cancer was 83 %, 90 %, 85 %, 80 % and
100 %. This was superior to CT alone (without FNA): 56 %, 37 %, 50 %, 28 % and 65
%, respectively (p < 0.05). There were 4 complications in 164 patients (2 %), including
2 major (perforation, bleeding) and 2 minor (fever). Comparison among the four centers
showed that institutions in which a cytologist was present during the procedure had
a significantly higher number of passes, cytologic yield, sensitivity and diagnostic
accuracy. Advantages of EUS-guided FNA include procuring a tissue diagnosis while
also obtaining additional TN staging information the avoidance of additional diagnostic
testing and/or surgery and the prognostic information relating to accurate TN staging.
In another report from a large single-institution study of 144 pancreatic lesions
undergoing EUS-guided FNA, showed a sensitivity, specificity, and diagnostic accuracy
of 82 %, 100 %, and 85 % respectively [3]. The most difficult diagnosis to make for any imaging test, including EUS-guided
FNA, is the differentiation between pancreatic carcinoma and chronic pancreatitis.
Contrast enhanced EUS may improve this differentiation with a recent paper showing
the sensitivity increasing from 73 % to 91 % and specificity increasing from 83 %
to 93 % with the addition of SonoVue intravenous constrast and power Doppler scanning
[4]. With FNA the positive predictive value is almost 100 %, although a negative FNA
is about 85 % accurate in the setting of pancreatitis. Positron emission tomography
(PET) with or without CT fusion may play a role in distinguishing pancreatic cancer
from chronic pancreatitis [5]
[6], although results are somewhat disparaging [7]
[8]
[9]. EUS-guided FNA of pancreatic lesions is also worthwhile in patients with a prior
negative tissue diagnosis by ERCP or CT of the abdomen. Gress et al. reported his
experience with EUS-guided FNA of pancreatic mass lesion in 102 patients who had negative
cytological tissue diagnosis by ERCP sampling or CT-guided FNA [10]. Among those patients, 57 of the 61 patients (93.4 %) with a final diagnosis of
pancreatic cancer had positive cytology results for adenocarcinoma by EUS-guided FNA.
The false positive results were zero.
There have been several papers written regarding the clinical and economic outcomes
of EUS/FNA. One single center study compared the management and survival of 136 patients
with pancreatic cancer between the pre and post EUS eras [11]. EUS detected carcinomas that were either not seen or only possibly seen by CT in
34 % and there were 75 % fewer required operations for diagnosis. The median survival
without liver metastases was also longer during the EUS period (102 versus 205 days;
p < 0.02, log-rank test) probably attributable, in part, to lead-time bias. The economic
impact of EUS-guided FNA was addressed in an earlier series of 44 consecutive patients
who underwent EUS with or without FNA as part of their pancreatic cancer evaluation
[12]. Surgery and further diagnostic testing were avoided in 41 % and 57 % of patients
respectively. A substantial cost saving of $ 3300 per patient was calculated. In a
series of 216 consecutive patients, the use of EUS with EUS-guided FNA as the initial
approach to patients with obstructive jaundice was studied by Erickson et al [13]. EUS/FNA proved useful not only as a diagnostic and staging modality, but also served
in directing the need for subsequent therapeutic endoscopic retrograde cholangiopancreatography
(ERCP), saving approximately $1007 to $1313 per patient. In addition, if EUS/ EUS-guided
FNA were not utilized at all, an extra $2200 would be spent per patient. EUS-guided
FNA of the pancreas unlike CT-guided FNA can be preformed during the initial endosonographic
procedure. The overall complication rate of EUS-guided FNA was reported to be 0.5
%-2.9 %.
We believe that all patients thought to have operable disease based on initial CT
imaging should undergo EUS ± FNA prior to surgical intervention (see Clinical Algorithm
in Fig. [1]). At the same time, considering the possibility of a false negative result (up to
20 %, especially in the setting of chronic pancreatitis), we believe that surgical
intervention should not be precluded in a patient with a high suspicion of resectable
pancreatic carcinoma and a negative FNA cytology.
In the near future, EUS/FNA will go beyond cytology diagnosis to assess for molecular
and/or genetic alterations within the tumor tissue. This is now possible with such
techniques as cDNA microarrays which can screen for hundreds of genes simultaneously
[14]. Using cDNA microarray, investigators can evaluate specific tumors for chemoresistance-related
genes. One such study will have been presented at this year’s DDW [15].
Fig. 1 Algorithm for Diagnosis and Staging of Pancreatic Cancer.
Cystic neoplasms
EUS can be helpful in distinguishing cystic neoplasms from pancreatic pseudocyst,
although even here, the specificity is not perfect [16]. The more problematic discernment is between serous and mucinous cysts, with the
latter considered pre-malignant. The interobserver agreement for the interpretation
of cystic lesions in the pancreas is quite low. The interobserver agreement on 31
pancreatic cyst cases among eight expert endosonographers was shown to be ”fair” between
endosonographers for diagnosis of neoplastic versus non-neoplastic lesions (kappa
= 0.24) [17]. Agreement for individual types of lesions was moderately good for serous cystadenomas
(kappa = 0.46) but fair for the remainder. Accuracy rates of EUS for the diagnosis
of neoplastic versus non-neoplastic lesions ranged from 40 % to 93 %. Thus, EUS imaging
alone is often inadequate for the clinical management of these patients. EUS-guided
FNA of cystic contents can be analyzed for cytology, biochemistry and tumor markers.
Since cytology is a relatively insensitive test, cyst fluid tumor markers such as
CEA have been employed to improve the sensitivity for the detection of malignancy.
Cyst fluid CEA values are uniformly low in serous cystadenomas, higher in mucinous
lesions, and markedly elevated in mucinous cystadenocarcinomas [18]. A recent cooperative group study examined a battery of tumor markers from pancreatic
cysts (CEA, CA 72 - 4, CA 125, CA 19 - 9, and CA 15 - 3) among 341 patients (112 with
surgical resection). The final diagnosis of the cystic lesions were 68 mucinous, 7
serous, 27 inflammatory, 5 endocrine, and 5 other. Receiver operator curve analysis
of the tumor markers demonstrated that cyst fluid CEA (optimal cutoff of 192 ng/mL)
demonstrated the greatest area under the curve (0.79) for differentiating mucinous
vs. nonmucinous cystic lesions. The accuracy of CEA (88 of 111, 79 %) was significantly
greater than the accuracy of EUS morphology (57 of 112, 51 %) or cytology (64 of 109,
59 %) (P < 0.05). There was no combination of tests that provided greater accuracy
than CEA alone (P < 0.0001). We routinely send cyst fluid for cytology, amylase and
CEA. Pseudocysts have very high amylase levels, often over 50,000 IU/L, with a normal
CEA and benign cytology. Serous cystadenomas will usually have benign cytology, normal
CEA and amylase. Mucinous cystadenomas usually differ from serous cystadenoma in having
a high CEA. Mucinous cystadenocarcinoma classically will have malignant cytology,
a low amylase, and a markedly elevated CEA. Whereas the cytology from the fluid of
malignant cysts may be non-diagnostic. We have found that targeting any solid component,
including the cyst wall, may enhance the yield on FNA cytology [19].
Endocrine tumors
EUS is very accurate in the detection of neuroendocrine tumors of the pancreas.
Zimmer et al reported their results in localizing and staging neuroendocrine tumors
of the foregut in 40 patients examined by EUS, somatostatin receptor scintigraphy
(SRS), computed tomography (CT), magnetic resonance imaging (MRI) and transabdominal
ultrasound (US) [20]. EUS showed the highest sensitivity in localizing insulinomas compared with SRS,
US, CT and MRI. They suggested that US and EUS should be the first-line diagnostics
if insulinoma has been proven by a fasting test. Further diagnostic procedures were
unnecessary in most cases. Further diagnostics such as CT or MRI to search for distant
metastases are necessary in large tumors or local invasive tumors. For gastrinomas,
EUS has the highest accuracy to detect or exclude pancreatic gastrinomas, but fails
to detect extrapancreatic gastrinomas in about 50 %. The combination of EUS and SRS
may give complementary information. They recommended that the first-line diagnostics
in gastrinoma patients should be SRS and CT or MRI. If no metastases are detected,
EUS should be the next preoperative imaging procedure. In nonfunctional neuroendocrine
tumors, EUS provides the best information on local tumor invasion and regional lymph
node involvement. EUS has also been shown to be cost effective in the preoperative
localization of pancreatic endocrine tumors [21] largely because of reductions in the number of diagnostic angiograms and venous
sampling procedures performed. The more specific utility of EUS-guided FNA in these
patients was recently reported [22] and shown to be helpful. In addition, EUS may also be useful in marking these subtle
lesions using EUS-guided fine needle ”tattooing” prior to surgery to assist in intra-operative
localization [23].
EUS-guided FNA in the staging of pancreatic cancer
Although EUS has historically been superior to CT or MR in staging pancreatic cancer,
this may no longer be the case. A recent review analyzed the pooled data among 4 comparative
studies and still showed superiority of EUS to helical CT in detection of pancreatic
tumor (97 % vs 73 %), in accuracy for respectability (91 % vs 83 %), and sensitivity
for vascular invasion (91 % vs 64 %) [24]. However, with even newer imaging modalities such as contrast-enhanced multi-detector
row helical CT (MDR-CT), which allows for 3-dimensional maximum intensity projection
(MIP) and volume rendered images (VRI), the vascular staging of pancreatic cancer
by CT will likely surpass that of EUS [25]
[26]. In addition, the fusion of CT with PET may give additional distant staging information.
However, EUS-guided FNA will continue to play an important role for staging pancreatic
cancer in sampling metastatic lymph nodes, liver lesions, and ascites. The economic
impact of EUS-guided FNA in the preoperative staging of patients with pancreatic head
adenocarcinoma was clearly demonstrated in a decision analysis model [27]. The use of EUS-guided FNA prevented 16 surgeries per 100 patients compared to 8
per 100 patients if CT-guided FNA was performed for non-peritumoral lymph nodes. If
the frequency of non-peritumoral lymph nodes was > 4 % then EUS-guided FNA is the
least costly procedure ($ 15,938) vs ($ 16,378) for CT-FNA and ($18,723) for surgery.
According to a multivariate analysis, lymph node metastasis, intrapancreatic perineural
invasion, and portal vein invasion are significant prognostic factors in patients
with pancreatic cancer after curative resection [28]. In a multi-center study 171 patients underwent EUS-gduied FNA of 192 lymph nodes
(46 benign, 146 malignant) [29]. When comparing EUS-guided FNA with EUS size criteria (£ 10mm = benign), the sensitivity
(90 % versus 91 %, P = n. s.) and accuracy (92 % versus 83 %, P = n. s.) for EUS-guided
FNA were similar whereas the specificity was superior to that of EUS size criteria
alone (100 % versus 47 %, p < .001). Not only can EUS-guided FNA improve the specificity
of lymph node metastasis with cytologic confirmation, most recently FNA has been used
to detect genetic alterations in cytologic negative nodes [30]. Although there was no significant difference in overall survival rates between
the pathological node-negative and -positive patients, overall survival of the patients
with nodes-negative for the mutated K-ras gene were significantly better than that
of the patients with genetically metastasis-positive nodes (p < 0.001). These findings
suggest that detection of K-ras gene mutations in lymph nodes may be clinically useful
to stratify patients who may be at higher risk for recurrence after curative resection.
Liver metastasis
EUS was not traditionally thought to be clinically applicable in imaging the liver
imaging. However, both prospective [31] and retrospective [32] studies have shown the ability of EUS to detect lesions not seen on CT and the ability
to safely perform EUS-guided FNA on the same procedure. EUS-guided FNA should be considered
when a liver lesion is poorly accessible to percutaneous FNA or when US or CT-guided
FNA fail to make a diagnosis. If EUS detects a liver lesion de novo in the setting
of staging pancreatic cancer, EUS-guided FNA should be attempted first, even prior
to taking biopsies of the primary pancreatic tumor. Liver lesions have a much higher
cytologic yield (less needle passes requires, less inflammatory and fibrotic reaction)
and give the highest staging information.
Ascites
The utility of EUS/FNA was evaluated for detection and aspiration of scant ascites
among patients undergoing EUS for diagnosis and staging of GI malignancies [33]. Eighty-five patients (15 % of a series of 571 patients) were found to have ascites
by EUS. Pre-EUS CT identified ascites in only 18 % of patients with ascites on EUS.
31 of the 85 patients underwent EUS-guided FNA paracentesis and in 5 patients, malignant
ascites was diagnosed by EUS-guided FNA. The clinical impact was high in these patients
as surgery was avoided.
EUS-guided FNA in biliary lesions
Diagnosis and staging of cholangiocarcinoma
EUS-guided FNA is now being used to diagnose and stage cholangiocarcinoma. In one
case series, 10 patients with bile duct strictures at the hepatic hilum, diagnosed
by CT and/or ERCP, underwent EUS-guided FNA. Adequate material was obtained in nine
patients [34]. Cytology revealed cholangiocarcinoma in seven and hepatocellular carcinoma in one.
One benign inflammatory lesion identified on cytology proved to be a false-negative
finding by frozen section. Metastatic locoregional hilar lymph nodes were detected
in two patients, and in one patient the celiac and para-aortic lymph nodes were aspirated
to obtain tissue proof of distant metastasis. In a retrospective series of 238 patients
with suspected or known biliary strictures, EUS-guided FNA obtained a tissue diagnosis
in 12/26 (46 %) patients, which were negative on cytology, or had a unsuccessful ERCP
[35]. There were no complications. These studies suggest that EUS with FNA is safe, and
effective in evaluating proximal biliary strictures. When used in combination with
ERCP, it helps distinguish benign from malignant strictures, and facilitates a definitive
diagnosis by increasing tissue yield.
Diagnosis and staging of ampullary cancer
Conventional abdominal imaging studies such as CT, MRI, and transabdominal ultrasound
frequently fail to detect ampullary lesions. EUS is a sensitive modality for detecting
and staging ampullary tumors. Accurate staging may be affected by biliary stenting,
which is frequently performed in these patients with obstructive jaundice. Combined
data from two centers reported the accuracy of ampullary tumor staging with multiple
imaging modalities in patients with and those without endobiliary stents [36]. Fifty consecutive patients with ampullary neoplasms were preoperatively staged
by EUS plus CT (37 patients), MRI (13 patients), or angiography (10 patients) over
a 3.5 year period. Twenty-five of the 50 patients had a transpapillary endobiliary
stent present at the time of endosonographic examination. EUS was shown to be more
accurate than CT and MRI in the overall assessment of the T stage of ampullary neoplasms
(EUS 78 %, CT 24 %, MRI 46 %). No significant difference in N stage accuracy was noted
between the three imaging modalities (EUS 68 %, CT 59 %, MRI 77 %). EUS T stage accuracy
was reduced from 84 % to 72 % in the presence of a transpapillary endobiliary stent.
This was most prominent in the understaging of T2/T3 carcinomas. More recently, a
retrospective study was published in which the role of EUS-guided FNA in the diagnosis
and staging of ampullary lesions has reported [37]. EUS-guided FNA was performed in 20 of 27 (74 %) patients with suspected ampullary
tumors. EUS-guided FNA made the initial ampullary tissue diagnosis in 7 patients (adenocarcinoma-5,
adenoma-1, neuroendocrine tumor-1). In addition, EUS-guided FNA resulted in a change
of the diagnosis from adenoma to adenocarcinoma in one patient. In 1 patient, EUS-guided
FNA diagnosed a liver metastasis not seen on CT. Overall, EUS-guided FNA provided
new histologic information in 9/27 patients (33 %).
Conclusions
EUS-guided FNA is extremely useful in the diagnosis and staging of pancreaticobiliary
lesions such as pancreatic cancers, cystic tumors, neuroendocrine neoplasms, ampullary
and cholangiocarcinomas. In addition, this technique has now been extended to therapeutic
modalities such as celiac nerve block, cyst-gastrostomy and delivery of anti-tumor
agents (see associated article on FNI).
