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Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis
Journal Pre-proof Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis Antonio Facciorusso, MD, PhD, Valentina Del Prete, MD, Matteo Antonino, MD, Vincenzo Rosario Buccino, MD, Sachin Wani, MD, PhD PII:
S0016-5107(20)30096-1
DOI:
https://doi.org/10.1016/j.gie.2020.01.038
Reference:
YMGE 11954
To appear in:
Gastrointestinal Endoscopy
Received Date: 5 November 2019 Accepted Date: 22 January 2020
Please cite this article as: Facciorusso A, Del Prete V, Antonino M, Buccino VR, Wani S, Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2020.01.038. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy
Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis Antonio Facciorusso, MD, PhD1, Valentina Del Prete, MD1, Matteo Antonino, MD1, Vincenzo Rosario Buccino, MD1, Sachin Wani, MD, PhD2 1
Gastroenterology Unit, University of Foggia, Italy; 2 University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
Short Title: Microforceps biopsy
Correspondence: Antonio Facciorusso Gastroenterology Unit, Department of Medical Sciences University of Foggia AOU Ospedali Riuniti Viale Pinto, 1 71100 Foggia-Italy Fax: 0039 0881733545 Phone: 0039 0881732110 e-mail: [email protected]
Guarantor of the article: Antonio Facciorusso Specific author contributions: Antonio Facciorusso designed the study and performed the statistical analysis; Matteo Antonino, Valentina Del Prete and Vincenzo Rosario Buccino collected the data; Antonio Facciorusso and Sachin Wani revised the manuscript. All the authors approved the final draft submitted.
Conflict of interest: Sachin Wani-Consultant for Boston Scientific, Medtronic, Interpace, Cernostics Disclosures: Sachin Wani-supported by the Department of Medicine Outstanding Early Scholars Program. The other authors do not have financial ties to disclose.
1
Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis Antonio Facciorusso1, Valentina Del Prete1, Matteo Antonino1, Vincenzo Rosario Buccino1, Sachin Wani2 1
Gastroenterology Unit, University of Foggia, Italy; 2 University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
Short Title: Microforceps biopsy
Correspondence: Antonio Facciorusso Gastroenterology Unit, Department of Medical Sciences University of Foggia AOU Ospedali Riuniti Viale Pinto, 1 71100 Foggia-Italy Fax: 0039 0881733545 Phone: 0039 0881732110 e-mail: [email protected]
Guarantor of the article: Antonio Facciorusso Specific author contributions: Antonio Facciorusso designed the study and performed the statistical analysis; Matteo Antonino, Valentina Del Prete and Vincenzo Rosario Buccino collected the data; Antonio Facciorusso and Sachin Wani revised the manuscript. All the authors approved the final draft submitted. Conflict of interest: Sachin Wani-Consultant for Boston Scientific, Medtronic, Interpace, Cernostics Disclosures: Sachin Wani-supported by the Department of Medicine Outstanding Early Scholars Program. The other authors do not have financial ties to disclose.
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ABSTRACT Background and Aims: There is currently limited evidence supporting the use of endoscopic ultrasound-guided through-the-needle biopsy for sampling pancreatic cystic lesions. The aim of this meta-analysis was to provide a pooled estimate of the diagnostic performance of through-the-needle biopsy for sampling of pancreatic cysts. Methods: A bibliographic search on the main databases was performed through September 2019. Pooled effects were calculated using a random-effects model by means of DerSimonian and Laird test. The primary outcome was sample adequacy. Additional endpoints were diagnostic accuracy, optimal histological core procurement, mean number of needle passes, pooled specificity, and sensitivity. Adverse event rates were also analyzed. Results: Eleven studies enrolling 490 patients were included. Eight articles compared through-theneedle biopsy to cytology/cystic fluid analysis. Most patients were female, and body/tail was the most frequent location of cystic lesions. Sample adequacy with through-the-needle biopsy was 85.3% (78.2%-92.5%) and subanalysis was performed according to cyst morphology, size, and location confirmed the above reported result. Through-the-needle biopsy clearly outperformed fineneedle aspiration both in terms of sample adequacy (odds ratio, 4.83; 95% CI, 1.63-14.31; p=0.004) and diagnostic accuracy (odds ratio, 3.44; 95% CI, 1.32-8.96; p=0.01). Pooled diagnostic accuracy rate, sensitivity and specificity of through-the-needle biopsy were 78.8%, 82.2%, and 96.8%, respectively. A mean of 3.121 (2.98-3.25) passes through the cyst was needed to obtain adequate histological samples. The incidence rates of mild bleeding and pancreatitis were 4% and 2%, respectively. Conclusion: Our meta-analysis speaks in favor of the use of through-the-needle biopsy as a safe and effective tool in EUS-guided tissue acquisition of pancreatic cysts.
Key words: EUS; microforceps; pancreas; sensitivity; accuracy.
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INTRODUCTION Pancreatic cystic lesions (PCLs) are increasingly diagnosed in clinical practice due to the increase of the average lifespan in the general population and the improvement in diagnostic tools. A pancreatic cyst is incidentally diagnosed in up to 20% of patients undergoing routine abdominal imaging1,2. As several kinds of PCLs at different risk of malignancy are described, the exact diagnostic characterization of the lesion is of paramount importance for the adequate management of these patients. In particular mucinous cysts, including intraductal papillary mucosal neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), constitute the most frequent premalignant lesions3. Although endoscopic ultrasound (EUS) plays a pivotal role in distinguishing different kinds of PCLs, simple morphological characterization of the lesion is not sufficient to draw definitive conclusions on the exact diagnosis and the relevant risk of malignancy; therefore, EUS-guided fineneedle aspiration (FNA) through the use of 19-gauge or 22-gauge FNA needles is commonly used in order to collect adequate samples for cytology and cystic fluid analysis4. Despite the large experience based on CEA or amylase concentration or the evaluation of the presence of mucus in the cystic fluid, none of these methods was proved to be able to accurately discriminate the type of lesion and the risk of malignancy5-7. In particular, the relatively low sensitivity, reported to be as high as 54% in differentiating mucinous from nonmucinous cysts5,8, represents a major drawback of standard FNA. Despite the encouraging results observed with cyst fluid molecular analysis9 and with novel devices such as confocal laser endomicroscopy (CLE)10, the high costs and the limited experience make these techniques a “niche” diagnostic tool not available worldwide.
4
Recently, a through-the-needle microforceps biopsy (TTNB) device (Moray Microforceps, US Endoscopy, Mentor, Ohio, USA) that can be passed through a standard 19-gauge EUS-FNA needle was developed for histologic sampling of PCLs. There is currently limited evidence supporting the use of TTNB for sampling PCLs, and the recent guidelines mention microforceps biopsy as a promising tool but not include any specific statements concerning its use in the clinical practice due to the limited number and the low quality of available studies11. Since the release of the latest guidelines, several observational studies testing TTNB have been published, hence the pressing need to systematically assess the increasing body of evidence in the field in order to better define the role and safety of this novel device in the endoscopic practice. The aim of this meta-analysis was to provide a pooled estimate of the diagnostic performance and safety profile of through-the-needle microforceps biopsy for sampling of PCLs, thus attempting to determine its comparative efficacy with respect to standard FNA. The primary outcome was sample adequacy. Additional endpoints were diagnostic accuracy, optimal histological core procurement, mean number of needle passes, pooled specificity and sensitivity. Safety data were also analyzed.
MATERIALS AND METHODS
Inclusion and exclusion criteria The literature search strategy was based on the following inclusion criteria: (1) articles enrolling patients undergoing EUS-guided tissue acquisition of PCLs with TTNB; (2) studies published in English; (3) articles reporting sample adequacy or diagnostic accuracy. Small case series, nonendoscopic studies, review articles, and animal models were excluded.
Search strategy
5
Literature search was conducted on PubMed, EMBASE, Cochrane Library, and Google Scholar including all studies fulfilling the inclusion criteria published through September 2019 (Appendix 1). Relevant reviews and meta-analyses on tissue sampling of PCLs were examined for potential suitable studies. Authors of included studies were contacted to obtain full text or further information when needed. Data extraction was performed by 2 authors (A.F. and V.D.P.) using a standardized approach (PRISMA Statement)12. The quality of included studies was rated by 2 reviewers independently (A.F., V.D.P.) based on the Newcastle-Ottawa scale13 for nonrandomized studies. Disagreements were solved by discussion and after a third opinion (V.R.B.).
Outcomes Primary endpoint was sample adequacy, defined as the ability to achieve tissue samples adequate for diagnosis; additional endpoints were diagnostic accuracy, defined as the ability to diagnose the exact kind of PCL (true positive + true negative/ total number of patients); procurement rate of optimal core histological tissue, defined as samples with high cellularity and quality enabling appropriate core assessment in terms of tissue architecture; specificity (true negative/ true negative + false positive), sensitivity (true positive/ true positive + false negative), number of needle passes, and adverse events.
Statistical analysis Study outcomes were pooled through a random-effects model based on DerSimonian and Laird test, and results were expressed as rates and 95% confidence interval (CI). Comparison between TTNB and FNA was based on a random-effects model.
6
The presence of heterogeneity was calculated through I² tests with I²<20% interpreted as low-level heterogeneity. Any potential publication bias was verified through visual assessment of funnel plots. The rates of adverse events, in particular bleeding and pancreatitis, were also pooled. Sensitivity analysis was conducted restricted to (1) high quality studies, (2) prospective studies, and (3) fulltext articles. Subgroup analysis of the primary outcome (sample adequacy) was performed based on (1) cyst morphology (unilocular versus septated), (2) cyst size (< 3 cm versus ≥3 cm), and (3) cyst location (head/uncinate versus body/tail). A further subgroup analysis of diagnostic accuracy was conducted in those patients with surgical confirmation of the diagnosis. All statistical analyses were conducted using RevMan version 5 from the Cochrane collaboration and OpenMeta[Analyst] software. For all calculations a 2-tailed P value of less than 0.05 was considered statistically significant.
RESULTS
Characteristics of included studies As described in Figure 1, out of 645 studies initially screened, 28 relevant articles potentially fulfilling the inclusion criteria were examined. Among these studies, 17 were excluded because they were duplicate overlapping series or case series enrolling < 10 patients. Finally, 11 studies14-24 with 490 patients were included in the meta-analysis. The main characteristics of included studies are reported in Table 1. The recruitment period ranged from 2013 to 2018. Eight articles compared TTNB with FNA/cystic fluid analysis14-16,18,19,22-24, of which 2 prospective16,23. Three articles were published as conference proceedings15,19,24.
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Most patients were female, and body/tail was the most frequent location of PCLs. Mucinous cysts were prevalent in most of the included studies. Quality was deemed mainly moderate/high with only 4 studies assessed as low-quality articles15,17,19,24. Details on methodological characteristics and quality of included articles are shown in Supplementary Table 1.
Sample adequacy As reported in Figure 2, per-patient analysis of overall sample adequacy showed rates of adequate samples for diagnosis of 85.3% (78.2%-92.5%; I2=41.5%) with TTNB. Subanalysis performed according to cyst morphology (unilocular versus septated), size (<3 cm versus ≥3 cm), and location (head/uncinate versus body/tail) confirmed the above reported results, with rates of sample adequacy ranging from 78.5% to 88.6% (Table 2). The findings of the main analysis were confirmed in sensitivity analysis restricted to full-text articles and high-quality studies (Supplementary Table 2). Of note, sensitivity analysis restricted to the 2 prospective studies16,23 showed a high rate of sample adequacy (91.6%, 76.1%-100%; Supplementary Table 2). There was no evidence of publication bias. As depicted in Figure 3, a total of 7 studies14-16,18,22-24 directly compared TTNB with standard FNA, showing a clear advantage in terms of sample adequacy with TTNB (OR, 4.83; 95% CI, 1.6314.31; p=0.004 and I2 =36%). Of note, the study by Robles-Medranda et al19 was excluded from the analysis due to the lack of comparative data and because the rates of sample adequacy were not reported.
Optimal histologic core procurement, diagnostic accuracy, sensitivity and specificity The rate of histological optimal core procurement obtained with TTNB was reported to be as high as 80% (73.1%-86.9%; I2=49.7%) in a pooled analysis of 7 studies14,17,18,20,21,23,24 (Supplementary Figure 1).
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A pooled analysis of 8 studies14,15,17-21,23 found an overall diagnostic accuracy rate of 78.8% (73.4%-84.2%; I2=28.36%). Moderate evidence of heterogeneity was reported and no risk of publication bias was detected (Figure 4). Three studies14,15,18 compared diagnostic accuracy rate between TTNB and FNA. As reported in Supplementary Figure 2, TTNB clearly overperformed FNA (OR, 3.44; 95% CI, 1.32-8.96; p=0.01), with moderate evidence of heterogeneity (I2=41%). Subgroup analysis restricted to 59 patients with surgical confirmation of the diagnosis showed a diagnostic accuracy rate of 88.3% (80.1%-96.5%; I2=0%; Supplementary Figure 3). Based on three studies18,19,23 reporting diagnostic sensitivity (or data useful for its calculation), pooled sensitivity of TTNB was 82.2% (74.1%-90.2%) and pooled specificity was 96.8% (91.5%100%; data not shown).
Number of passes and adverse events Pooled analysis of number of needle passes through the cyst needed to achieve adequate samples is reported in Supplementary Figure 4. A mean of 3.121 (2.98-3.25) passes of microforceps biopsy through the cyst was needed to obtain adequate histological samples (I2=16.46%, Supplementary Figure 4). Details on the adverse events registered in the included studies are reported in Supplementary Table 3. Out of 490 patients recruited in the included studies, 20 subjects experienced mild bleeding (4%) and 10 (2%) mild pancreatitis. Of note, all of these adverse events were mild and did not impact on patient outcomes.
DISCUSSION
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Obtaining adequate cytological samples of PCLs is challenging as current techniques based on FNA are affected by relatively low sensitivity mainly due to the high rates of false negative or inadequate specimens. Fine-needle biopsy (FNB) of the cyst wall provided interesting results in presence of intramural nodules, but the diagnostic sensitivity of reverse-bevel FNB was disappointing in PCLs without solid components25. In fact, an Italian series reported rates of sample adequacy below 40% in patients without solid components in the PCL, very similar to cytology of cystic fluid25. Therefore, no more studies on FNB have been published and in recent years, new techniques have been studied and developed to increase diagnostic power in PCLs. The main advantage of TTNB is to obtain adequate specimens retaining the stroma covered with the epithelial lining and, therefore, to preserve the histological architecture of the sampled tissue. These aspects allow ancillary techniques such as immunohistochemistry both on epithelium and on the stroma, thus improving the diagnostic and prognostic value of the technique26. Moreover, TTNB allows collecting adequate volumes of cystic fluid for either biochemical and molecular biology analysis and for cytology, which can be associated with histology to improve diagnosis, as reported in several series18,23. Given the increasing body of evidence concerning the use of TTNB, there is a clear need to systematically evaluate the impact of this newer sampling technique in the clinical practice. Through a meta-analysis of 11 studies assessing the diagnostic yield of TTNB in PCLs (alone or in comparison to standard FNA), we made several key observations. First, overall sample adequacy rate with TTNB was 85.3%, with diagnostic accuracy and sensitivity of 78.8% and 82.2%, respectively. These findings represent a striking result considering that current techniques (FNA with cystic fluid analysis) showed median diagnostic accuracy and sensitivity values of less than 50%26. Furthermore, the diagnostic performance of standard FNA is highly influenced by the presence of an expert pancreatic cytologist, who is not available in many centers. The TTNB technique may obviate to these problems by providing histological samples of the cyst wall
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including both the epithelium and the stroma, an aspect particularly important in mucinous neoplasms characterized by the presence of an ovarian-like stroma27,28. Hence the capability of discriminating among different kinds of PCLs even in absence of an expert pathologist. As a result of the aforementioned findings, TTNB clearly outperformed standard FNA in comparative pairwise meta-analysis, showing a clear advantage in terms of sample adequacy (OR, 4.83; 95% CI, 1.6314.31; p=0.004) and diagnostic accuracy (OR, 3.44; 95% CI, 1.32-8.96; p=0.01). Second, the diagnostic performance of TTNB was confirmed in subanalysis performed according to cyst morphology (unilocular versus septated), size (<3 cm versus ≥3 cm), and location (head/uncinate versus body/tail). These results further support the wide use of TTNB in the endoscopic practice. Third, a mean of 3.121 (2.98-3.25) passes of microforceps biopsy through the cyst was found to be needed to obtain adequate histological samples, mainly due to the need to sample different components of the cyst wall. Finally, the TTNB technique resulted relatively safe although 4% of enrolled patients experienced mild bleeding and 2% pancreatitis; of note, these adverse events were mild and did not influence significantly the clinical course of the patients. In spite of the undoubted advantages of TTNB in comparison to FNA, diagnostic accuracy and sensitivity are still considerably inferior to solid pancreatic masses29-31. In fact, it is possible to sample only the opposite wall of the PCL with respect to the point of entrance of the needle and due to the uneven distribution of dysplasia inside the PCLs, there is a considerable risk of underestimate the real grade of dysplasia inside the cyst26. Moreover, some PCLs might have the so-called “denuded epithelium,”32 thus making difficult to obtain adequate specimens even with a high number of passes. Among the weaknesses of our study, the lack of randomized studies did not allow a robust comparison between TTNB and standard FNA, thus calling for a particular note of caution when interpreting our comparative findings. It should be noted that the FNA/cytology group did not include any fine-needle core biopsy results and a comparison with FNB needles was not feasible
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due to the lack of available studies. Second, as only a minor part of the patients enrolled in the included studies finally underwent surgery, diagnostic accuracy analysis might be biased by the lack of histological diagnosis on the surgical specimens. In conclusion, despite these limitations, our meta-analysis speaks in favor of the use of TTNB as a safe and effective tool in EUS-guided tissue acquisition of PCLs. Being able to accurately discriminate among different kinds of cysts and to identify more lesions with advanced neoplasia, TTNB may be considered a helpful adjunct tool in the evaluation of PCLs. Large RCTs and prospective studies are needed in order to confirm these promising results.
REFERENCES [1] Farrell JJ, Fernández-del Castillo C. Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology. 2013;144:1303–1315. [2] F Stark A, Donahue TR, Reber HA, et al. Pancreatic Cyst Disease: A Review. JAMA. 2016;315:1882–1893. [3] Fernández-del Castillo C, Adsay NV. Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2010;139:708–713, 713.e1-713.e2 [4] van Riet PA, Cahen DL, Poley JW, et al. Mapping international practice patterns in EUSguided tissue sampling: outcome of a global survey. Endosc Int Open 2016;4: E360 – 70 [5] Thornton GD, McPhail MJ, Nayagam S, et al. Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis. Pancreatology 2013;13:48–57. [6] van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. GastrointestEndosc 2005;62:383– 9.
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[7] Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330–6. [8] de Jong K, Poley JW, van Hooft JE, et al. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. Endoscopy. 2011;43:585-90. [9] Singhi AD, McGrath K, Brand RE, et al. Pre-operative next-generation sequencing of pancreatic cyst fluid is highlyaccurate in cyst classification and detection of advanced neoplasia. Gut. 2018;67:2131-2141 [10]
Anand K, Kahaleh M, Tyberg A. Use of needle-based confocal laser
endomicroscopy in the diagnosis and management of pancreatic cyst lesions. Endosc Ultrasound. 2018;7:306-309 [11]
Dumonceau JM, Deprez PH, Jenssen C, et al. Indications, results, and clinical impact
of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline - Updated January 2017. Endoscopy. 2017;49:695-714. [12]
Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336-341 [13]
Wells GA , Shea B , O’Connell D, et al. The Newcastle – Ottawa Scale (NOS) for
assessing the quality of nonrandomised studies in meta-analyses; available from: http://www.ohri.ca/programs/ clinical_epidemiology/oxford.htm , accessed on September 2019. [14]
Basar O, Yuksel O, Yang DJ, et al. Feasibility and safety of microforceps biopsy in
the diagnosis of pancreatic cysts. Gastrointest Endosc. 2018;88:79-86.
13
[15]
Cheesman AR, Zhu H, Kumta NA, et al. Eus-guided microforceps biopsy and
needle-based confocal laser endomicroscopy significantly improve the diagnostic yield and have major impact on clinical management of pancreatic cystic lesions [abstract]. Gastrointest Endosc 2019, 89: AB144 [16]
Crinò SF, Bernardoni L, Brozzi L, et al. Association between macroscopically
visible tissue samples and diagnostic accuracy of EUS-guided through-the-needle microforceps biopsy sampling of pancreatic cystic lesions. Gastrointest Endosc. 2019, in press [17]
Kovacevic B, Karstensen JG, Havre RF, et al. Initial experience with EUS-guided
microbiopsy forceps in diagnosing pancreatic cystic lesions: A multicenter feasibility study (with video). Endosc Ultrasound. 2018;7:383-388 [18]
Mittal C, Obuch JC, Hammad H, et al. Technical feasibility, diagnostic yield, and
safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video). Gastrointest Endosc. 2018;87:1263-1269. [19]
Robles-Medranda C, Olmos JI, et al. Eus-through-the-needle technologies in the
diagnosis and malignancy detection of pancreatic cysts: a comparative study between different technologies [abstract]. Gastrointest Endosc 2019; 89: AB608-9 [20]
Samarasena J, Yu A, Lee D, et al. EUS-guided through-the-needle biopsy for
pancreatic cystic lesions. VideoGIE. 2019;4:436-439 [21]
Vestrup Rift C, Melchior LC, Kovacevic B, et al. Next-generation sequencing of
endoscopic
ultrasound
guided
microbiopsies
from
pancreatic
cystic
neoplasms.
Histopathology. 2019, in press. [22]
Zhang ML, Arpin RN, Brugge WR, et al. Moray micro forceps biopsy improves the
diagnosis of specific pancreatic cysts. Cancer Cytopathol. 2018 ;126:414-420.
14
[23]
Yang D, Trindade AJ, Yachimski P, et al. Histologic Analysis of Endoscopic
Ultrasound-Guided Through the Needle Microforceps Biopsies Accurately Identifies Mucinous Pancreas Cysts. Clin Gastroenterol Hepatol. 2019 ;17:1587-1596 [24]
Wilen J, Visrodia K, Lan G, et al. The feasibility and value of cyst wall biopsy using
micro forceps in the diagnosis of pancreatic cysts [abstract]. Gastrointest Endosc 2019; 89:AB605. [25]
Barresi L, Tarantino I, Traina M, et al. Endoscopic ultrasound-guided fine needle
aspiration and biopsy using a 22-gauge needle with side fenestration in pancreatic cystic lesions. Dig Liver Dis 2014;46:45–50. [26]
Barresi L, Tacelli M, Ligresti D, et al.
Tissue acquisition in pancreatic cystic
lesions. Dig Liver Dis. 2019 ;51:286-292 [27]
Crinò SF, Bernardoni L, Gabbrielli A, et al. Beyond pancreatic cyst epithelium:
evidence of ovarian-like stroma in eus-guided through the-needle micro-forceps biopsy specimens. Am J Gastroenterol 2018;113:1059-60. [28]
Barresi L, Tacelli M, Chiarello G, et al. Mucinous cystic neoplasia with denuded
epithelium: EUS through-the-needle biopsy diagnosis. Gastrointest Endosc 2018;88:771-4. [29]
Facciorusso A, Wani S, Triantafyllou K, et al. Comparative accuracy of needle sizes
and designs for EUS tissue sampling of solid pancreatic masses: a network meta-analysis. Gastrointest Endosc. 2019, in press [30]
Facciorusso A, Bajwa HS, Menon K, et al. Comparison between 22G aspiration and
22G biopsy needles for EUS-guided sampling of pancreatic lesions: A meta-analysis. Endosc Ultrasound. 2019, in press [31]
Facciorusso A, Stasi E, Di Maso M, et al. Endoscopic ultrasound-guided fine needle
aspiration of pancreatic lesions with 22 versus 25 Gauge needles: A meta-analysis. United European Gastroenterol J. 2017;5:846-853
15
[32]
Gómez V, Majumder S, Smyrk TC, et al. Pancreatic cyst epithelial denudation: a
natural phenomenon in the absence of treatment. Gastrointest Endosc 2016;84:788–93.
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Table 1. Characteristics of included studies
Study
Country
Sample size
Study period/ design
FNA cytology/cys t fluid analysis
Age
Gender male
Lesion size (cm)
Location (head/uncinate)
Diagnosis of mucinous cysts
Intramura l nodules
Septations
Basar 201814
USA
42
2015-2016/
Yes
69 (27-
19 (45.2%)
2.82 (1.2-6)
16 (38.1%)
NR
4 (9.6%)
25 (60%)
Number of patients with surgical confirmation of diagnosis 7 (17%)
91) Retrospectiv e Cheesman 2019
USA
41
NR/
Yes
66
15 (36.6%)
3.7 (1.6-5)
12 (29.3%)
NR
8 (19.5%)
21 (51.2%)
13 (31.7%)
Yes
50.2±14.
14 (22.9%)
4.07±1.42
18 (29.5%)
16 (26.2%)
NR
27 (44.3%)
20 (32.7%)
13 (46.4%)
3 (2.2-4.75)
12 (42.9%)
NR
NR
NR
NR
11 (40.7%)
3.78±1.69
14 (52%)
13 (48.1%)
1 (3.7%)
NR
NR
11 (29.8%)
NR
15 (42.6%)
34 (95.7%)
NR
NR
NR
15a
Retrospectiv e Crinò 2019
16
Italy
61
2016-2018/
7 Prospective Kovacevic 2018
17
Multicen
28
NR/
No
65.5±11. 8
ter Retrospectiv e
Mittal 2018
18
USA
27
2016-2017/
Yes
Retrospectiv
65 (3287)
e RoblesMedranda 2019
19a
Ecuador
36
2013-2018/ Retrospectiv e
Yes
64 (2494)
17 Samarasena
USA
15
NR/
No
201920
67 (54-
7 (46.6%)
80)
2.5 (0.48-
8 (53.3%)
8 (53.3%)
NR
NR
NR
3.9)
Retrospectiv e Vestrup Rift 2019
Denmark
27
21
2016-2017/
No
Retrospectiv
70.9 (40-
15 (55.5%)
3.5 (1.2-13)
14 (51.8%)
19 (70.3%)
NR
NR
3 (11.1%)
23 (47.9%)
3.1±1.1
15 (31.3%)
29 (60.4%)
NR
NR
9 (18.7%)
50 (43.9%)
3.51±2.52
39 (34.2%)
63 (55.2%)
6 (5.3%)
36 (31.6%)
23 (20.2%)
NR
2.73
14 (46.6%)
NR
NR
NR
NR
87)
e Zhang 201822
USA
48
2016-2017/
Yes
Retrospectiv
69.6±11. 1
e Yang 201923
USA
114
2016-2018/
Yes
Prospective Wilen 201924a
USA
30
2016-2018/
64.2±15. 1
Yes
NR
Retrospectiv e Data are reported as absolute numbers (percentages) or mean (± standard deviation or with range) Abbreviations: FNA, Fine Needle Aspiration; NR, Not Reported
18
Table 2. Subgroup analysis of sample adequacy. Subgroup analysis was performed based on (1) cyst morphology (unilocular versus septated), (2) cyst size (< 3 cm versus ≥3 cm), and (3) cyst location (head/uncinate versus body/tail). Numbers in parentheses indicate 95% confidence intervals.
Variable
Subgroup
No. of cohorts
No. of patients
Summary estimate (95% CI)
Within-group heterogeneity (I2)
85.8% (72.8%-98.8%) 83.9% (76.3%-91.4%) 85.3% (77.8%-92.7%) 78.5% (70.6%-86.3%) 88.6% (77.3%-99.8%) 82.5% (76.2%-88.8%)
81.04% 0% 15.9% 0% 61.7% 0%
Sample Adequacy Cyst morphology Cyst size Cyst location
Unilocular Septated < 3 cm ≥ 3 cm Head/uncinate Body/tail
Abbreviation: CI, Confidence Interval.
3 3 5 4 3 3
126 91 128 103 73 139
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FIGURE LEGENDS
Figure 1. Flow chart of included studies. Figure 2. Pooled analysis assessing rates of sample adequacy of microforceps biopsy in targeting pancreatic cyst lesions. Sample adequacy in targeting pancreatic cysts was 85.3% (78.2%-92.5%; I2=41.59%).
Figure 3. Meta-analysis comparing rates of sample adequacy between microforceps biopsy and standard fine-needle aspiration (cytology/cyst fluid analysis). Microforceps biopsy (MFB) resulted significantly superior to fine-needle aspiration (FNA) in targeting pancreatic cysts (OR, 4.83; 1.63-14.31, p=0.004; I2=36%).
Figure 4. Pooled analysis assessing rates of diagnostic accuracy of microforceps biopsy in targeting pancreatic cyst lesions. Diagnostic accuracy in targeting pancreatic cysts was 78.8% (73.4%-84.2%; I2=28.36%).
Appendix 1. Details of search strategy
Search ((((endoscopic ultrasound[MeSH Terms]) AND microforceps biopsy) OR biopsy forceps) OR through the needle) AND pancreas cyst[MeSH Terms]
ONLINE SUPPLEMENTARY Tables and Suppl Fig Legends
Supplementary Table 1. Risk of bias assessment and quality of included studies.
Supplementary Table 2. Sensitivity analysis of sample adequacy. Sensitivity analysis was restricted to (1) high quality studies, (2) prospective studies, and (3) full-text articles. Numbers in parentheses indicate 95% confidence intervals.
Variable
Subgroup
No. of Cohorts
No. of patients
Summary Estimate (95% CI)
Within-group 2 heterogeneity (I )
84.5% (79.5%-89.5%) 91.6% (76.1%-100%) 86.1% (78.1%-94.1%)
0% 15.9% 41.7%
Sample Adequacy Study quality Study design Publication
High quality Prospective studies Full-text articles
Abbreviation: CI, Confidence Interval.
3 2 8
202 175 362
Supplementary Table 3. Adverse events reported in the included studies
Study, Year
Adverse events
Basar 2018
Mild pain (1 patient: 2.3%) Mild bleeding (1 patient: 2.3%)
Cheesman 2019
Mild pain (1 patient: 2.4%)
Crinò 2019
Mild pancreatitis (2 patients: 3.3%) Mild bleeding (11 patients: 18%) Mild fever (1 patient: 1.6%)
Kovacevic 2018
Mild pancreatitis (2 patients 7.1%) Mild pain (1 patient: 3.6%)
Samarasena 2019
Mild bleeding (1 patient: 6.6%)
Yang 2019
Mild pancreatitis (6 patients: 4.1%) Mild bleeding (7 patients: 4.8%) Bradycardia (1 patient: 0.7%)
Supplementary Figure 1. Histological core procurement obtained with microforceps biopsy.
Supplementary Figure 2. Forrest plot of direct comparison between microforceps biopsy versus standard fine-needle aspiration in terms of diagnostic accuracy.
Supplementary Figure 3. Forest plot of diagnostic accuracy in the subgroup of patients with surgical confirmation of diagnosis.
Supplementary Figure 4. Number of passes through the cystic lesion needed to obtain adequate samples with microforceps biopsy.
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Facciorusso Antonio DIAGNOSTIC YIELD OF ENDOSCOPIC ULTRASOUND-GUIDED THROUGH-THE-NEEDLE BIOPSY IN PANCREATIC CYSTS: A META-ANALYSIS
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11/05/2019
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DIAGNOSTIC YIELD OF ENDOSCOPIC ULTRASOUND-GUIDED THROUGH-THENEEDLE BIOPSY IN PANCREATIC CYSTS: A META-ANALYSIS Antonio Facciorusso1, Valentina Del Prete1, Matteo Antonino1, Vincenzo Rosario Buccino1, Sachin Wani2 1
Gastroenterology Unit, University of Foggia, Italy; 2 University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
Abbreviations list:
CLE, confocal laser endomicroscopy; EUS, endoscopic ultrasound; FNA, fine needle aspiration; FNB, Fine needle biopsy; IPMNs, Intraductal papillary mucosal neoplasms; PCLs, MCNs, mucinous cystic neoplasms; TTNB, through-the-needle tissue biopsy.
S0016-5107(20)30096-1
DOI:
https://doi.org/10.1016/j.gie.2020.01.038
Reference:
YMGE 11954
To appear in:
Gastrointestinal Endoscopy
Received Date: 5 November 2019 Accepted Date: 22 January 2020
Please cite this article as: Facciorusso A, Del Prete V, Antonino M, Buccino VR, Wani S, Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2020.01.038. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 by the American Society for Gastrointestinal Endoscopy
Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis Antonio Facciorusso, MD, PhD1, Valentina Del Prete, MD1, Matteo Antonino, MD1, Vincenzo Rosario Buccino, MD1, Sachin Wani, MD, PhD2 1
Gastroenterology Unit, University of Foggia, Italy; 2 University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
Short Title: Microforceps biopsy
Correspondence: Antonio Facciorusso Gastroenterology Unit, Department of Medical Sciences University of Foggia AOU Ospedali Riuniti Viale Pinto, 1 71100 Foggia-Italy Fax: 0039 0881733545 Phone: 0039 0881732110 e-mail: [email protected]
Guarantor of the article: Antonio Facciorusso Specific author contributions: Antonio Facciorusso designed the study and performed the statistical analysis; Matteo Antonino, Valentina Del Prete and Vincenzo Rosario Buccino collected the data; Antonio Facciorusso and Sachin Wani revised the manuscript. All the authors approved the final draft submitted.
Conflict of interest: Sachin Wani-Consultant for Boston Scientific, Medtronic, Interpace, Cernostics Disclosures: Sachin Wani-supported by the Department of Medicine Outstanding Early Scholars Program. The other authors do not have financial ties to disclose.
1
Diagnostic yield of EUS-guided through-the-needle biopsy in pancreatic cysts: a meta-analysis Antonio Facciorusso1, Valentina Del Prete1, Matteo Antonino1, Vincenzo Rosario Buccino1, Sachin Wani2 1
Gastroenterology Unit, University of Foggia, Italy; 2 University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
Short Title: Microforceps biopsy
Correspondence: Antonio Facciorusso Gastroenterology Unit, Department of Medical Sciences University of Foggia AOU Ospedali Riuniti Viale Pinto, 1 71100 Foggia-Italy Fax: 0039 0881733545 Phone: 0039 0881732110 e-mail: [email protected]
Guarantor of the article: Antonio Facciorusso Specific author contributions: Antonio Facciorusso designed the study and performed the statistical analysis; Matteo Antonino, Valentina Del Prete and Vincenzo Rosario Buccino collected the data; Antonio Facciorusso and Sachin Wani revised the manuscript. All the authors approved the final draft submitted. Conflict of interest: Sachin Wani-Consultant for Boston Scientific, Medtronic, Interpace, Cernostics Disclosures: Sachin Wani-supported by the Department of Medicine Outstanding Early Scholars Program. The other authors do not have financial ties to disclose.
2
ABSTRACT Background and Aims: There is currently limited evidence supporting the use of endoscopic ultrasound-guided through-the-needle biopsy for sampling pancreatic cystic lesions. The aim of this meta-analysis was to provide a pooled estimate of the diagnostic performance of through-the-needle biopsy for sampling of pancreatic cysts. Methods: A bibliographic search on the main databases was performed through September 2019. Pooled effects were calculated using a random-effects model by means of DerSimonian and Laird test. The primary outcome was sample adequacy. Additional endpoints were diagnostic accuracy, optimal histological core procurement, mean number of needle passes, pooled specificity, and sensitivity. Adverse event rates were also analyzed. Results: Eleven studies enrolling 490 patients were included. Eight articles compared through-theneedle biopsy to cytology/cystic fluid analysis. Most patients were female, and body/tail was the most frequent location of cystic lesions. Sample adequacy with through-the-needle biopsy was 85.3% (78.2%-92.5%) and subanalysis was performed according to cyst morphology, size, and location confirmed the above reported result. Through-the-needle biopsy clearly outperformed fineneedle aspiration both in terms of sample adequacy (odds ratio, 4.83; 95% CI, 1.63-14.31; p=0.004) and diagnostic accuracy (odds ratio, 3.44; 95% CI, 1.32-8.96; p=0.01). Pooled diagnostic accuracy rate, sensitivity and specificity of through-the-needle biopsy were 78.8%, 82.2%, and 96.8%, respectively. A mean of 3.121 (2.98-3.25) passes through the cyst was needed to obtain adequate histological samples. The incidence rates of mild bleeding and pancreatitis were 4% and 2%, respectively. Conclusion: Our meta-analysis speaks in favor of the use of through-the-needle biopsy as a safe and effective tool in EUS-guided tissue acquisition of pancreatic cysts.
Key words: EUS; microforceps; pancreas; sensitivity; accuracy.
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INTRODUCTION Pancreatic cystic lesions (PCLs) are increasingly diagnosed in clinical practice due to the increase of the average lifespan in the general population and the improvement in diagnostic tools. A pancreatic cyst is incidentally diagnosed in up to 20% of patients undergoing routine abdominal imaging1,2. As several kinds of PCLs at different risk of malignancy are described, the exact diagnostic characterization of the lesion is of paramount importance for the adequate management of these patients. In particular mucinous cysts, including intraductal papillary mucosal neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), constitute the most frequent premalignant lesions3. Although endoscopic ultrasound (EUS) plays a pivotal role in distinguishing different kinds of PCLs, simple morphological characterization of the lesion is not sufficient to draw definitive conclusions on the exact diagnosis and the relevant risk of malignancy; therefore, EUS-guided fineneedle aspiration (FNA) through the use of 19-gauge or 22-gauge FNA needles is commonly used in order to collect adequate samples for cytology and cystic fluid analysis4. Despite the large experience based on CEA or amylase concentration or the evaluation of the presence of mucus in the cystic fluid, none of these methods was proved to be able to accurately discriminate the type of lesion and the risk of malignancy5-7. In particular, the relatively low sensitivity, reported to be as high as 54% in differentiating mucinous from nonmucinous cysts5,8, represents a major drawback of standard FNA. Despite the encouraging results observed with cyst fluid molecular analysis9 and with novel devices such as confocal laser endomicroscopy (CLE)10, the high costs and the limited experience make these techniques a “niche” diagnostic tool not available worldwide.
4
Recently, a through-the-needle microforceps biopsy (TTNB) device (Moray Microforceps, US Endoscopy, Mentor, Ohio, USA) that can be passed through a standard 19-gauge EUS-FNA needle was developed for histologic sampling of PCLs. There is currently limited evidence supporting the use of TTNB for sampling PCLs, and the recent guidelines mention microforceps biopsy as a promising tool but not include any specific statements concerning its use in the clinical practice due to the limited number and the low quality of available studies11. Since the release of the latest guidelines, several observational studies testing TTNB have been published, hence the pressing need to systematically assess the increasing body of evidence in the field in order to better define the role and safety of this novel device in the endoscopic practice. The aim of this meta-analysis was to provide a pooled estimate of the diagnostic performance and safety profile of through-the-needle microforceps biopsy for sampling of PCLs, thus attempting to determine its comparative efficacy with respect to standard FNA. The primary outcome was sample adequacy. Additional endpoints were diagnostic accuracy, optimal histological core procurement, mean number of needle passes, pooled specificity and sensitivity. Safety data were also analyzed.
MATERIALS AND METHODS
Inclusion and exclusion criteria The literature search strategy was based on the following inclusion criteria: (1) articles enrolling patients undergoing EUS-guided tissue acquisition of PCLs with TTNB; (2) studies published in English; (3) articles reporting sample adequacy or diagnostic accuracy. Small case series, nonendoscopic studies, review articles, and animal models were excluded.
Search strategy
5
Literature search was conducted on PubMed, EMBASE, Cochrane Library, and Google Scholar including all studies fulfilling the inclusion criteria published through September 2019 (Appendix 1). Relevant reviews and meta-analyses on tissue sampling of PCLs were examined for potential suitable studies. Authors of included studies were contacted to obtain full text or further information when needed. Data extraction was performed by 2 authors (A.F. and V.D.P.) using a standardized approach (PRISMA Statement)12. The quality of included studies was rated by 2 reviewers independently (A.F., V.D.P.) based on the Newcastle-Ottawa scale13 for nonrandomized studies. Disagreements were solved by discussion and after a third opinion (V.R.B.).
Outcomes Primary endpoint was sample adequacy, defined as the ability to achieve tissue samples adequate for diagnosis; additional endpoints were diagnostic accuracy, defined as the ability to diagnose the exact kind of PCL (true positive + true negative/ total number of patients); procurement rate of optimal core histological tissue, defined as samples with high cellularity and quality enabling appropriate core assessment in terms of tissue architecture; specificity (true negative/ true negative + false positive), sensitivity (true positive/ true positive + false negative), number of needle passes, and adverse events.
Statistical analysis Study outcomes were pooled through a random-effects model based on DerSimonian and Laird test, and results were expressed as rates and 95% confidence interval (CI). Comparison between TTNB and FNA was based on a random-effects model.
6
The presence of heterogeneity was calculated through I² tests with I²<20% interpreted as low-level heterogeneity. Any potential publication bias was verified through visual assessment of funnel plots. The rates of adverse events, in particular bleeding and pancreatitis, were also pooled. Sensitivity analysis was conducted restricted to (1) high quality studies, (2) prospective studies, and (3) fulltext articles. Subgroup analysis of the primary outcome (sample adequacy) was performed based on (1) cyst morphology (unilocular versus septated), (2) cyst size (< 3 cm versus ≥3 cm), and (3) cyst location (head/uncinate versus body/tail). A further subgroup analysis of diagnostic accuracy was conducted in those patients with surgical confirmation of the diagnosis. All statistical analyses were conducted using RevMan version 5 from the Cochrane collaboration and OpenMeta[Analyst] software. For all calculations a 2-tailed P value of less than 0.05 was considered statistically significant.
RESULTS
Characteristics of included studies As described in Figure 1, out of 645 studies initially screened, 28 relevant articles potentially fulfilling the inclusion criteria were examined. Among these studies, 17 were excluded because they were duplicate overlapping series or case series enrolling < 10 patients. Finally, 11 studies14-24 with 490 patients were included in the meta-analysis. The main characteristics of included studies are reported in Table 1. The recruitment period ranged from 2013 to 2018. Eight articles compared TTNB with FNA/cystic fluid analysis14-16,18,19,22-24, of which 2 prospective16,23. Three articles were published as conference proceedings15,19,24.
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Most patients were female, and body/tail was the most frequent location of PCLs. Mucinous cysts were prevalent in most of the included studies. Quality was deemed mainly moderate/high with only 4 studies assessed as low-quality articles15,17,19,24. Details on methodological characteristics and quality of included articles are shown in Supplementary Table 1.
Sample adequacy As reported in Figure 2, per-patient analysis of overall sample adequacy showed rates of adequate samples for diagnosis of 85.3% (78.2%-92.5%; I2=41.5%) with TTNB. Subanalysis performed according to cyst morphology (unilocular versus septated), size (<3 cm versus ≥3 cm), and location (head/uncinate versus body/tail) confirmed the above reported results, with rates of sample adequacy ranging from 78.5% to 88.6% (Table 2). The findings of the main analysis were confirmed in sensitivity analysis restricted to full-text articles and high-quality studies (Supplementary Table 2). Of note, sensitivity analysis restricted to the 2 prospective studies16,23 showed a high rate of sample adequacy (91.6%, 76.1%-100%; Supplementary Table 2). There was no evidence of publication bias. As depicted in Figure 3, a total of 7 studies14-16,18,22-24 directly compared TTNB with standard FNA, showing a clear advantage in terms of sample adequacy with TTNB (OR, 4.83; 95% CI, 1.6314.31; p=0.004 and I2 =36%). Of note, the study by Robles-Medranda et al19 was excluded from the analysis due to the lack of comparative data and because the rates of sample adequacy were not reported.
Optimal histologic core procurement, diagnostic accuracy, sensitivity and specificity The rate of histological optimal core procurement obtained with TTNB was reported to be as high as 80% (73.1%-86.9%; I2=49.7%) in a pooled analysis of 7 studies14,17,18,20,21,23,24 (Supplementary Figure 1).
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A pooled analysis of 8 studies14,15,17-21,23 found an overall diagnostic accuracy rate of 78.8% (73.4%-84.2%; I2=28.36%). Moderate evidence of heterogeneity was reported and no risk of publication bias was detected (Figure 4). Three studies14,15,18 compared diagnostic accuracy rate between TTNB and FNA. As reported in Supplementary Figure 2, TTNB clearly overperformed FNA (OR, 3.44; 95% CI, 1.32-8.96; p=0.01), with moderate evidence of heterogeneity (I2=41%). Subgroup analysis restricted to 59 patients with surgical confirmation of the diagnosis showed a diagnostic accuracy rate of 88.3% (80.1%-96.5%; I2=0%; Supplementary Figure 3). Based on three studies18,19,23 reporting diagnostic sensitivity (or data useful for its calculation), pooled sensitivity of TTNB was 82.2% (74.1%-90.2%) and pooled specificity was 96.8% (91.5%100%; data not shown).
Number of passes and adverse events Pooled analysis of number of needle passes through the cyst needed to achieve adequate samples is reported in Supplementary Figure 4. A mean of 3.121 (2.98-3.25) passes of microforceps biopsy through the cyst was needed to obtain adequate histological samples (I2=16.46%, Supplementary Figure 4). Details on the adverse events registered in the included studies are reported in Supplementary Table 3. Out of 490 patients recruited in the included studies, 20 subjects experienced mild bleeding (4%) and 10 (2%) mild pancreatitis. Of note, all of these adverse events were mild and did not impact on patient outcomes.
DISCUSSION
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Obtaining adequate cytological samples of PCLs is challenging as current techniques based on FNA are affected by relatively low sensitivity mainly due to the high rates of false negative or inadequate specimens. Fine-needle biopsy (FNB) of the cyst wall provided interesting results in presence of intramural nodules, but the diagnostic sensitivity of reverse-bevel FNB was disappointing in PCLs without solid components25. In fact, an Italian series reported rates of sample adequacy below 40% in patients without solid components in the PCL, very similar to cytology of cystic fluid25. Therefore, no more studies on FNB have been published and in recent years, new techniques have been studied and developed to increase diagnostic power in PCLs. The main advantage of TTNB is to obtain adequate specimens retaining the stroma covered with the epithelial lining and, therefore, to preserve the histological architecture of the sampled tissue. These aspects allow ancillary techniques such as immunohistochemistry both on epithelium and on the stroma, thus improving the diagnostic and prognostic value of the technique26. Moreover, TTNB allows collecting adequate volumes of cystic fluid for either biochemical and molecular biology analysis and for cytology, which can be associated with histology to improve diagnosis, as reported in several series18,23. Given the increasing body of evidence concerning the use of TTNB, there is a clear need to systematically evaluate the impact of this newer sampling technique in the clinical practice. Through a meta-analysis of 11 studies assessing the diagnostic yield of TTNB in PCLs (alone or in comparison to standard FNA), we made several key observations. First, overall sample adequacy rate with TTNB was 85.3%, with diagnostic accuracy and sensitivity of 78.8% and 82.2%, respectively. These findings represent a striking result considering that current techniques (FNA with cystic fluid analysis) showed median diagnostic accuracy and sensitivity values of less than 50%26. Furthermore, the diagnostic performance of standard FNA is highly influenced by the presence of an expert pancreatic cytologist, who is not available in many centers. The TTNB technique may obviate to these problems by providing histological samples of the cyst wall
10
including both the epithelium and the stroma, an aspect particularly important in mucinous neoplasms characterized by the presence of an ovarian-like stroma27,28. Hence the capability of discriminating among different kinds of PCLs even in absence of an expert pathologist. As a result of the aforementioned findings, TTNB clearly outperformed standard FNA in comparative pairwise meta-analysis, showing a clear advantage in terms of sample adequacy (OR, 4.83; 95% CI, 1.6314.31; p=0.004) and diagnostic accuracy (OR, 3.44; 95% CI, 1.32-8.96; p=0.01). Second, the diagnostic performance of TTNB was confirmed in subanalysis performed according to cyst morphology (unilocular versus septated), size (<3 cm versus ≥3 cm), and location (head/uncinate versus body/tail). These results further support the wide use of TTNB in the endoscopic practice. Third, a mean of 3.121 (2.98-3.25) passes of microforceps biopsy through the cyst was found to be needed to obtain adequate histological samples, mainly due to the need to sample different components of the cyst wall. Finally, the TTNB technique resulted relatively safe although 4% of enrolled patients experienced mild bleeding and 2% pancreatitis; of note, these adverse events were mild and did not influence significantly the clinical course of the patients. In spite of the undoubted advantages of TTNB in comparison to FNA, diagnostic accuracy and sensitivity are still considerably inferior to solid pancreatic masses29-31. In fact, it is possible to sample only the opposite wall of the PCL with respect to the point of entrance of the needle and due to the uneven distribution of dysplasia inside the PCLs, there is a considerable risk of underestimate the real grade of dysplasia inside the cyst26. Moreover, some PCLs might have the so-called “denuded epithelium,”32 thus making difficult to obtain adequate specimens even with a high number of passes. Among the weaknesses of our study, the lack of randomized studies did not allow a robust comparison between TTNB and standard FNA, thus calling for a particular note of caution when interpreting our comparative findings. It should be noted that the FNA/cytology group did not include any fine-needle core biopsy results and a comparison with FNB needles was not feasible
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due to the lack of available studies. Second, as only a minor part of the patients enrolled in the included studies finally underwent surgery, diagnostic accuracy analysis might be biased by the lack of histological diagnosis on the surgical specimens. In conclusion, despite these limitations, our meta-analysis speaks in favor of the use of TTNB as a safe and effective tool in EUS-guided tissue acquisition of PCLs. Being able to accurately discriminate among different kinds of cysts and to identify more lesions with advanced neoplasia, TTNB may be considered a helpful adjunct tool in the evaluation of PCLs. Large RCTs and prospective studies are needed in order to confirm these promising results.
REFERENCES [1] Farrell JJ, Fernández-del Castillo C. Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology. 2013;144:1303–1315. [2] F Stark A, Donahue TR, Reber HA, et al. Pancreatic Cyst Disease: A Review. JAMA. 2016;315:1882–1893. [3] Fernández-del Castillo C, Adsay NV. Intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2010;139:708–713, 713.e1-713.e2 [4] van Riet PA, Cahen DL, Poley JW, et al. Mapping international practice patterns in EUSguided tissue sampling: outcome of a global survey. Endosc Int Open 2016;4: E360 – 70 [5] Thornton GD, McPhail MJ, Nayagam S, et al. Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis. Pancreatology 2013;13:48–57. [6] van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. GastrointestEndosc 2005;62:383– 9.
12
[7] Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330–6. [8] de Jong K, Poley JW, van Hooft JE, et al. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides inadequate material for cytology and laboratory analysis: initial results from a prospective study. Endoscopy. 2011;43:585-90. [9] Singhi AD, McGrath K, Brand RE, et al. Pre-operative next-generation sequencing of pancreatic cyst fluid is highlyaccurate in cyst classification and detection of advanced neoplasia. Gut. 2018;67:2131-2141 [10]
Anand K, Kahaleh M, Tyberg A. Use of needle-based confocal laser
endomicroscopy in the diagnosis and management of pancreatic cyst lesions. Endosc Ultrasound. 2018;7:306-309 [11]
Dumonceau JM, Deprez PH, Jenssen C, et al. Indications, results, and clinical impact
of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline - Updated January 2017. Endoscopy. 2017;49:695-714. [12]
Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic
reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336-341 [13]
Wells GA , Shea B , O’Connell D, et al. The Newcastle – Ottawa Scale (NOS) for
assessing the quality of nonrandomised studies in meta-analyses; available from: http://www.ohri.ca/programs/ clinical_epidemiology/oxford.htm , accessed on September 2019. [14]
Basar O, Yuksel O, Yang DJ, et al. Feasibility and safety of microforceps biopsy in
the diagnosis of pancreatic cysts. Gastrointest Endosc. 2018;88:79-86.
13
[15]
Cheesman AR, Zhu H, Kumta NA, et al. Eus-guided microforceps biopsy and
needle-based confocal laser endomicroscopy significantly improve the diagnostic yield and have major impact on clinical management of pancreatic cystic lesions [abstract]. Gastrointest Endosc 2019, 89: AB144 [16]
Crinò SF, Bernardoni L, Brozzi L, et al. Association between macroscopically
visible tissue samples and diagnostic accuracy of EUS-guided through-the-needle microforceps biopsy sampling of pancreatic cystic lesions. Gastrointest Endosc. 2019, in press [17]
Kovacevic B, Karstensen JG, Havre RF, et al. Initial experience with EUS-guided
microbiopsy forceps in diagnosing pancreatic cystic lesions: A multicenter feasibility study (with video). Endosc Ultrasound. 2018;7:383-388 [18]
Mittal C, Obuch JC, Hammad H, et al. Technical feasibility, diagnostic yield, and
safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video). Gastrointest Endosc. 2018;87:1263-1269. [19]
Robles-Medranda C, Olmos JI, et al. Eus-through-the-needle technologies in the
diagnosis and malignancy detection of pancreatic cysts: a comparative study between different technologies [abstract]. Gastrointest Endosc 2019; 89: AB608-9 [20]
Samarasena J, Yu A, Lee D, et al. EUS-guided through-the-needle biopsy for
pancreatic cystic lesions. VideoGIE. 2019;4:436-439 [21]
Vestrup Rift C, Melchior LC, Kovacevic B, et al. Next-generation sequencing of
endoscopic
ultrasound
guided
microbiopsies
from
pancreatic
cystic
neoplasms.
Histopathology. 2019, in press. [22]
Zhang ML, Arpin RN, Brugge WR, et al. Moray micro forceps biopsy improves the
diagnosis of specific pancreatic cysts. Cancer Cytopathol. 2018 ;126:414-420.
14
[23]
Yang D, Trindade AJ, Yachimski P, et al. Histologic Analysis of Endoscopic
Ultrasound-Guided Through the Needle Microforceps Biopsies Accurately Identifies Mucinous Pancreas Cysts. Clin Gastroenterol Hepatol. 2019 ;17:1587-1596 [24]
Wilen J, Visrodia K, Lan G, et al. The feasibility and value of cyst wall biopsy using
micro forceps in the diagnosis of pancreatic cysts [abstract]. Gastrointest Endosc 2019; 89:AB605. [25]
Barresi L, Tarantino I, Traina M, et al. Endoscopic ultrasound-guided fine needle
aspiration and biopsy using a 22-gauge needle with side fenestration in pancreatic cystic lesions. Dig Liver Dis 2014;46:45–50. [26]
Barresi L, Tacelli M, Ligresti D, et al.
Tissue acquisition in pancreatic cystic
lesions. Dig Liver Dis. 2019 ;51:286-292 [27]
Crinò SF, Bernardoni L, Gabbrielli A, et al. Beyond pancreatic cyst epithelium:
evidence of ovarian-like stroma in eus-guided through the-needle micro-forceps biopsy specimens. Am J Gastroenterol 2018;113:1059-60. [28]
Barresi L, Tacelli M, Chiarello G, et al. Mucinous cystic neoplasia with denuded
epithelium: EUS through-the-needle biopsy diagnosis. Gastrointest Endosc 2018;88:771-4. [29]
Facciorusso A, Wani S, Triantafyllou K, et al. Comparative accuracy of needle sizes
and designs for EUS tissue sampling of solid pancreatic masses: a network meta-analysis. Gastrointest Endosc. 2019, in press [30]
Facciorusso A, Bajwa HS, Menon K, et al. Comparison between 22G aspiration and
22G biopsy needles for EUS-guided sampling of pancreatic lesions: A meta-analysis. Endosc Ultrasound. 2019, in press [31]
Facciorusso A, Stasi E, Di Maso M, et al. Endoscopic ultrasound-guided fine needle
aspiration of pancreatic lesions with 22 versus 25 Gauge needles: A meta-analysis. United European Gastroenterol J. 2017;5:846-853
15
[32]
Gómez V, Majumder S, Smyrk TC, et al. Pancreatic cyst epithelial denudation: a
natural phenomenon in the absence of treatment. Gastrointest Endosc 2016;84:788–93.
16
Table 1. Characteristics of included studies
Study
Country
Sample size
Study period/ design
FNA cytology/cys t fluid analysis
Age
Gender male
Lesion size (cm)
Location (head/uncinate)
Diagnosis of mucinous cysts
Intramura l nodules
Septations
Basar 201814
USA
42
2015-2016/
Yes
69 (27-
19 (45.2%)
2.82 (1.2-6)
16 (38.1%)
NR
4 (9.6%)
25 (60%)
Number of patients with surgical confirmation of diagnosis 7 (17%)
91) Retrospectiv e Cheesman 2019
USA
41
NR/
Yes
66
15 (36.6%)
3.7 (1.6-5)
12 (29.3%)
NR
8 (19.5%)
21 (51.2%)
13 (31.7%)
Yes
50.2±14.
14 (22.9%)
4.07±1.42
18 (29.5%)
16 (26.2%)
NR
27 (44.3%)
20 (32.7%)
13 (46.4%)
3 (2.2-4.75)
12 (42.9%)
NR
NR
NR
NR
11 (40.7%)
3.78±1.69
14 (52%)
13 (48.1%)
1 (3.7%)
NR
NR
11 (29.8%)
NR
15 (42.6%)
34 (95.7%)
NR
NR
NR
15a
Retrospectiv e Crinò 2019
16
Italy
61
2016-2018/
7 Prospective Kovacevic 2018
17
Multicen
28
NR/
No
65.5±11. 8
ter Retrospectiv e
Mittal 2018
18
USA
27
2016-2017/
Yes
Retrospectiv
65 (3287)
e RoblesMedranda 2019
19a
Ecuador
36
2013-2018/ Retrospectiv e
Yes
64 (2494)
17 Samarasena
USA
15
NR/
No
201920
67 (54-
7 (46.6%)
80)
2.5 (0.48-
8 (53.3%)
8 (53.3%)
NR
NR
NR
3.9)
Retrospectiv e Vestrup Rift 2019
Denmark
27
21
2016-2017/
No
Retrospectiv
70.9 (40-
15 (55.5%)
3.5 (1.2-13)
14 (51.8%)
19 (70.3%)
NR
NR
3 (11.1%)
23 (47.9%)
3.1±1.1
15 (31.3%)
29 (60.4%)
NR
NR
9 (18.7%)
50 (43.9%)
3.51±2.52
39 (34.2%)
63 (55.2%)
6 (5.3%)
36 (31.6%)
23 (20.2%)
NR
2.73
14 (46.6%)
NR
NR
NR
NR
87)
e Zhang 201822
USA
48
2016-2017/
Yes
Retrospectiv
69.6±11. 1
e Yang 201923
USA
114
2016-2018/
Yes
Prospective Wilen 201924a
USA
30
2016-2018/
64.2±15. 1
Yes
NR
Retrospectiv e Data are reported as absolute numbers (percentages) or mean (± standard deviation or with range) Abbreviations: FNA, Fine Needle Aspiration; NR, Not Reported
18
Table 2. Subgroup analysis of sample adequacy. Subgroup analysis was performed based on (1) cyst morphology (unilocular versus septated), (2) cyst size (< 3 cm versus ≥3 cm), and (3) cyst location (head/uncinate versus body/tail). Numbers in parentheses indicate 95% confidence intervals.
Variable
Subgroup
No. of cohorts
No. of patients
Summary estimate (95% CI)
Within-group heterogeneity (I2)
85.8% (72.8%-98.8%) 83.9% (76.3%-91.4%) 85.3% (77.8%-92.7%) 78.5% (70.6%-86.3%) 88.6% (77.3%-99.8%) 82.5% (76.2%-88.8%)
81.04% 0% 15.9% 0% 61.7% 0%
Sample Adequacy Cyst morphology Cyst size Cyst location
Unilocular Septated < 3 cm ≥ 3 cm Head/uncinate Body/tail
Abbreviation: CI, Confidence Interval.
3 3 5 4 3 3
126 91 128 103 73 139
19
FIGURE LEGENDS
Figure 1. Flow chart of included studies. Figure 2. Pooled analysis assessing rates of sample adequacy of microforceps biopsy in targeting pancreatic cyst lesions. Sample adequacy in targeting pancreatic cysts was 85.3% (78.2%-92.5%; I2=41.59%).
Figure 3. Meta-analysis comparing rates of sample adequacy between microforceps biopsy and standard fine-needle aspiration (cytology/cyst fluid analysis). Microforceps biopsy (MFB) resulted significantly superior to fine-needle aspiration (FNA) in targeting pancreatic cysts (OR, 4.83; 1.63-14.31, p=0.004; I2=36%).
Figure 4. Pooled analysis assessing rates of diagnostic accuracy of microforceps biopsy in targeting pancreatic cyst lesions. Diagnostic accuracy in targeting pancreatic cysts was 78.8% (73.4%-84.2%; I2=28.36%).
Appendix 1. Details of search strategy
Search ((((endoscopic ultrasound[MeSH Terms]) AND microforceps biopsy) OR biopsy forceps) OR through the needle) AND pancreas cyst[MeSH Terms]
ONLINE SUPPLEMENTARY Tables and Suppl Fig Legends
Supplementary Table 1. Risk of bias assessment and quality of included studies.
Supplementary Table 2. Sensitivity analysis of sample adequacy. Sensitivity analysis was restricted to (1) high quality studies, (2) prospective studies, and (3) full-text articles. Numbers in parentheses indicate 95% confidence intervals.
Variable
Subgroup
No. of Cohorts
No. of patients
Summary Estimate (95% CI)
Within-group 2 heterogeneity (I )
84.5% (79.5%-89.5%) 91.6% (76.1%-100%) 86.1% (78.1%-94.1%)
0% 15.9% 41.7%
Sample Adequacy Study quality Study design Publication
High quality Prospective studies Full-text articles
Abbreviation: CI, Confidence Interval.
3 2 8
202 175 362
Supplementary Table 3. Adverse events reported in the included studies
Study, Year
Adverse events
Basar 2018
Mild pain (1 patient: 2.3%) Mild bleeding (1 patient: 2.3%)
Cheesman 2019
Mild pain (1 patient: 2.4%)
Crinò 2019
Mild pancreatitis (2 patients: 3.3%) Mild bleeding (11 patients: 18%) Mild fever (1 patient: 1.6%)
Kovacevic 2018
Mild pancreatitis (2 patients 7.1%) Mild pain (1 patient: 3.6%)
Samarasena 2019
Mild bleeding (1 patient: 6.6%)
Yang 2019
Mild pancreatitis (6 patients: 4.1%) Mild bleeding (7 patients: 4.8%) Bradycardia (1 patient: 0.7%)
Supplementary Figure 1. Histological core procurement obtained with microforceps biopsy.
Supplementary Figure 2. Forrest plot of direct comparison between microforceps biopsy versus standard fine-needle aspiration in terms of diagnostic accuracy.
Supplementary Figure 3. Forest plot of diagnostic accuracy in the subgroup of patients with surgical confirmation of diagnosis.
Supplementary Figure 4. Number of passes through the cystic lesion needed to obtain adequate samples with microforceps biopsy.
Journal CME Conflict of Interest: Disclosure and Attestation Lead Author: Article:
Facciorusso Antonio DIAGNOSTIC YIELD OF ENDOSCOPIC ULTRASOUND-GUIDED THROUGH-THE-NEEDLE BIOPSY IN PANCREATIC CYSTS: A META-ANALYSIS
Date:
11/05/2019
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DIAGNOSTIC YIELD OF ENDOSCOPIC ULTRASOUND-GUIDED THROUGH-THENEEDLE BIOPSY IN PANCREATIC CYSTS: A META-ANALYSIS Antonio Facciorusso1, Valentina Del Prete1, Matteo Antonino1, Vincenzo Rosario Buccino1, Sachin Wani2 1
Gastroenterology Unit, University of Foggia, Italy; 2 University of Colorado Anschutz Medical Campus, Aurora, Colorado, U.S.A
Abbreviations list:
CLE, confocal laser endomicroscopy; EUS, endoscopic ultrasound; FNA, fine needle aspiration; FNB, Fine needle biopsy; IPMNs, Intraductal papillary mucosal neoplasms; PCLs, MCNs, mucinous cystic neoplasms; TTNB, through-the-needle tissue biopsy.