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INTRODUCTION
Endoscopic ultrasound-guided tissue acquisition (EUSTA) is a well-established method for tissue diagnosis of solid pancreatic neoplasm [1-3]. Currently, EUS-guided fine-needle aspiration (EUS-FNA) is the standard diagnostic tool for the accurate diagnosis of pancreatic neoplasm [4-6]. The final results of EUS-FNA vary in terms of sensitivity (64%–95%), specificity (75%–100%), and diagnostic accuracy (78%–95%) [4,7,8]. However, EUS-FNA has limitations. It often provides only a cytological sample for diagnosis. In some pancreatic neoplasms, such as stromal tumors and lymphomas, histological specimens are required [9]. Further, the diagnostic accuracy of EUS-FNA can be affected by the presence of a rapid on-site cytopathology evaluation (ROSE); in some centers, ROSE is not available [10].
To overcome these limitations, newly designed needles for core biopsy, i.e., EUS-guided fine-needle biopsy (EUS-FNB), were developed. Initially, 19 G needles, which had a firing system, were developed. The diagnostic accuracy of these 19 G needles was 89.4% in a previous study involving 47 cases of pancreatic neoplasm [11].
Because of the technical difficulty in the use of 19 G needles for transduodenal procedures, novel needle sizes of 22 G and 25 G were developed. This article focuses on (1) addressing the current role of EUS-FNA/FNB in pancreatic neoplasm, (2) comparing EUS-FNA with EUS-FNB, (3) exploring the variables that impact diagnostic accuracy and specimen adequacy, (4) evaluating the adverse events of EUS-FNA/FNB, and (5) determining the future of EUS-FNA/FNB for precision medicine.
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DEVELOPMENT OF NEEDLES FOR EUSTA
EUS-TA for solid lesions in the pancreas is the test of choice for nonoperative pathological diagnosis [12-15]. Moreover, in cases of negative or indeterminate diagnoses based on EUS-guided tissue sampling findings in the presence of suspected pancreatic malignancy, recent guidelines recommend either performing revision on the initial pathology specimens obtained or repeating EUS-TA. For pancreatic cystic lesions with worrisome features, including clinical symptoms of pancreatitis, cysts measuring more than 3 cm, enhancing mural nodules measuring less than 5 mm, thickened/enhancing cyst walls, main duct size of 5–9 mm, abrupt change in the caliber of the pancreatic duct with distal pancreatic atrophy, lymphadenopathy, increased serum CA19-9 level, and cyst growth rate of more than 5 mm every 2 years, the European Society of Gastrointestinal Endoscopy (ESGE) recommended EUS-TA for biochemical and cytological evaluations. At first, only EUS-FNA needles measuring either 19 or 22 to 25 G were available for tissue acquisition [13]. EUS-FNB needles were introduced thereafter owing to the limitations of EUS-FNA needles.
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CURRENTLY AVAILABLE NEEDLES FOR EUS-TA
Trucut biopsy needles (QuickCore® needle; Cook Medical, Inc., Winston-Salem, NC, USA) were initially used as EUSFNB needles (Fig. 1). However, the size of the trucut biopsy needle available for EUS-FNB was 19 G, which was relatively stiff. Thus, there was considerable resistance in the firing of the cutting sheath for tissue cutting. Currently, the following three EUS-FNB needles are available for clinical use: (1) Procore ® needle (Cook Medical, Inc.) with a cutting bevel (reverse for 19, 22, and 25 G and 20 G antegrade beveled side slot) at the needle tip (Fig. 2A), (2) AcquireTM end-cutting needle (Boston Scientific Co., Marlborough, MA, USA) with a threepoint needle tip (22 and 25 G) (Fig. 2B), and (3) SharkCoreTM needle (Medtronic, Minneapolis, MN, USA) with six distal cutting edges at the needle tip (19, 22, and 25 G) (Fig. 2C) [16]. However, higher rates of adverse events and technical failure are noted with the use of large needles. Furthermore, smaller needle sizes, such as 22 and 25 G, are more technically feasible [16-18]. In general, more tissue will be obtained for histological assessment with larger needle sizes.
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DIAGNOSTIC YIELD OF EUS-TA: EUS-FNA VS. EUS-FNB
According to the characteristics of the pancreatic lesion, the diagnostic yields are somewhat different. In cases of pancreatic cancers, only cytology is enough for diagnosis; however, histology and immunohistochemical staining are required for the nonmalignant pancreatic mass [19]. In this aspect, a larger needle (19 G) is preferred in lesions requiring tissue architectural and immunohistochemical stains for diagnosis, such as metastatic pancreatic neoplasm and lymphoma. In previous studies, the reported cytological diagnostic accuracies were 89.7%–90% (EUS-FNA) and 93.1%–93.3% (EUS-FNB) in solid pancreatic neoplasm. Moreover, the histological diagnostic accuracies were relatively lower than the cytological diagnostic accuracies, i.e., 77.6%–80% vs. 71.7%–82.8% (p=0.642) for EUS-FNA and EUS-FNB needles in solid pancreatic neoplasm, respectively [18,20]. Several crossover comparative studies investigated both needles. Vanbiervliet et al. reported that the overall diagnostic accuracy was not different between EUS-FNA and EUS-FNB needles (92.5% vs. 90%, respectively, p=0.68) [21]. According to the most recently conducted randomized controlled trial, EUS-FNA and EUS-FNB had a diagnostic accuracy of 84% and 90%, respectively (p=0.8) [22]. In this study, EUS-FNB demonstrated higher histological quality than EUS-FNA. The results of previous randomized controlled trials are summarized in Table 1 [20-27]. In their previous meta-analysis, Wang et al. demonstrated that EUSFNB is comparable to EUS-FNA in terms of the diagnostic accuracy, adverse events, and technical success [28]. Currently, the ESGE guideline recommends both 25 and 22 G needles for sampling pancreatic solid masses regardless of the needle type [29]. However, a fewer number of needle passes are needed for obtaining sufficient tissue and achieving higher specimen adequacy in EUS-FNB than in EUS-FNA (Table 1) [30,31]. In cases of metastatic pancreatic neoplasm and lymphoma, the ESGE guideline recommends the use of a large-bore FNB needle (19 or 22 G) for complete tissue architecture [12].
Table 1.
Comparison of Endoscopic Ultrasound-Guided Fine-Needle Aspiration and Endoscopic Ultrasound-Guided Fine-Needle Biopsy of the Previous Randomized Controlled Trials
| Study | Patients (FNA : FNB) | Needles size (G) | Needle manufacturer | Diagnostic accuracy (odds ratio, 95% CI) | Specimen adequacy (odds ratio, 95% CI) | Number of needle pass (mean difference, 95% CI) | Adverse (odds ratio, 95% CI) | Technical success (odds ratio, 95% CI) |
|---|---|---|---|---|---|---|---|---|
| Lee et al. (2014) [20] | 58 : 58 | 22 G FNA 30 | Cook Medical | 0.32 (0.03–3.19) | - | - | 0.32 (0.03–3.19) | - |
| 25 G FNA 28 | ||||||||
| 22 G FNB 34 | ||||||||
| 25 G FNB 24 | ||||||||
| Vanbiervliet et al. (2014) [21] | 80 : 80 | 22 G FNA 80 | Cook Medical | 1.37 (1.45–4.15) | 1.90 (0.61–5.95) | - | - | - |
| 22 G FNB 80 | ||||||||
| Strand et al. (2014) [22] | 32 : 32 | 22 G FNA 32 | Cook Medical | - | - | 1.50 (0.91–2.09) | - | 13.00 (0.69–245.72) |
| 22 G FNB 32 | ||||||||
| Bang et al. (2012) [23] | 28 : 28 | 22 G FNA 28 | Boston | 7.82 (0.39–158.87) | - | 0.33 (-0.05–0.71) | 1.00 (0.06–16.82) | 3.11 (0.12–79.64) |
| 22 G FNB 28 | Scientific | |||||||
| Cook Medical | ||||||||
| Hucl et al. (2013) [24] | 69 : 69 | 22 G FNA 69 | Cook Medical | 0.48 (0.20–1.13) | 0.52 (0.17–1.64) | 1.04 (0.78–1.30) | - | - |
| 22 G FNB 69 | ||||||||
| Aadam et al. (2016) [25] | 70 : 70 | 19 G FNA 0 | Cook Medical | 0.33 (0.08–1.36) | 0.42 (0.14–1.27) | - | - | - |
| 19 G FNB 7 | ||||||||
| 22 G FNA 48 | ||||||||
| 22 G FNB 37 | ||||||||
| 25 G FNA 22 | ||||||||
| 25 G FNB 26 | ||||||||
| Kamata et al. (2016) [26] | 108 : 106 | 25 G FNA 108 | Cook Medical | 0.83 (0.43–1.57) | 0.53 (0.28–1.00) | - | - | - |
| 25 G FNB 106 | ||||||||
| Alatawi et al. (2015) [27] | 50 : 50 | 22 G FNA 50 | Cook Medical | 0.58 (0.18–1.92) | 0.08 (0.00–1.52) | 0.69 (0.38–1.00) | - | - |
| 22 G FNB 50 | ||||||||
| Total | - | - | - | 0.72 (0.49–1.07) | 0.57 (0.37–0.89) | 0.86 (0.45–1.26) | 0.49 (0.09–2.74) | 7.74 (0.94–64.00) |
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DETERMINING FACTORS OF DIAGNOSTIC ACCURACY AND SPECIMEN ADEQUACY
Several variables can affect the results, including (1) the procedure technique, (2) needle type and size, (3) competency of endosonographers, and (4) presence of cytopathologists or cytotechnologists.
Technique
Application of suction during EUS-TA is dependent on the quality of the first sample. In case the first pass has a large amount of blood contamination based on ROSE or gross examination findings, no suction aspiration should be performed in the next pass. Similarly, an insufficient tissue amount of the first puncture without suction requires application of suction in the next puncture. Tailored use of capillary (slow pull-back of stylet during needle passes) or suction according to the characteristics of target pancreatic lesion and/or ROSE or gross examination of specimen may increase the diagnostic yield. A previous randomized controlled trial has compared the diagnostic yield and cytological characteristics of EUS-FNA samples with and without the suction technique in patients with pancreatic neoplasm [1]. EUS-FNA samples in which the suction technique was used showed higher diagnostic yield, accuracy, bloodiness, and cellularity than did those in which the technique was not used. This might be because most target lesions were pancreatic cancers. In cases of EUS-FNA samples of lymph nodes, EUS-FNA with suction increases bloodiness without impacting the diagnostic yield [32]. The usefulness of capillary, wet suction, and suction with high negative pressure techniques need to be validated according to different pancreatic lesions [25,33,34].
The most recently conducted randomized controlled trial reported that the “fanning” motion of needles was superior to sampling in a single lesion per pass [35]. It may affect multiple regions in the pancreatic lesion during each pass of the needle. Several previous randomized controlled trials have demonstrated that there was no difference between groups of patients undergoing EUS-TA with and without the use of a stylet. Thus, the use of a stylet during EUS-TA cannot be recommended [36-38]. Instead, air flushing by gently pushing seems to be superior to EUS-TA with the use of a stylet according to a recent randomized controlled trial. Further, another recent randomized controlled trial reported that at least six needle passes for lesions measuring less than or equal to 2 cm and four needle passes for lesions measuring greater than 2 cm should be performed to optimize the sensitivity in pancreatic neoplasms without ROSE [24]. Most experts think that proper puncturing during EUS-TA is important to improve the diagnostic yield in addition to obtaining adequate gross samples and arriving to the expected diagnosis of a lesion based on pretest examination findings.
Needle type and size
A recent meta-analysis reported that there is no significant difference in the diagnostic accuracy and sample adequacy for pathological and histological examinations between EUS-FNA and EUS-FNB needles. However, a fewer number of needle passes were required to achieve diagnosis in EUS-FNB [28]. Although 22 or 25 G EUS-FNA needles are routinely used in pancreatic solid lesions and lymph nodes, a meta-analysis reported a higher sensitivity with the use of a 25 G needle than with that of a 22 G needle (pooled sensitivity, 0.93 [95% confidence interval, 0.91–0.96] vs. 0.85 [95% confidence interval, 0.82–0.88]) during EUS-FNA of pancreatic neoplasms [4]. In the comparisons between 22 and 25 G core biopsy needles in EUS-FNB, no significant difference in diagnostic performance has been reported [39].
Competency/experience of endosonographers
The American Society for Gastrointestinal Endoscopy recommended 150 supervised EUS procedures before competency [40]. Current guidelines recommend a minimum of 225 procedures (most for pancreatic biliary indications) before competency can be determined [41]. However, this is further complicated by other societies because of limited data and reliance on expert opinions. Current studies reported that advanced endoscopy trainees had different rates of learning curves in EUS, and specific cases in EUS were not related to competency [42-44]. Interestingly, in most advanced procedures, the volumes of operators and centers are closely related to each other. However, in EUS, they do not seem to be closely related.
Presence of cytopathologists/cytotechnologists and ROSE
Real-time feedback of EUS-TA (EUS-FNA/FNB) specimens by cytopathologists and cytotechnologists can not only make an accurate diagnosis but also increase efficiency with fewer numbers of needle passes during the procedure. However, a previous randomized controlled trial reported that there is no significant difference in the rates of inadequate specimens obtained and diagnostic yield of malignancy [45]. This study compared between EUS-FNA specimens with and without ROSE. Further, several studies demonstrated that there was no significant difference in the diagnostic yield during EUSFNB [25,46,47].
Nevertheless, ROSE may have a crucial role for less experienced endosonographers and medical centers with low tissue specimen adequacy [48]. Moreover, appropriate selection for additional tests (molecular analysis, flow cytometry, immunohistochemistry, and cytogenetics) with limitations of specimens can be possible with ROSE by cytopathologists and cytotechnologists [49,50]. The role of ROSE will continue to increase because of technical improvements in EUS-TA, including the newer EUS-FNB.
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ADVERSE EVENTS RELATED TO EUS-TA
The incidence of adverse events in EUS-TA (EUS-FNA/FNB) was relatively low in a previous comprehensive nationwide retrospective study [51]. Infection and pancreatitis were the most common adverse events. In the study, clinically severe adverse events occurred only in 0.29% of all EUS-TA cases without any mortality. This result is consistent with that of the survey on severe adverse event rates in Japan (0.23%) [52]. The adverse event rate for EUS-FNA is less than 1% [53]. Yang et al. reported that EUS-FNB had a comparable adverse event rate with EUS-FNA [54]. The diagnostic accuracy and specimen adequacy in previous clinical studies are described in Table 1 [20,23,24,26]. The recent meta-analysis conducted by Wang et al. reported that only one study found adverse events after surgery, including acute pancreatitis, abdominal pain, bleeding, and gastric hematoma, and all patients recovered rapidly after conservative treatment [28]. The pooled analysis showed that the rate of adverse events did not significantly differ between their two groups.
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FUTURE PROSPECT OF EUS-TA
With the recent developments in human genomics and sequencing technology, personalized medicine of cancer has become a reality [55]. Next-generation sequencing (NGS) has been widely implemented for gene sequencing (Fig. 3) [56]. Recently, several studies have revealed the mutational landscape of pancreatic cancer using NGS. For genomic analyses, formalin-fixed and paraffin-embedded specimens have been preferred. Thus, it was believed that EUS-FNB may be necessary and superior for obtaining adequate tumor tissue for NGS. However, several studies reported that the cytological samples obtained in EUS-FNA are superior to the histological samples obtained in EUS-FNB. One previous study has demonstrated that the cytological samples in EUS-FNA confer a high concentration of pure tumor cells compared with the histological samples in EUS-FNB [57]. Furthermore, alcohol-based fixation for cytological samples preserves nucleic acid for genomic analyses [58]. Cytological samples also have intact cells compared with histological specimens owing to the sectioning procedure for the latter. However, the relatively low proportion of adequate materials for NGS in EUS-FNA remains a problem. Only 12.4% of materials for NGS in EUS-FNA were obtained from malignant pancreatic masses [59]. Nevertheless, a recent report concurrently assessing FNA and core needle biopsies found that EUS-FNA may be sufficient for NGS owing to better cellularity and NGS metrics and higher tumor fractions compared with EUS-FNB [60]. Thus, it is uncertain whether EUS-FNB is more superior to EUS-FNA in regard to tissue acquisition for NGS. Multicenter prospective studies are required to elucidate the role of EUS-TA and factors for successful EUS-TA sampling in any type of tissues for diagnostic and theranostic purposes.
Several studies demonstrated that new methods, such as cytological sampling using smears, ThinPrep slides, and cell blocks, are available for genomic analysis. Among these methods, liquid cytological sampling (FNA rinse material) is excellent and often superior for personalized medicine [61,62]. Further, RNA and microRNA sequencing [63-66], fluorescence in situ hybridization [67], use of protein and immune markers and tumor organoids [68-71], and low-cost whole-exome sequencing are currently the emerging fields in EUS-TA. Successful NGS from single circulating tumor cells was also reported [72,73]. By using circulating tumor cells, sampling is completely different from previous methods, such as sampling from peripheral blood [74] or EUS-guided portal vein sampling [75]. However, there are limited reports on these new emerging methods. Future studies need to determine whether EUS-FNB is superior to EUS-FNA in combination with the new emerging methods.
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CONCLUSIONS
First, this article summarized the current knowledge regarding the role of EUS-TA, comparing between EUS-FNA and EUS-FNB. Second, this article documented the outcomes, variables, and adverse events of EUS-TA for routine clinical practice. Third, this article explored the prospect of EUS-TA for pancreatic masses for personalized medicine. Currently, EUS-TA clearly plays a vital role in oncological care. Although the comparison between EUS-FNA and EUS-FNB for the diagnosis of pancreatic neoplasm is still controversial, several previous randomized clinical trials have reported that EUSFNB is comparable to EUS-FNA in terms of the diagnostic accuracy, adverse events, and technical success. Meanwhile, EUS-FNB requires a fewer number of needle passes to obtain sufficient tissue and higher specimen adequacy. Further, both EUS-FNA and FNB are very safe. Although EUSTAs were performed in many pancreatic cancer cases, EUSTA methods are not standardized due to multiple variables. As we have mentioned, complex processes with different variables, including sampling techniques, are closely related to improvement of the final results of EUS-TA for the diagnosis of pancreatic neoplasm. Thus, it is important to approach EUS-TA in a multidisciplinary manner not only for diagnostics but also for theranostics. EUS-TA currently has an important role in the upcoming era of personalized medicine. However, future higher-grade multicenter prospective studies are needed to optimize EUS-TA for theranostic purposes.
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