Pancreatic cancer, biopsy, endosonography,
fine needle aspiration
Few clinical problems warrant as much urgency
for definitive diagnosis as pancreatic masses. Because of
its unique diagnostic capabilities, endoscopic ultrasound
(EUS) and EUS-guided fine needle aspiration (EUS-FNA) have
become important tools in the evaluation of pancreatic masses
(1-7). The first commercially available radial echoendoscopes
were introduced in Japan (8) and Europe (9) in the mid to
late 1980s. Although radial instruments were used for fine
needle aspiration (10), EUS-FNA did not become technologically
practical until the early 1990s (11) when linear echoendoscopes
were introduced. This introduction generated ultrasonic images
parallel to the shaft of the instrument over the exit port
of the biopsy channel. With this modification, objects exiting
the biopsy channel of the endoscope (e.g., a needle) could
be followed and guided into lesions in "real-time.”
Very soon after the introduction of linear echoendoscopes,
the first report of EUS-FNA of the pancreas appeared (12)
and, shortly thereafter, of EUS-FNA of a pancreatic cancer
(13). Since 1994, there have been numerous series reporting
on the safety, technique, and yield of EUS-FNA of the pancreas
(4, 6, 10, 14-24). This review will focus on our current understanding
of the utility, technique, and safety of EUS-FNA of the pancreas.
UTILITY OF EUS-FNA OF THE PANCREAS
The foremost indication for EUS-FNA of the pancreas is for
the definitive diagnosis of pancreatic masses. Approximately
90% of pancreatic neoplasms are adenocarcinomas, another 5%
are cystic lesions, and some 2-5% are neuroendocrine tumors
(25). The remainder are metastatic lesions to the pancreas,
primarily from renal cancer, lung cancer, and lymphomas. Because
cystadenocarcinomas (26) and neuroendocrine tumors (27) of
the pancreas have a significantly better prognoses than pancreatic
adenocarcinoma, accurate cytologic preoperative identification
can significantly alter the subsequent management of these
As an imaging modality, many series (1,
3-6) have demonstrated that EUS is superior to CT, MRI, and
ERCP (29) in the diagnosis of pancreatic diseases and especially
neoplasms. Detection rates for pancreatic cancer using EUS,
even lesions less than 3 cm, have been consistently in the
range of 95-100%. However, the superiority of EUS for pancreatic
pathology detection is being continually challenged by the
technologic advances in CT and MRI imaging, although well-controlled,
head-to-head trials of comparable patients are still scare
(30). Positron emission tomography (PET) also may play a significant
role in pancreatic cancer detection, especially in looking
for occult pancreatic malignancies or metastatic disease (31).
However, just finding an imaging abnormality is often not
enough to determine subsequent management of patients with
pancreatic masses. The rational for attempting to obtain a
cytologic diagnosis of most pancreatic masses have been detailed
elsewhere (1, 32). When combined with FNA capabilities, EUS
has the powerful advantage over all other imaging techniques
of being able to immediately sample any suspicious lesions
seen in the pancreas. The one area where malignancies can
be still easily missed by EUS, even with EUS-FNA, is in the
setting of underlying chronic pancreatitis (3, 6, 12, 18,
23, 33-35). No single or combination of imaging modalities
has yet proven accurate in definitively determining when a
patient with chronic pancreatitis has developed pancreatic
cancer. This clinical dilemma may have to await continued
progress in the molecular diagnosis of cancer (36, 37).
The technique of EUS-guided FNA has been described in detail
elsewhere (19, 23) but basically involves passing an 18 to
22 gauge metal needle through the biopsy port of a linear
echoendoscope under real-time guidance into an endosonographically
visualized pancreatic mass, associated lymph node, liver metastasis,
or fluid collection. The needle is then moved back and forth
5 to 10 times through the lesion with varying degrees of suction
applied to it. The specimen is then deposited on a cytology
slide(s) for immediate fixation and staining and cytopathologic
examination. Since its initial inception, there have been
significant technologic advances in needle technology and
are now at least three manufacturers of effective disposable
and semi-disposable EUS-FNA needles. There are also new innovative
devices such as spring activated needles to help penetrate
firm lesions and cutting needles to provide small cores of
tissue to try and perhaps improve diagnostic accuracy (38).
Biopsy most distant disease
first: Because the specificity of a cytologic
diagnosis of malignancy is almost 100%, in performing EUS-FNA
for pancreatic neoplasms, a general guiding principle is to
try to cytologically confirm the most advanced stage of the
tumor. Thus, during EUS-FNA of pancreatic masses, needle aspiration
should first be done of any potentially metastatic disease
in the liver (Figures 1-4) or in the peritoneum (ascites),
then any distant pathologic lymph nodes, then regional nodes,
and, finally, if these are negative, the primary mass can
be aspirated. In addition to cytologically documenting the
most advanced degree of the patient's tumor stage, EUS-FNA
of malignant liver lesions is usually easier than pancreatic
mass FNA in that it only takes 1 to 2 needle passes for a
positive cytology. Likewise, lymph nodes usually only require
1 to 4 passes to obtain a cytologically positive diagnosis
(17, 23, 39-41).
The yield of EUS-FNA of primary pancreatic malignancies has
been reported to run from 80-93% (4, 6, 10, 14-21, 23). Obtaining
a high yield of positive diagnoses in pancreatic EUS-FNA is
very dependent on FNA technique and the active involvement
of a cytopathologist. Most very active EUS-FNA centers have
a cytopathologist on site to provide immediate feedback on
the adequacy and preliminary cytologic diagnosis (10, 14,
15, 18-21, 23). Live feedback from a cytopathologist results
in about a 10% increase in the yield of a positive diagnosis
(17, 21, 23).
Where to aspirate a pancreatic
mass: Choosing what part of a pancreatic mass
to aspirate is something of an art that comes with experience
in aspirating these lesions. The most difficult pancreatic
masses to aspirate are those located near the uncinate portion
of the pancreas where it can be very hard to direct the needle
around the second and third portion of the duodenum to enter
the lesion. Novice endosonographers are also surprised by
how much force it may take to make an FNA needle penetrate
deeply into the typical pancreatic adenocarcinoma because
of the surrounding desmoplastic reaction. The usual temptation
is to biopsy deep into the center of a mass; however, this
may yield only necrotic debris with few intact tumor cells.
EUS-FNA of the edge of the tumor may yield only peritumor
pancreatitis (Figures 5A and 5B). The best yield of diagnostic
cells usually seems to come from 1 cm to 2 cm deep to the
echolucent margin of the tumor (Figures 5B-7). Color flow
Doppler can be used prior to EUS-FNA to help avoid vessels
overlying the proposed path of the aspiration needle such
as are seen when there is underlying portal vein or splenic
Number of EUS-FNA passes:
Most pancreatic EUS-FNA series report taking an average of
three to four needle passes to make a definitive cytologic
diagnosis of pancreatic cancer. The major determinant of the
number of EUS-FNA passes needed to diagnose pancreatic adenocarcinoma
is the differentiation of the tumor (23). Some well-differentiated
tumors may take over ten separate passes to obtain enough
diagnostic material. Although, performing this many passes
may be frustrating for the endoscopist and cytopathologist,
the consequences of a non-diagnostic aspirate may mean more
procedures, including unnecessary surgery, for the patient.
If a cytopathologist is not available to immediately assess
the slides, then five to six passes of the lesion are recommended
(23). However, this approach may produce non-diagnostic EUS-FNAs
15-20% of the time.
The ideal EUS-FNA specimen should produce just a few drops
of slightly serosanguinous fluid, perhaps with a few particles
of tissue visible within the specimen. If an aspirate just
looks like pure blood, it is less likely to have much diagnostic
material within it. Whether to use hard suction or minimal
suction on the aspiration needle is a matter of preference
in pancreatic EUS-FNA. My own approach is to usually use moderate
suction initially for pancreatic masses (5 ml of suction in
a 10 ml syringe). If I get a bloody pass with this approach,
I make subsequent passes with minimal or no suction. Often
just pulling back the needle trocar about 10 cm with each
stroke or two of the needle in the tumor will provide enough
suction to retrieve a diagnostic specimen. Whether using larger
needles will increase diagnostic yields with the same degree
of safety as 22 gauge needles is still unclear (38). Sometimes
a few additional passes are needed to provide the cytopathologist
with adequate material for special cytologic analyses (Figures
6 and 7). This most commonly occurs when the initial EUS-FNA
suggests that the tumor may be something other than a pancreatic
adenocarcinoma such as a lymphoma, islet cell tumor, or metastatic
tumor. Lymphoma diagnosis by cell surface markers depends
on obtaining enough viable tumor cells preserved in a special
medium for cell-surface marker determination (42). If a cytopathologist
is not present to warn the endosonographer that one of these
diagnoses is suspected, then the EUS-FNA may result in an
equivocal cytopathologic diagnosis for lack of adequate material
for special processing.
EUS-FNA of Cystic Pancreatic
Masses: EUS-FNA of cystic pancreatic lesions
is different than for solid lesions. About 75% of cystic pancreatic
lesions are pseudocysts (43). The goal of EUS and EUS-FNA
is to differentiate truly benign lesions such as pseudocysts
and serous cystadenomas from precancerous lesions such as
mucinous cystadenomas (44) and intraductal papillary mucinous
tumors (IPMT) (45) of the pancreas from frankly malignant
cystadenocarcinomas (Figures 1 and 3). There are a number
of studies demonstrating the endosonographic characteristics
of these various cystic lesions (44-46); however, EUS-FNA
continues to play a role especially in examining the suspicious
multiseptated pancreatic cystic lesion. Obtaining a diagnostic
cytology from malignant cystic lesions by just aspirating
the cyst contents is low yield. If there is any solid component
to the wall of a pancreatic cyst, this should be aspirated
aggressively after draining the cyst contents. Chemical analysis
of the cyst fluid has been studied extensively. Only an elevated
cyst fluid carcinoembryonic antigen (CEA) seems to have any
consistent predictive power in identifying likely mucinous
cystadenomas and cystadenocarcinomas (44).
EUS-FNA for benign disease:
EUS-FNA for benign disease other than pancreatic cystic lesions
is still in its infancy. Although it appears to be safe, pancreatic
EUS-FNA does not appear to add significantly to the diagnostic
accuracy of EUS for chronic pancreatitis (47).
COMPLICATIONS OF EUS-GUIDED FINE
The overall complication rate of pancreatic EUS-FNA appears
to be about 1-2% (4, 6, 10, 14-21, 23, 48), similar to that
reported with CT, ultrasound-guided FNA, or biopsy. The major
complications reported with EUS-FNA are bleeding, pancreatitis,
and infection. Only one death has been reported to date with
pancreatic EUS-FNA (10) which was uncontrollable bleeding
after EUS-FNA using a radial echoendoscope. Extraluminal bleeding
can actually be observed while doing EUS-FNA as an expanding
echo-poor lesion adjacent to the aspirated lesion (49). In
my own experience, bleeding is especially likely when the
patient has portal hypertension from portal vein or splenic
vein obstruction from the pancreatic neoplasm or when aspirating
metastatic renal carcinoma to the pancreas (Figures 8-11).
Pancreatitis after EUS-FNA is most likely to occur in patients
already being evaluated for recurrent pancreatitis and when
the FNA needle is passed through more than 2 cm to 3 cm of
normal pancreas to obtain a specimen. Fortunately, bacteremia
following EUS-FNA is quite uncommon (50); however, EUS-FNA
of cystic pancreatic lesions has a higher risk of infectious
complications (48). Because of this risk, broad-spectrum intravenous
antibiotics during aspiration followed by a few days of oral
antibiotics are routinely given for EUS-FNA of cystic pancreatic
lesions. The risk of cancer seeding by EUS-FNA appears to
be very low. I know of only one anecdotal case of documented
EUS-FNA peritoneal seeding after aspirating a cystadenocarcinoma
(Goldin SB, personal communication). Supporting the low incidence
of peritoneal seeding with EUS-FNA is a recent interesting
abstract (51) which reported a significantly lower incidence
of peritoneal carcinomatosis after EUS-FNA of pancreatic cancers
compared to percutaneous FNA.
EUS-FNA is a powerful technique that has
greatly impacted the role of EUS in the management of pancreatic
masses (7). Pancreatic EUS-FNA is one of the most difficult
of endosonographic techniques and should not be attempted
by novice practitioners. However, in the hands of a skilled
endosonographers, cytologically diagnostic samples should
be obtainable in over 80% of pancreatic neoplasms with minimal
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