Introduction
Incidental detection of subepithelial lesions of the gastrointestinal tract is common
owing to widespread use of endoscopy [1 ]
[2 ]
[3 ]. These lesions are found in approximately 1 in 300 of all upper endoscopy procedures,
with the majority of them being gastrointestinal stromal tumors (GIST) [2 ]
[3 ]. Traditionally, endoscopic ultrasound-guided tissue acquisition (EUS-TA) has been
the gold standard for identifying the layer in which the subepithelial lesion resides,
obtaining accurate measurements, but also obtaining tissue. The goal of tissue acquisition
is to obtain not only a sample that can yield spindle cells, but also a sample in
which immunohistochemistry (IHC) can be performed. IHC staining for CD117, DOG1, S100,
CD34, and PDGFRA can differentiate GISTs from other subepithelial lesions [4 ].
Traditionally EUS-guided fine-needle aspiration (EUS-FNA) was the mainstay of obtaining
tissue. Diagnostic yield is variable and has been reported to be anywhere from 46 %
to 93 % [3 ]
[5 ]
[6 ]
[7 ]
[8 ]. The yield of EUS-FNA has been suboptimal and overall, it has been limited in its
ability to provide a quantity of tissue sufficient for IHC [3 ]
[9 ]. To help overcome this issue for sampling of GIST and other lesions, core needles
were developed. However, trials showed mixed results and the upwards diagnostic yield
of 75 % was still not optimal [10 ]
[11 ]. Recently newer core needles have been developed for EUS-guided fine-needle biopsy
(EUS-FNB) that can help optimize diagnostic yield for stromal tumors. Most of these
data have been evaluated for diagnostic yield of fork-tip FNB needle in pancreatic
masses [12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]. The fork-tip needle has six cutting surfaces that help obtain a core tissue. Studies
comparing the fork-tip needle to FNA have shown an increased diagnostic yield, sufficient
aspirated material for histology compared to cytology for FNA needles, and need for
fewer passes.
Although an abundant body of literature now exists for use of the newer-generation
core needles for pancreatic masses, data are lacking on their use for suspected GIST.
There is one retrospective study comparing EUS-FNA to EUS-FNB with the fork-tip needle
[9 ]. That study compared 91 patients with EUS-FNA using a 22-gauge needle to only 15
patients for EUS-FNB using the 22-gauge fork-tip needle. The study found a significant
difference in diagnostic yield (53 % vs 87 %, P = 0.01). Although these data are encouraging, only 15 patients were included in the
study who underwent FNB with a fork-tip needle. Thus more data are needed on the diagnostic
yield of the fork-tip core needle before it can be considered as the primary needle
for use in suspected GIST. The aim of this study was to report the diagnostic yield
of this needle in a large multicenter study for consecutive patients undergoing EUS-FNB
sampling versus EUS-FNA sampling.
Patients and methods
This was a retrospective multicenter study of five endosonographers from five academic
tertiary care hospitals in the United States. Each endosonographer primarily used
the fork-tip FNB needle since its inception as their primary needle for suspected
GIST. Prior to this, EUS-FNA was performed with standard FNA needles. Institutional
Review Board approval was obtained from each participating center. Procedures were
in accordance with ethical standards as they are considered the standard of care and
with the Helsinki Declaration of 1975. Informed consent was obtained for every procedure.
Data were abstracted from prospectively maintained endoscopic databases. Patients
were included if they: 1) had a suspected GIST based on EUS characteristics (i. e.,
lesions that were fourth-layer lesions, hypoechoic, and heterogeneous) [18 ]; 2) underwent EUS-guided sampling using a fork-tip FNB needle (Sharkcore, Medtronic,
United States) or with standard FNA needles; and 3) were age18 or older. Indications
for EUS-FNB were to obtain a diagnosis to justify surgery or differentiate from a
benign lesion such as a leiomyoma that would not require further endoscopic follow-up. This
was especially the case for lesions smaller than 2 cm. Patients were excluded if they:
1) underwent sampling with both a FNA and FNB needle, as it would be unclear which
needle contributed to a positive yield; 2) were younger than age 18; or 3) had repeat
procedures that were also negative on the first session, so as to not artificially
decrease the yield of the FNA group (most of repeat procedures occurred in FNA group).
Procedure characteristics that were abstracted included lesion size and location,
echogenicity, homogeneity, size of needle used, number of passes, and presence of
rapid onsite cytology. Cytopathology characteristics abstracted were ability to detect
spindle cells or diagnostic cells and ability to perform IHC. All reports were de-identified
and made available to all investigators among all five sites to ensure data accuracy.
De-identified reports were uploaded to an institutional encrypted server to which
all investigators had access. None of the cases in this study have been published
elsewhere in full manuscript form.
The technique used for FNB was the slow-pull stylet technique or suction technique.
For the slow-pull technique, once the needle was advanced into the lesion under endosonographic
guidance, the stylet was slowly removed by an assistant, while at least five throws
of the needle were made into the mass. The goal was to obtain a visible core of tissue
([Fig. 1 ]). EUS-FNA technique was at the discretion of the endoscopist but included standard
suction, wet suction, or no suction technique. Number of passes taken in each group
was at the discretion of the endoscopist. This was mainly decided based on the yield
of material that was being obtained.
Fig. 1 Example of a lesion from this study. a Endoscopic view of a subepithelial lesion in the stomach suspected of being a gastrointestinal
stromal tumor (GIST). b Fine-needle biopsy under endoscopic ultrasound guidance. c Visible core of tissue obtained after one pass placed in formalin. Histology and
immunohistochemistry were consistent with a GIST.
For cases in which a cytotechnologist was present, a portion of the FNA or FNB specimen
was placed on a slide. The slide was air dried and then stained with Diff-Quik. This
was used to determine adequacy of the sample. A second slide was fixed with 95 % ethyl
alcohol and polyethylene glycol and dipped into Papanicolaou stain for more detailed
cytologic examination. For cases in which a cytotechnologist was not present, the
sample was placed in formalin and processed as a typical cell block. If a sample had
spindle cells on cytopathology, it was then stained for IHC (CD117 and DOG-3).
The study had three primary outcomes. Ability to yield material for evaluation (e. g.:
obtain spindle cells) was defined as the cytopathology yield. Technically in FNB,
a core sample is yielded that can be analyzed by pathology for histology rather than
cytology. However. for purposes of the study, to be consistent between both groups,
we termed this cytopathologic yield. Ability to perform IHC in order to obtain a diagnosis
of a GIST was defined as the IHC yield. Ability to yield a distinct diagnosis (when
combining cytology and IHC) was defined as the diagnostic yield. If cytology showed
spindle cells but there was not enough material to perform IHC, then that patient
was defined as someone for whom a cytologic yield was possible but not a diagnostic
yield. However, when a sample had spindle cells on cytopathology and stained positive
for IHC markers of a GIST (CD117, DOG-3), then it had both a cytologic and diagnostic
yield.
Chi square testing was performed for categorical variables. A student t test was performed for continuous variables. Statistical significance was defined
as P < 0.05. All statistics were performed using SAS version 9.4 (Cary, North Carolina,
United States).
Results
A total of 147 patients were included in the study, of whom 101 underwent EUS-FNB
using a Fork-tip needle and 46 underwent EUS-FNA. Thirty-two patients were excluded
as multiple needles were used in the procedure. Patient and lesion characteristics
are shown in [Table 1 ]. Median age of patients was 66 in each group. Both groups had a high percentage
of males (57 % in FNA vs 52 % in FNB, P = 0.57). There were no statistically significant differences between the two groups
in regards to lesion size or median number of passes taken. The majority of suspected
lesions were in the stomach in both groups. In both groups, the 22-gauge needle was
the most common needle used (85 % in FNB group vs 61 % in the FNA group, P = 0.001) although the FNA group also had higher usage of the 25-gauge and 19-gauge
needle versus the FNB group (20 % vs 9 %, P = 0.07 and 20 % vs 6 %, P = 0.01). There were no reported immediate AEs recorded in the procedure reports for
either group. No reported delayed AEs were abstracted from the charts in either group.
Table 1
Patient and lesion characteristics.
Characteristics
All patients
FNA
FNB
P value
Age, median
66
66
66
0.31
Gender, male: female
78:69
26:20
52:49
69 (47 %)
20 (43.5 %)
49 (48.5 %)
0.57
78 (53 %)
26 (56.5 %)
52 (51.5 %)
0.57
Size of mass, median mm
23
20.5
25
0.25
Lesion location, no. (%)
18 (12.3 %)
7 (15.2 %)
11 (10.9 %)
0.46
115 (78.2 %)
31 (67.4 %)
84 (83.2 %)
0.03
5 (3.4 %)
2 (4.4 %)
3 (3.0 %)
0.70
6 (4.1 %)
4 (8.7 %)
2 (2.0 %)
0.06
3 (2.0 %)
2 (4.4 %)
1 (1 %)
0.18
Distribution of lesion type (%)
40 (27.2 %)
29 (63 %)
11 (10.9 %)
0.0001
87 (59.2 %)
12 (26.1 %)
75 (74.3 %)
0.0001
14 (9.52 %)
3 (6.5 %)
11 (10.9 %)
0.32
6 (4.1 %)
2 (4.4 %)
4 (4 %)
0.91
Lesion EUS features, no. (%)
106 (72.11 %)
36 (78.3 %)
70 (69.3 %)
0.2635
41 (27.9 %)
10 (21.7 %)
31 (30.7 %)
0.2635
133 (88.7 %)
38 (82.6 %)
90 (89.11 %)
0.2777
17 (11.3 %)
8 (17.4 %)
11 (10.9 %)
0.2777
[Table 2 ] contains information on procedure characteristics and outcomes. Ninety-three patients
in the FNB group had material aspirated with a cytopathology yield while 21 patients
had a cytopathology yield in the FNA group (92 % vs 46 %, P = 0.001). Subgroup analysis was performed by lesion size ([Table 3 ]). The groups analyzed were < 10 mm, 11 to 15 mm, 16 to 20 mm, 21 to 30 mm, and > 30 mm.
FNB had a statistically significant higher cytopathology yield in every size group
except for lesions < 10 mm. No difference was observed in diagnostic yield based on
location in the stomach. Lesions that underwent FNB in the fundus, body, and cardia
had a diagnostic yield of 87.5 %, 88 %, and 89 %, respectively (P values not significant).
Table 2
Procedure characteristics and outcomes.
Characteristics
All patients
FNA
FNB
P value
Needle size, gauge, and no. (%)
15 (10.2 %)
9 (19.6 %)
6 (5.9 %)
0.01
114 (77.6 %)
28 (60.9 %)
86 (85.2 %)
0.001
18 (12.2 %)
9 (19.6 %)
9 (8.9 %)
0.07
No. of passes, median
3.5
3.5
3.5
NS
Diagnostic yield (%)
107 (72.8 %)
17 (37 %)
90 (89.1 %)
0.0001
Adequate tissue obtained to perform IHC (IHC yield)
109 (74.2 %)
19 (41.3 %)
90 (89.1 %)
0.0001
Use of rapid onsite cytology
34 (22.7 %)
15 (32.6 %)
19 (18.3 %)
0.06
Cytopathology yield
112 (74.7 %)
21 (45.7 %)
93 (92.1 %)
0.0001
Table 3
Subgroup analysis based on lesion size.
< 10 mm
P value
11 – 15 mm
P value
16 – 20 mm
P value
21 – 30 mm
P value
> 30 mm
P value
Diagnostic yield for FNB
4/7 (57.1 %)
NS
11/13 (84.6 %)
NS
17/19 (89.5 %)
0.0005
29/30 (96.7 %)
0.0001
29/32 (90.6 %)
0.002
Diagnostic yield for FNA
3/6 (50 %)
4/8 (50 %)
2/9 (22.2 %)
4/14 (28.6 %)
4/9 (44.4 %)
GISTs in FNB group
3/7 (42.9 %)
NS
6/13 (46.2 %)
NS
15/19 (79 %)
0.0009
24/30 (80 %)
0.0002
27/32 (84.4)
0.02
GIST in FNA group
0
4/8 (50 %)
1/9 (11.1 %)
3/14 (21.4 %)
4/9 (44.4 %)
Leiomyoma in FNB group
1/7 (14.3 %)
NS
4/13 (30.8 %)
NS
2/19 (10.5 %)
NS
2/30 (6.7 %)
NS
2/32 (6.3 %)
NS
Leiomyoma in FNA group
2/6 (33.3 %)
0
1/9 (11.1 %)
0
0
Other in FNB group
0/7
NS
1/13 (7.7 %)
NS
0
NS
3/30 (10 %)
NS
0 (0 %)
NS
Other in FNA group
1/6 (16.7 %)
0
0
1/14 (7.1 %)
0 (%)
IHC in FNB group
4/7 (42.9 %)
NS
11/13 (84.6 %)
NS
17/19 (89.5 %)
0.0005
29/30 (96.7 %)
0.0001
29/32 (90.6 %)
0.01
IHC in FNA group
3/6 (50 %)
4/8 (50 %)
2/9 (22.2 %)
5/14 (35.7 %)
5/9 (55.6 %)
Cytopathology yield for FNB
4/7 (57.1 %)
NS
12/13 (92.3)
0.03
17/19 (89.5 %)
0.0005
29/30 (96.7 %)
0.0001
31/32 (96.9 %)
0.008
Cytopathology yield for FNA
4/6 (66.7 %)
4/8 (50 % )
2/9 (22.2 %)
5/14 (35.7 %)
6/9 (66.7 %)
FNB, fine-needle biopsy; GIST, gastrointestinal stromal tumor; FNA, fine-needle aspiration.
NS, not significant or cannot calculate due to null values in one group.
An IHC yield was obtained in 90 patients in the FNB group and 19 patients in the FNA
group (89 % vs 41 %, P < 0.001). Subgroup analysis was also performed by size for IHC yield ([Table3 ]). FNB had a statistically higher IHC yield for lesions > 16 mm. Lesions ≤ 15 mm
had no statistical difference. Overall when incorporating the cytology and IHC, the
EUS-FNB group had an overall diagnostic yield of 89 % vs 37 % for the EUS-FNA group
(P < 0.0001). Subgroup analysis was also performed by size for diagnostic yield ([Table 3 ]). FNB had a statistically higher diagnostic yield for lesions > 16 mm. Lesions ≤ 15 mm
had no statistical difference.
Rapid On-Site Evaluation (ROSE) was utilized in 18 % of patients who underwent FNB
and 32 % of patients with FNA (P = 0.06). There were no specific features of a lesion (eg lesion size, location, etc.)
that predicted when ROSE was used.
Discussion
In this multicenter retrospective study, we showed that EUS-FNB has a statistically
higher diagnostic yield for suspected GIST lesions than EUS- FNA. Diagnostic yield
for FNB was more than double that of FNA. These data provide compelling evidence to
support new core needles, specifically the fork-tip needle used in this study, as
the standard of care needle for suspected GIST lesions.
Most of the data for the new fine needle biopsy needles have been from studies looking
at diagnostic yield in pancreas masses. Both a recent randomized controlled trial
[19 ] and an updated meta-analysis [20 ] of EUS-FNA vs EUS-FNB for pancreatic masses show similar diagnostic yields between
the two needles. Thus the exact role of FNB needles in regards to diagnostic yield
of pancreatic masses is unclear [21 ]. Per expert opinion, EUS-FNA would suffice for most tissue acquisition for most
pancreatic masses [21 ]. The additional benefit of FNB may be for personalized medicine to obtain histologic
grade tissue for genotyping.
The role of FNB for suspected GIST lesions, unlike with pancreatic masses, seems more
straightforward. From the available literature on FNB for suspected GIST lesions (the
aforementioned smaller study [9 ] and this current study) the diagnostic yield is significantly higher for FNB. This
correlates with our personal experience where it was common to bring a patient back
for additional tissue for a non-diagnostic result from EUS-FNA. However, because of
use of the fork-tip FNB needles, it is now uncommon to bring patients back for repeat
sampling. It should be noted that a previous prospective study was performed with
a reverse bevel core needle on all suspected subepithelial lesions on 70 patients
from 2012 to 2015 [22 ]. Patients also underwent FNA at the same session. This study showed a higher diagnostic
yield for the FNB needle. Although this study did not evaluate one of the newer FNB
needles, it did support use of FNB over FNA.
In the current study, 63 % of patients in the FNA group had a non-diagnostic result.
These patients either underwent another repeat procedure or if clinical suspicion
was high, went to surgery for lesion removal. Although this was not a cost-effective
analysis study, use of a FNB needle prevented repeat EUS procedures or unnecessary
surgery on lesions found to be benign at surgery. Thus, increased cost of the FNB
needle may be justified in EUS sampling cases of suspected GIST lesions.
This study had limitations. First, it was retrospective. However, the cases were abstracted
from prospective endoscopic databases of consecutive patients. Thus the study design
was adequate to show the difference between FNA and FNB. It should also be noted that
the cases were performed in academic tertiary care centers, thus the study results
are applicable only to tertiary care centers. Another limitation is that the FNA and
FNB groups were heterogeneous in regards to sampling techniques (for both FNA and
FNB groups) and needle gauge (FNA group). The needles used in the FNA group included
needles from three different manufacturers (Medtronic Beacon needle, Boston Scientific
Expect needle, and Cook Medical EchoTip needle). However, all sampling techniques
were standard best practices so as to obtain a high diagnostic result, and thus reflect
a real-world situation. A prospective study would likely use the same sampling techniques
and gauge needles, as these are standard-of-care practices. Finally, because the procedures
were performed at tertiary care centers, the patients were referred back to their
local gastroenterologists and surgeons, thus surgical follow-up is lacking.
Conclusion
In conclusion, in this large multicenter study, we showed that FNB needles for suspected
GIST lesions are superior to FNA needles for diagnostic yield. Although the evidence
in this study strongly supports use of FNB needles for suspected GIST lesion, they
ideally require confirmation with a prospective study.
