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Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis
Journal Pre-proof Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis Dr. Andrea Lisotti, Dr. Leonardo Frazzoni, Lorenzo Fuccio, Prof., Dr. Marta Serrani, Dr. Anna Cominardi, Franco Bazzoli, Prof., Pietro Fusaroli, Prof. PII:
S0016-5107(20)30092-4
DOI:
https://doi.org/10.1016/j.gie.2020.01.034
Reference:
YMGE 11950
To appear in:
Gastrointestinal Endoscopy
Received Date: 24 August 2019 Accepted Date: 20 January 2020
Please cite this article as: Lisotti A, Frazzoni L, Fuccio L, Serrani M, Cominardi A, Bazzoli F, Fusaroli P, Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2020.01.034. 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
Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis
Authors: Dr. Andrea Lisotti1, Dr. Leonardo Frazzoni2(first co-authors), Prof. Lorenzo Fuccio2, Dr. Marta Serrani1, Dr. Anna Cominardi1, Prof. Franco Bazzoli2, and Prof. Pietro Fusaroli1 Affiliations: 1
Gastroenterology Unit, Hospital of Imola, Department of Medical and Surgical Sciences,
University of Bologna, Italy. 2
Gastroenterology Unit, Sant’Orsola Hospital, Department of Medical and Surgical Sciences,
University of Bologna, Italy.
Correspondence to: Dott. Andrea Lisotti, MD Gastroenterology Unit, Hospital of Imola. Department of Medical and Surgical Sciences, University of Bologna, Italy Via Montericco 4; 40026 Imola (BO), Italy. E-mail: [email protected] Authors' contributions A.L. and Le.Fr. Contributed equally to the work; A.L. and P.F. designed the study, collected data and drafted the article; A.L., Le.Fr. And Lo.Fu. analyzed the data; A.C., M.S. and F.B. revised the manuscript for pivotal intellectual content. All Authors approved the final version of the manuscript.
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Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis Short title: Repeated EUS-FNA after inconclusive results Authors: Andrea Lisotti1, Leonardo Frazzoni2 (first co-authors), Lorenzo Fuccio2, Marta Serrani1, Anna Cominardi1, Franco Bazzoli2, and Pietro Fusaroli1 Affiliations: 1
Gastroenterology Unit, Hospital of Imola, Department of Medical and Surgical Sciences,
University of Bologna, Italy. 2
Gastroenterology Unit, Sant’Orsola Hospital, Department of Medical and Surgical Sciences,
University of Bologna, Italy. Grant support The Authors received no support or funding for this study. List of Abbreviations: EUS: endoscopic ultrasound; FP: false positive; FN: false negative; NPV: negative predictive value; PC: pancreatic carcinoma; PPV: positive predictive value; rEUS-FNA: repeat EUS-FNA; ROSE: role of rapid on-site evaluation; SROC: summary receiving operating characteristic; TN: true negative; TP: true positive.
Correspondence to: Dott. Andrea Lisotti, MD Gastroenterology Unit, Hospital of Imola. Department of Medical and Surgical Sciences, University of Bologna, Italy Via Montericco 4; 40026 Imola (BO), Italy. E-mail: [email protected] Conflict of interest: The Authors declare no conflict of interest. Writing assistance: 1
No writing assistance was required to draft the manuscript Authors' contributions A.L. and Le.Fr. Contributed equally to the work; A.L. and P.F. designed the study, collected data and drafted the article; A.L., Le.Fr. And Lo.Fu. analyzed the data; A.C., M.S. and F.B. revised the manuscript for pivotal intellectual content. All Authors approved the final version of the manuscript.
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Abstract Background and Aims: EUS-guided fine-needle aspiration (EUS-FNA) is the criterion standard for the diagnosis of solid pancreatic lesions. Several studies assessed the role of repeat EUS-FNA (rEUS-FNA) after an inconclusive examination. Our aim was to evaluate the pooled diagnostic accuracy of rEUS-FNA after nondiagnostic result. Methods: We conducted systematic research on electronic databases (MEDLINE, PubMed, EMBASE) and meta-analysis to obtain pooled sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. Summary ROC curve was used to calculate area under the curve. Subgroup analysis was used to assess the role of rapid on-site evaluation (ROSE). Results: Twelve studies (505 patients) were included. Sensitivity was 77% (66%–86%) and specificity 98% (78%–100%); positive and negative predictive values were 99% (98%-100%) and 61 (60%-63%), respectively. At 73% of disease prevalence (pre-test probability), positive rEUS-FNA increased the disease probability to 99%, whereas negative result decreased the disease probability to 39%. The sensitivity was 83% (64%-93%) and specificity 98% (80%-100%) when ROSE was available and 65% (57%-73%) and 94% (31%-100%) when not available. The number-neededto-diagnose was 1.2 (1.1-2.3) and 1.7 (1.4-8.3) in ROSE+ and ROSE- cases, respectively. The number of correctly diagnosed cases increased from 6 (1-7) to 8 (4-9) out of 10 patients without and with ROSE, respectively. Conclusions: This study objectively substantiated the added value of rEUS-FNA for the diagnosis of solid pancreatic masses, in case of a previous nondiagnostic or inconclusive result. Moreover, our data suggested that ROSE may be beneficial in this setting, as it increased the proportion of definitive diagnoses.
Keywords: pancreatic cancer; pancreatic ductal adenocarcinoma; PDAC; EUS-FNA; EUS-FNB; EUStissue acquisition.
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Introduction EUS has a pivotal role in the management of pancreatic cancer (PC) that is one of the most lethal neoplasm with a 5-year survival that has not significantly increased over the last decades [1-4]. In this setting, EUS was demonstrated to be accurate for detection even of small lesions, for local staging and for tissue sampling [5,6]. EUS-guided tissue sampling is indicated in all patients with borderline-resectable, unresectable, or metastatic PC, although its role in resectable masses is still debated but nevertheless often required, based on local multidisciplinary team consensus [3,4]. Along with EUS-guided fine-needle aspiration (EUS-FNA), which has represented the standard approach for several years, EUS-fine-needle biopsy (EUS-FNB) has emerged as the technique of choice for pathological characterization of solid pancreatic tumors, showing optimal positive predictive value (PPV), with fair negative predictive value (NPV). Meta-analysis in this setting reported pooled sensitivity ranging from 85% to 89% with a pooled specificity up to 100% [7-9]. Several studies aimed to identify factors related to nondiagnostic or false-negative EUS-FNA, and to improve its diagnostic yield using different needle gauge and tissue acquisition techniques (eg, fanning, suction or stylet use). Moreover, the presence of a pathologist for rapid on-side evaluation (ROSE) has been advocated to increase EUS-FNA accuracy, although mixed results are available in this regard [10-12]. Last, there is preliminary evidence showing that EUS image enhancement techniques such as contrast-enhanced harmonic and elastography might increase the diagnostic yield of EUS-FNA by allowing to target the needle away from necrotic areas [13]. Despite all the technical improvements, a not-negligible risk of false negative or inconclusive results with EUS-guided tissue sampling still exists. In such cases, major guidelines recommend repeating EUS-guided tissue sampling [4]. The value of repeated EUS-FNA (rEUS-FNA) after an initial negative examination was investigated by different studies, reporting sensitivity for the diagnosis of malignancy in the range 35% to 100% [8].
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The aim of this study was to evaluate the pooled diagnostic sensitivity and specificity of rEUS-FNA for the diagnosis of solid pancreatic masses after an initial nondiagnostic or inconclusive EUS-FNA.
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Methods Search strategy and study selection We conducted a comprehensive systematic review of English-language articles up to January 31, 2019 through MEDLINE using PubMed, EMBASE, SCOPUS, the Cochrane Central register and Google Scholar interfaces (see Appendix 1). Additionally, the bibliography of retrieved articles and reviews was manually analyzed to find other additional eligible studies that eluded the primary search.
Study selection Original studies (randomized controlled trials, prospective studies and retrospective studies) designed to evaluate the diagnostic accuracy of rEUS-FNA after previous nondiagnostic or inconclusive result in solid pancreatic masses were included; only studies with sufficient data for identification of true positive (TP), false positive (FP), false negative (FN), and true negative (TN) cases were considered. Only full-text articles were included. Studies were excluded in case of unavailable, incomplete, duplicated or updated data, or in case of case report or case series enrolling <10 patients. Data extraction and quality assessment Two physicians independently recorded the following data: first author, affiliation, country of origin, year of publication, study design, number of centers involved in the study, type of needle (FNA vs FNB), presence of rapid on-site evaluation (ROSE), and number of included cases, patients’ age and gender, prevalence of malignant masses. In case of missing data, the number of TP, FP, FN and TN cases was extracted from reported data; an email to the corresponding manuscripts’ authors was sent to confirm the results. Disagreements during data extraction were resolved through discussion among all authors. Qualitative assessment and evaluation of potential bias were performed according to the Quality 6
Assessment of Diagnostic Accuracy Studies (QUADAS-2) system, based on 4 domains: patient selection, index tests, reference standard, and flow-and-timing [14].
Statistical analysis We computed sensitivity and specificity with 95% confidence interval (95% CI) by means of 2 X 2 tables for each study and depicted them in coupled forest plots. Summary estimates of sensitivity, specificity, positive and negative likelihood ratio were computed by applying a bivariate, mixedeffects regression model. A summary receiving operating characteristic (SROC) curve was built [15,16]. Based on 95%CI of the pooled prevalence of solid pancreatic malignancies (ie, pre-test probability), unconditional negative and positive predictive values were computed [17]. The clinical utility of the rEUS-FNA was evaluated using the likelihood ratios to (1) calculate post-test probability based on Bayes’ theorem, and graphically depicted with Fagan’s nomograms [18]; (2) build a likelihood ratio scattergram, defining quadrants of test informativeness [19]. Heterogeneity between studies was assessed through visual examination of the forest plot and SROC curve, and by Higgins’ I2 index. In order to find possible sources of heterogeneity, the following variables were added as covariates, if appropriate, to a bivariate regression model: type of publication (ie, retrospective vs prospective study), study sample size, rapid on-site evaluation (ROSE), enrollment period of publication as dichotomized before and after 2011. Subgroup analyses for any covariates significantly associated with the summary estimates were performed. We applied Cook’s distance to assess for influential studies and depicted a scatter plot of standardized level 2 residuals to identify outliers. Publication bias was assessed by funnel plot with regression line, and by Deeks’ test. All analyses were performed with STATA version 13 (StataCorp, College Station, Tex, USA).
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Results Included studies and quality assessment After applying the selection criteria and exclusion of a study with overlapping population [20], 12 studies on 505 patients were finally included in the qualitative and quantitative analysis [21-32] (Table 1). The details on the selection process and study flow-chart are reported in Supplementary Figure 1. All studies showed high quality in terms of risk of bias and applicability of index test and reference standard (Supplementary Figure 2). However, the risk of bias and applicability of patient selection in two studies [26,29] was high and in 4 studies [24,25,27,30] was unclear. The risk of bias regarding study flow and timing was unclear in 6 studies [24,25,27,29,30,32].
Diagnostic performance Nine out of 12 studies reported the diagnostic performance of rEUS-FNA for the diagnosis of pancreatic solid malignancies, whereas in 3 studies the parameters were computed based on data [23,28,29]. Summary estimates were as follows: sensitivity 77% (95% CI, 66%-86%), specificity 98% (95% CI, 78%-100%), positive likelihood ratio 38.9 (95% CI, 2.8-539.9), and negative likelihood ratio 0.23 (95% CI, 0.14-0.39) (see Figure 1 for details). Summary sensitivity and specificity, along with 95% confidence and prediction regions, are represented in the SROC curve (Figure 2). Based on the observed prevalence of pancreatic solid malignancies (ie, 73%; 95% CI, 64%-81%), positive predictive value was 99% (95% CI, 98%-100%), and negative predictive value was 61% (95% CI, 60%-63%). The summary estimates of diagnostic performance are shown in Table 2. The impact of rEUS-FNA on pre-test probabilities (ie, the pooled prevalence of solid pancreatic malignancies, along with 95% CI) to yield post-test probabilities in case of positive or negative results is depicted in Figure 3. At 73% of disease prevalence, a positive rEUS-FNA increased the disease probability to
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99%, whereas a negative result decreased the disease probability to 39%. In other words, as shown by the likelihood ratio scattergram in Supplementary Figure 3, as the positive likelihood ratio was above 10, while the negative likelihood ratio was not below 0.10, the rEUS-FNA is adequately informative only in case of positive result (ie, confirmation only), whereas in case of negative result a false negative cannot be reliably excluded.
Influence of ROSE on diagnostic accuracy Overall, 8 study arms with 325 patients were conducted with ROSE whereas 5 study arms comprising 180 patients were not (see Table 1). Subgroup analysis showed that studies performed with ROSE had a higher pooled sensitivity with similar pooled specificity; in particular, sensitivity and specificity were 83% (95% CI, 64%-93%) and 98% (95% CI, 80%-100%) when ROSE was present, as compared with 65% (95% CI, 57%-73%) and 94% (95% CI, 31%-100%), when ROSE was not available. The number needed to diagnose (NND) was 1.3 (95% CI, 1.2-2.3) overall. In other words, 7 (95% CI, 4-8) on 10 patients who repeat EUS-FNA would receive a correct diagnosis. According to the presence of ROSE, the NND was 1.2 (95% CI, 1.1-2.3) for ROSE+ studies, and 1.7 (95% CI, 1.4-8.3) in ROSE- studies. This means that 8 (95% CI, 4-9) on 10 patients with ROSE, and 6 (95% CI, 1-7) on 10 patients without ROSE who repeat EUS-FNA would receive a correct diagnosis.
Heterogeneity and Publication bias assessment Heterogeneity between studies was high, as I2 index was 83% overall, 82% for sensitivity and 82% for specificity, respectively. In the bivariate regression model, ROSE (p = 0.01 for sensitivity; p = 0.79 for specificity; p = 0.27 for joint model) explained some of the heterogeneity, which was decreased to 23% overall. Enrolment period had a relevant effect on heterogeneity as well (p = 9
0.01 for both sensitivity and specificity, I2 68%); indeed, sensitivity was 67% (95% CI, 50%-83%) and 84% (95% CI, 75%-94%), and specificity was 99% (95% CI, 97%-100%) and 87% (95% CI, 69%-100%) for studies enrolling patients before and after 2011, respectively. Study sample size did not influence heterogeneity (p = 0.99 for sensitivity; p = 0.97 for specificity; p = 0.59 for joint model). The study by Nicaud [24] was shown by Cook’s distance to be influential, and further identified as outlier having the lowest standardized residuals for sensitivity (Supplementary Figure 4). After excluding the study by Nicaud, sensitivity did not change (80%; 95% CI, 68%-88%) and specificity slightly increased (98%; 95% CI, 73%-100%). No significant publication bias as assessed by funnel plot (Supplementary Figure 5) and Deeks’ regression test (p = 0.44) was detected.
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Discussion We have presented the first study focused on the pooled diagnostic yield of repeating EUS-FNA of solid pancreatic masses after initial inconclusive or nondiagnostic results. This meta-analysis demonstrates that rEUS-FNA has an optimal pooled specificity (97%) with high pooled sensitivity (78%) for diagnosis of malignancy. Moreover, a positive rEUS-FNA is highly reliable, whereas a negative result significantly reduces but does not abolish the risk of underlying malignancy. The clinical impact of rEUS-FNA is further improved by the presence of ROSE, as the number of patients who receive a correct diagnosis is substantially increased in this group. Several high-quality meta-analyses have been published on the diagnostic accuracy of EUS-FNA in PC, reporting 85% to 89% of pooled sensitivity and 98% to 99% of pooled specificity [33,34]. Despite these robust data, we emphasize that the NPV of EUS-FNA for PC is <70%; therefore, negative or nondiagnostic results do not allow to draw a definitive diagnosis of a benign condition. Different guidelines give heterogeneous recommendations about the management of negative EUS-FNA and are not based on high-quality evidence. Although NCCN guidelines recommend repeating biopsy [4], ESMO guidelines [3] do not cover this topic and ESGE and EFSUMB guidelines [7-9] include also ancillary techniques, such as K-ras gene mutation analysis, and even follow-up in low-risk cases[35]. Overall, although not evidence-based, it is common practice to perform rEUSFNA in most centers. We believe that our results provide high-quality evidence supporting the practice of repeating EUS-FNA after initial negative or inconclusive tissue sampling. The optimal pooled 98% specificity, coupled with the low false-positive rate (<3%) demonstrates that a rEUS-FNA substantially increases the diagnostic yield. Based upon our data, we suggest that this strategy may change the diagnostic and therapeutic approach in up to 60% of cases. Of note, a negative result of a rEUSFNA could further reduce the risk of underlying malignancy to less than 40%. 11
Interestingly, when ROSE was used the diagnostic accuracy of rEUS-FNA was further increased; in detail, studies with ROSE showed a higher sensitivity with a slightly higher specificity as compared with studies without ROSE. Furthermore, a correct diagnosis with rEUS-FNA was achieved in 8 out of 10 patients with ROSE versus 6 out of 10 patients without ROSE. Because the role of ROSE, after initial enthusiasm, is undergoing a downsizing of its applications, our findings are relevant as they strongly support the implementation of ROSE for the particular setting of rEUS-FNA. In this context, ROSE may bring a significant increase in definitive diagnosis thereby reducing the need for further examinations and healthcare-related costs. Our research has some limitations. First, all but one of the included studies were retrospective, therefore a subgroup analysis according to study design was not feasible. Second, 6 studies had unclear or high risk of patients’ selection bias. Third, because all the published studies were conducted in tertiary referral centers, it is possible that good results with rEUS-FNA can be replicated only in high-volume centers but not in low-volume centers. Last, temporal bias represents another possible limitation, as the first published study [21] included patients enrolled in 2000, whereas the most recent one [30] closed the enrollment in 2014. Indeed, meta-regression identified temporal bias as a possible heterogeneity factor on rEUS-FNA diagnostic accuracy; this trend might reflect the diagnostic improvement observed in EUS-guided tissue acquisition over decades, due to technological, technical and knowledge innovations. EUS-FNB needles have significantly influenced daily EUS-guided tissue acquisition methods and results. The use of these needles allows to increase the diagnostic yield (up to 95%) and to obtain histologic core samples. To date, use of new-generation FNB needles represents the criterion standard for tissue characterization for all solid pancreatic neoplasms. However, because no data on the role of EUSFNB after nondiagnostic or inconclusive results are still available, we can only hypothesize that these results could be replicated in this setting. We believe that our study has some relevant of
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implications for future research. First, we think that the evaluation of the diagnostic performance of repeating EUS tissue sampling with FNB is warranted. Second, prospective comparisons of rEUSFNA with versus without ROSE would be appropriate to confirm our findings. In conclusion, this study objectively substantiated the added value of rEUS-FNA for the diagnosis of solid pancreatic masses, in case of previous nondiagnostic or inconclusive results. Moreover, our data suggested that ROSE may be highly beneficial in this setting to increase the amount of definitive diagnoses.
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Figure legends Figure 1. Forest plots of rEUS-FNA diagnostic performance for solid pancreatic malignancies. A, sensitivity. B, Specificity. C, Positive likelihood ratio. D, Negative likelihood ratio. Figure 2. Summary receiver operating characteristics (SROC) curve of rEUS-FNA sensitivity and specificity for solid pancreatic malignancies. Each circle indicates an individual study; red diamond represents summary sensitivity and specificity; inner and outer ellipses indicate 95% confidence region and prediction region, respectively. Figure 3. Fagan plot depicting the impact of rEUS-FNA on pre-test probabilities (ie, the pooled prevalence of solid pancreatic malignancies, along with 95% CI) to yield post-test probabilities in case of positive or negative result, respectively. For the purpose of the analysis, likelihood ratio is expressed in logarithmic form. A, 75% pre-test probability. B, 63% pre-test probability. C, 81% pretest probability.
Supplementary Figure 1. Flow chart of systematic literature search. Supplementary Figure 2. Risk of bias of included studies according to QUADAS-2 evaluation tool. Supplementary Figure 3. Likelihood ratio scattergram. Summary point of likelihood ratios, obtained as functions of mean sensitivity and specificity is depicted by red diamond. Its placement on the right upper quadrant suggests that rEUS-FNA is useful for confirmation of solid pancreatic malignancy (when positive) and not for its exclusion (when negative). Supplementary Figure 4. Graphical depiction of influence and outlier detection analyses. A, Cook’s distance. B, Scatter plot of standardized level-2 residuals. Supplementary Figure 5. Funnel plot with Deeks’ test. No significant publication bias was shown.
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Table 2. Pooled diagnostic performance of repeated EUS-FNA for solid pancreatic malignancies. 95% CI, 95% confidence interval. Overall pooled estimate (95% CI)
Pooled estimate for ROSE+ (95% CI)
Pooled estimate for ROSE- (95% CI)
Sensitivity
77% (66%-86%)
83% (64%-93%)
65% (57%-73%)
Specificity
98% (78%-100%)
98% (80%-100%)
94% (31%-100%)
Positive likelihood ratio
38.9 (2.8-539.9)
37.6 (3.6-398.4)
10.7 (0.4-292.1)
Negative likelihood ratio
0.23 (0.14-0.39)
0.18 (0.08-0.40)
0.37 (0.27-0.51)
Positive predictive value*
99% (98%-100%)
99% (98%-100%)
97% (93%-100%)
Negative predictive value*
61% (60%-63%)
68 (67%-69%)
50% (48%-53%)
1.3 [1.2 – 2.3]
1.2 (1.1-2.3)
1.7 (1.4-8.3)
Diagnostic performance
Number needed to diagnose
* Based on the observed prevalence of pancreatic solid malignancies (ie, 73%; 95% CI, 62%-81%).
Table 1. Characteristics of the studies included Author (First), year Zhang et al 2016 [32] Tellez-Avila et al 2016 [31] Mitchell et al 2016 [30] Alston et al 2016 [29]
Affiliation, Country Johns Hopkins Hospital, Baltimore, US Instituto Nacional Salvador Zubirán, Mexico University of British Columbia, Canada University of Alabama at Birmingham, US
No. of Center s
Study period
Technique
Diagnostic criteria*
Study population
Age (mean)
Male (%)
Malignant tumor (prevalence)
1
Jan 2006 – Oct 2010
EUS-FNA with ROSE
1,2,3,4,5
43
65.6 ± 12.5
55.2%
83.7%
1
Jan 2006 – Dec 2012
EUS-FNA
1,3,5
34
58.8 ± 16.1
50.0%
61.8%
Retrospective cohort study
1
2007 - 2014
EUS-FNA with ROSE
1,2,5
45
67.3 ± 9.5
62.0%
71.1%
Retrospective cohort study
1
Jul 2000 – Mar 2013
EUS-FNA with ROSE
1,2,3,4,5
40
66 ± 12
58.0%
92.5%
Study design Retrospective evaluation of prospective database Retrospective evaluation of prospective database
Sun et al 2015 [28]
Shanghai Medical College, China
Retrospective evaluation of prospective database
1
Dec 2011 – Dec 2013
EUS-FNA
1,2,3,4,5
38
59.0 ± 9.9
68.4%
81.6%
Suzuki et al 2013 [27]
MD Anderson Cancer Center, US
Retrospective cohort study
2
2005 - 2011
EUS-FNA with ROSE
1,2,3,4,5
80
63.1 ± 12.5
47.6%
90%
A case-controlled matched cohort study A case-controlled matched cohort study
1
Jan 2010 – Jun 2011
EUS-FNA
1,2,3,5
22
57.9
63.6%
45.5%
1
Jul 2011 – Dec 2012
EUS-FNA with ROSE
1,2,3,5
11
65.8
27.3%
81.8%
Prachayacul et al 2013 [25]
Washington University School of Medicine, US Washington University School of Medicine, US Mahidol University, Siriraj Hospital, Thailand
1
Jan 2007 – May 2011
EUS-FNA
1,3,5
15
57.0 ± 11.8
40.0%
73.3%
Nicaud et al 2010 [24]
University of Florida, US
1
2002 - 2008
EUS-FNA with ROSE
1,2,3,5
28
62 [34 – 82]
42.9%
60.7%
1
Jan 2002 – Dec 2006
EUS-FNA
1,2,3,5
71
59 [12 – 81]°
65.7%°
87.3%
Prospective study
1
Jan 2004 – Oct 2006
EUS-FNA with ROSE
1,2,3,5
46
56.3 [21 – 78]
61.0%
52.2%
Retrospective cohort study
1
Jan 2000 – Sep 2006
EUS-FNA with ROSE
1,2,3,4,5
32
59
53.1%
43.8%
Collins et al 2013** [26] Collins et al 2013** [26]
Ainsworth et al 2010 [23] Tadic et al 2008 [22] De Witt et al 2008 [21]
Odense University Hospital, Denmark Dubrava University Hospital, Croatia Indiana University Medical Center (IUMC), US
Retrospective cohort study Retrospective evaluation of prospective database Retrospective evaluation of prospective database
#
Abbreviations: EUS-FNA: endoscopic ultrasound-guided fine-needle aspiration; ROSE: Rapid On-site Evaluation. *Final diagnosis: 1: surgery; 2: histologic/cytologic examinations; 3: imaging techniques; 4: autopsy; 5: follow-up ** Collins et al. included two different cohorts: the first group (no. 22 patients) underwent repeated EUS-FNA without ROSE while the second group (no. 11 patients) underwent repeated EUS-FNA with ROSE. ° Data reported on the entire group of patients who underwent repeated EUS examination (no. 242); of them, only 71 underwent repeated EUS-FNA. #
Patients from different institute were referred to IUMC to perform a second EUS-FNA.
Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis
Appendix 1 Search strategy and study selection We conducted a comprehensive systematic review of English-language articles up to January 31, 2019 through MEDLINE using PubMed, EMBASE, SCOPUS, the Cochrane Central register and Google Scholar interfaces. Additionally, the bibliography of retrieved articles and reviews was manually analyzed to find other additional eligible studies that eluded the primary search. The search terms were (“Fine needle aspiration”[all fields] OR “Fine needle biopsy”[all fields] OR “EUS-guided tissue acquisition”[all fields] OR “EUS-tissue acquisition”[all fields] OR “EUS-FNA”[all fields] OR “EUS-guided-FNA”[all fields] OR “EUS-FNB”[all fields] OR “EUS-guided FNB”[all fields] OR “EUS-guided fine needle aspiration”[all fields] OR “FNA biopsy”[all fields] AND “pancreas”[all fields] AND English[lang]).
Supplementary Table 1. Impact of a positive or negative result of repeated EUS-FNA on pancreatic solid masses, according to a spectrum of pre-test prevalence of malignancy. Pre-test prevalence of malignancy (%) 40
50
60
70
80
90
Repeated EUS-FNA result
+ + + + + + -
Post-test probability of malignancy (%) 96 13 97 19 98 26 99 35 99 48 100 68
Repeated EUS-FNA of pancreatic masses after non-diagnostic or inconclusive results: systematic review and meta-analysis
Authors: Dr. Andrea Lisotti1, Dr. Leonardo Frazzoni2(first co-authors), Prof. Lorenzo Fuccio2, Dr. Marta Serrani1, Dr. Anna Cominardi1, Prof. Franco Bazzoli2, and Prof. Pietro Fusaroli1 Acronyms and abbreviations: EUS: endoscopic ultrasound; FP: false positive; FN: false negative; NPV: negative predictive value; PC: pancreatic carcinoma; PPV: positive predictive value; rEUS-FNA: repeat EUS-FNA; ROSE: role of rapid on-site evaluation; SROC: summary receiving operating characteristic; TN: true negative; TP: true positive.
1
S0016-5107(20)30092-4
DOI:
https://doi.org/10.1016/j.gie.2020.01.034
Reference:
YMGE 11950
To appear in:
Gastrointestinal Endoscopy
Received Date: 24 August 2019 Accepted Date: 20 January 2020
Please cite this article as: Lisotti A, Frazzoni L, Fuccio L, Serrani M, Cominardi A, Bazzoli F, Fusaroli P, Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis, Gastrointestinal Endoscopy (2020), doi: https://doi.org/10.1016/j.gie.2020.01.034. 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
Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis
Authors: Dr. Andrea Lisotti1, Dr. Leonardo Frazzoni2(first co-authors), Prof. Lorenzo Fuccio2, Dr. Marta Serrani1, Dr. Anna Cominardi1, Prof. Franco Bazzoli2, and Prof. Pietro Fusaroli1 Affiliations: 1
Gastroenterology Unit, Hospital of Imola, Department of Medical and Surgical Sciences,
University of Bologna, Italy. 2
Gastroenterology Unit, Sant’Orsola Hospital, Department of Medical and Surgical Sciences,
University of Bologna, Italy.
Correspondence to: Dott. Andrea Lisotti, MD Gastroenterology Unit, Hospital of Imola. Department of Medical and Surgical Sciences, University of Bologna, Italy Via Montericco 4; 40026 Imola (BO), Italy. E-mail: [email protected] Authors' contributions A.L. and Le.Fr. Contributed equally to the work; A.L. and P.F. designed the study, collected data and drafted the article; A.L., Le.Fr. And Lo.Fu. analyzed the data; A.C., M.S. and F.B. revised the manuscript for pivotal intellectual content. All Authors approved the final version of the manuscript.
1
Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis Short title: Repeated EUS-FNA after inconclusive results Authors: Andrea Lisotti1, Leonardo Frazzoni2 (first co-authors), Lorenzo Fuccio2, Marta Serrani1, Anna Cominardi1, Franco Bazzoli2, and Pietro Fusaroli1 Affiliations: 1
Gastroenterology Unit, Hospital of Imola, Department of Medical and Surgical Sciences,
University of Bologna, Italy. 2
Gastroenterology Unit, Sant’Orsola Hospital, Department of Medical and Surgical Sciences,
University of Bologna, Italy. Grant support The Authors received no support or funding for this study. List of Abbreviations: EUS: endoscopic ultrasound; FP: false positive; FN: false negative; NPV: negative predictive value; PC: pancreatic carcinoma; PPV: positive predictive value; rEUS-FNA: repeat EUS-FNA; ROSE: role of rapid on-site evaluation; SROC: summary receiving operating characteristic; TN: true negative; TP: true positive.
Correspondence to: Dott. Andrea Lisotti, MD Gastroenterology Unit, Hospital of Imola. Department of Medical and Surgical Sciences, University of Bologna, Italy Via Montericco 4; 40026 Imola (BO), Italy. E-mail: [email protected] Conflict of interest: The Authors declare no conflict of interest. Writing assistance: 1
No writing assistance was required to draft the manuscript Authors' contributions A.L. and Le.Fr. Contributed equally to the work; A.L. and P.F. designed the study, collected data and drafted the article; A.L., Le.Fr. And Lo.Fu. analyzed the data; A.C., M.S. and F.B. revised the manuscript for pivotal intellectual content. All Authors approved the final version of the manuscript.
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Abstract Background and Aims: EUS-guided fine-needle aspiration (EUS-FNA) is the criterion standard for the diagnosis of solid pancreatic lesions. Several studies assessed the role of repeat EUS-FNA (rEUS-FNA) after an inconclusive examination. Our aim was to evaluate the pooled diagnostic accuracy of rEUS-FNA after nondiagnostic result. Methods: We conducted systematic research on electronic databases (MEDLINE, PubMed, EMBASE) and meta-analysis to obtain pooled sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. Summary ROC curve was used to calculate area under the curve. Subgroup analysis was used to assess the role of rapid on-site evaluation (ROSE). Results: Twelve studies (505 patients) were included. Sensitivity was 77% (66%–86%) and specificity 98% (78%–100%); positive and negative predictive values were 99% (98%-100%) and 61 (60%-63%), respectively. At 73% of disease prevalence (pre-test probability), positive rEUS-FNA increased the disease probability to 99%, whereas negative result decreased the disease probability to 39%. The sensitivity was 83% (64%-93%) and specificity 98% (80%-100%) when ROSE was available and 65% (57%-73%) and 94% (31%-100%) when not available. The number-neededto-diagnose was 1.2 (1.1-2.3) and 1.7 (1.4-8.3) in ROSE+ and ROSE- cases, respectively. The number of correctly diagnosed cases increased from 6 (1-7) to 8 (4-9) out of 10 patients without and with ROSE, respectively. Conclusions: This study objectively substantiated the added value of rEUS-FNA for the diagnosis of solid pancreatic masses, in case of a previous nondiagnostic or inconclusive result. Moreover, our data suggested that ROSE may be beneficial in this setting, as it increased the proportion of definitive diagnoses.
Keywords: pancreatic cancer; pancreatic ductal adenocarcinoma; PDAC; EUS-FNA; EUS-FNB; EUStissue acquisition.
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Introduction EUS has a pivotal role in the management of pancreatic cancer (PC) that is one of the most lethal neoplasm with a 5-year survival that has not significantly increased over the last decades [1-4]. In this setting, EUS was demonstrated to be accurate for detection even of small lesions, for local staging and for tissue sampling [5,6]. EUS-guided tissue sampling is indicated in all patients with borderline-resectable, unresectable, or metastatic PC, although its role in resectable masses is still debated but nevertheless often required, based on local multidisciplinary team consensus [3,4]. Along with EUS-guided fine-needle aspiration (EUS-FNA), which has represented the standard approach for several years, EUS-fine-needle biopsy (EUS-FNB) has emerged as the technique of choice for pathological characterization of solid pancreatic tumors, showing optimal positive predictive value (PPV), with fair negative predictive value (NPV). Meta-analysis in this setting reported pooled sensitivity ranging from 85% to 89% with a pooled specificity up to 100% [7-9]. Several studies aimed to identify factors related to nondiagnostic or false-negative EUS-FNA, and to improve its diagnostic yield using different needle gauge and tissue acquisition techniques (eg, fanning, suction or stylet use). Moreover, the presence of a pathologist for rapid on-side evaluation (ROSE) has been advocated to increase EUS-FNA accuracy, although mixed results are available in this regard [10-12]. Last, there is preliminary evidence showing that EUS image enhancement techniques such as contrast-enhanced harmonic and elastography might increase the diagnostic yield of EUS-FNA by allowing to target the needle away from necrotic areas [13]. Despite all the technical improvements, a not-negligible risk of false negative or inconclusive results with EUS-guided tissue sampling still exists. In such cases, major guidelines recommend repeating EUS-guided tissue sampling [4]. The value of repeated EUS-FNA (rEUS-FNA) after an initial negative examination was investigated by different studies, reporting sensitivity for the diagnosis of malignancy in the range 35% to 100% [8].
4
The aim of this study was to evaluate the pooled diagnostic sensitivity and specificity of rEUS-FNA for the diagnosis of solid pancreatic masses after an initial nondiagnostic or inconclusive EUS-FNA.
5
Methods Search strategy and study selection We conducted a comprehensive systematic review of English-language articles up to January 31, 2019 through MEDLINE using PubMed, EMBASE, SCOPUS, the Cochrane Central register and Google Scholar interfaces (see Appendix 1). Additionally, the bibliography of retrieved articles and reviews was manually analyzed to find other additional eligible studies that eluded the primary search.
Study selection Original studies (randomized controlled trials, prospective studies and retrospective studies) designed to evaluate the diagnostic accuracy of rEUS-FNA after previous nondiagnostic or inconclusive result in solid pancreatic masses were included; only studies with sufficient data for identification of true positive (TP), false positive (FP), false negative (FN), and true negative (TN) cases were considered. Only full-text articles were included. Studies were excluded in case of unavailable, incomplete, duplicated or updated data, or in case of case report or case series enrolling <10 patients. Data extraction and quality assessment Two physicians independently recorded the following data: first author, affiliation, country of origin, year of publication, study design, number of centers involved in the study, type of needle (FNA vs FNB), presence of rapid on-site evaluation (ROSE), and number of included cases, patients’ age and gender, prevalence of malignant masses. In case of missing data, the number of TP, FP, FN and TN cases was extracted from reported data; an email to the corresponding manuscripts’ authors was sent to confirm the results. Disagreements during data extraction were resolved through discussion among all authors. Qualitative assessment and evaluation of potential bias were performed according to the Quality 6
Assessment of Diagnostic Accuracy Studies (QUADAS-2) system, based on 4 domains: patient selection, index tests, reference standard, and flow-and-timing [14].
Statistical analysis We computed sensitivity and specificity with 95% confidence interval (95% CI) by means of 2 X 2 tables for each study and depicted them in coupled forest plots. Summary estimates of sensitivity, specificity, positive and negative likelihood ratio were computed by applying a bivariate, mixedeffects regression model. A summary receiving operating characteristic (SROC) curve was built [15,16]. Based on 95%CI of the pooled prevalence of solid pancreatic malignancies (ie, pre-test probability), unconditional negative and positive predictive values were computed [17]. The clinical utility of the rEUS-FNA was evaluated using the likelihood ratios to (1) calculate post-test probability based on Bayes’ theorem, and graphically depicted with Fagan’s nomograms [18]; (2) build a likelihood ratio scattergram, defining quadrants of test informativeness [19]. Heterogeneity between studies was assessed through visual examination of the forest plot and SROC curve, and by Higgins’ I2 index. In order to find possible sources of heterogeneity, the following variables were added as covariates, if appropriate, to a bivariate regression model: type of publication (ie, retrospective vs prospective study), study sample size, rapid on-site evaluation (ROSE), enrollment period of publication as dichotomized before and after 2011. Subgroup analyses for any covariates significantly associated with the summary estimates were performed. We applied Cook’s distance to assess for influential studies and depicted a scatter plot of standardized level 2 residuals to identify outliers. Publication bias was assessed by funnel plot with regression line, and by Deeks’ test. All analyses were performed with STATA version 13 (StataCorp, College Station, Tex, USA).
7
Results Included studies and quality assessment After applying the selection criteria and exclusion of a study with overlapping population [20], 12 studies on 505 patients were finally included in the qualitative and quantitative analysis [21-32] (Table 1). The details on the selection process and study flow-chart are reported in Supplementary Figure 1. All studies showed high quality in terms of risk of bias and applicability of index test and reference standard (Supplementary Figure 2). However, the risk of bias and applicability of patient selection in two studies [26,29] was high and in 4 studies [24,25,27,30] was unclear. The risk of bias regarding study flow and timing was unclear in 6 studies [24,25,27,29,30,32].
Diagnostic performance Nine out of 12 studies reported the diagnostic performance of rEUS-FNA for the diagnosis of pancreatic solid malignancies, whereas in 3 studies the parameters were computed based on data [23,28,29]. Summary estimates were as follows: sensitivity 77% (95% CI, 66%-86%), specificity 98% (95% CI, 78%-100%), positive likelihood ratio 38.9 (95% CI, 2.8-539.9), and negative likelihood ratio 0.23 (95% CI, 0.14-0.39) (see Figure 1 for details). Summary sensitivity and specificity, along with 95% confidence and prediction regions, are represented in the SROC curve (Figure 2). Based on the observed prevalence of pancreatic solid malignancies (ie, 73%; 95% CI, 64%-81%), positive predictive value was 99% (95% CI, 98%-100%), and negative predictive value was 61% (95% CI, 60%-63%). The summary estimates of diagnostic performance are shown in Table 2. The impact of rEUS-FNA on pre-test probabilities (ie, the pooled prevalence of solid pancreatic malignancies, along with 95% CI) to yield post-test probabilities in case of positive or negative results is depicted in Figure 3. At 73% of disease prevalence, a positive rEUS-FNA increased the disease probability to
8
99%, whereas a negative result decreased the disease probability to 39%. In other words, as shown by the likelihood ratio scattergram in Supplementary Figure 3, as the positive likelihood ratio was above 10, while the negative likelihood ratio was not below 0.10, the rEUS-FNA is adequately informative only in case of positive result (ie, confirmation only), whereas in case of negative result a false negative cannot be reliably excluded.
Influence of ROSE on diagnostic accuracy Overall, 8 study arms with 325 patients were conducted with ROSE whereas 5 study arms comprising 180 patients were not (see Table 1). Subgroup analysis showed that studies performed with ROSE had a higher pooled sensitivity with similar pooled specificity; in particular, sensitivity and specificity were 83% (95% CI, 64%-93%) and 98% (95% CI, 80%-100%) when ROSE was present, as compared with 65% (95% CI, 57%-73%) and 94% (95% CI, 31%-100%), when ROSE was not available. The number needed to diagnose (NND) was 1.3 (95% CI, 1.2-2.3) overall. In other words, 7 (95% CI, 4-8) on 10 patients who repeat EUS-FNA would receive a correct diagnosis. According to the presence of ROSE, the NND was 1.2 (95% CI, 1.1-2.3) for ROSE+ studies, and 1.7 (95% CI, 1.4-8.3) in ROSE- studies. This means that 8 (95% CI, 4-9) on 10 patients with ROSE, and 6 (95% CI, 1-7) on 10 patients without ROSE who repeat EUS-FNA would receive a correct diagnosis.
Heterogeneity and Publication bias assessment Heterogeneity between studies was high, as I2 index was 83% overall, 82% for sensitivity and 82% for specificity, respectively. In the bivariate regression model, ROSE (p = 0.01 for sensitivity; p = 0.79 for specificity; p = 0.27 for joint model) explained some of the heterogeneity, which was decreased to 23% overall. Enrolment period had a relevant effect on heterogeneity as well (p = 9
0.01 for both sensitivity and specificity, I2 68%); indeed, sensitivity was 67% (95% CI, 50%-83%) and 84% (95% CI, 75%-94%), and specificity was 99% (95% CI, 97%-100%) and 87% (95% CI, 69%-100%) for studies enrolling patients before and after 2011, respectively. Study sample size did not influence heterogeneity (p = 0.99 for sensitivity; p = 0.97 for specificity; p = 0.59 for joint model). The study by Nicaud [24] was shown by Cook’s distance to be influential, and further identified as outlier having the lowest standardized residuals for sensitivity (Supplementary Figure 4). After excluding the study by Nicaud, sensitivity did not change (80%; 95% CI, 68%-88%) and specificity slightly increased (98%; 95% CI, 73%-100%). No significant publication bias as assessed by funnel plot (Supplementary Figure 5) and Deeks’ regression test (p = 0.44) was detected.
10
Discussion We have presented the first study focused on the pooled diagnostic yield of repeating EUS-FNA of solid pancreatic masses after initial inconclusive or nondiagnostic results. This meta-analysis demonstrates that rEUS-FNA has an optimal pooled specificity (97%) with high pooled sensitivity (78%) for diagnosis of malignancy. Moreover, a positive rEUS-FNA is highly reliable, whereas a negative result significantly reduces but does not abolish the risk of underlying malignancy. The clinical impact of rEUS-FNA is further improved by the presence of ROSE, as the number of patients who receive a correct diagnosis is substantially increased in this group. Several high-quality meta-analyses have been published on the diagnostic accuracy of EUS-FNA in PC, reporting 85% to 89% of pooled sensitivity and 98% to 99% of pooled specificity [33,34]. Despite these robust data, we emphasize that the NPV of EUS-FNA for PC is <70%; therefore, negative or nondiagnostic results do not allow to draw a definitive diagnosis of a benign condition. Different guidelines give heterogeneous recommendations about the management of negative EUS-FNA and are not based on high-quality evidence. Although NCCN guidelines recommend repeating biopsy [4], ESMO guidelines [3] do not cover this topic and ESGE and EFSUMB guidelines [7-9] include also ancillary techniques, such as K-ras gene mutation analysis, and even follow-up in low-risk cases[35]. Overall, although not evidence-based, it is common practice to perform rEUSFNA in most centers. We believe that our results provide high-quality evidence supporting the practice of repeating EUS-FNA after initial negative or inconclusive tissue sampling. The optimal pooled 98% specificity, coupled with the low false-positive rate (<3%) demonstrates that a rEUS-FNA substantially increases the diagnostic yield. Based upon our data, we suggest that this strategy may change the diagnostic and therapeutic approach in up to 60% of cases. Of note, a negative result of a rEUSFNA could further reduce the risk of underlying malignancy to less than 40%. 11
Interestingly, when ROSE was used the diagnostic accuracy of rEUS-FNA was further increased; in detail, studies with ROSE showed a higher sensitivity with a slightly higher specificity as compared with studies without ROSE. Furthermore, a correct diagnosis with rEUS-FNA was achieved in 8 out of 10 patients with ROSE versus 6 out of 10 patients without ROSE. Because the role of ROSE, after initial enthusiasm, is undergoing a downsizing of its applications, our findings are relevant as they strongly support the implementation of ROSE for the particular setting of rEUS-FNA. In this context, ROSE may bring a significant increase in definitive diagnosis thereby reducing the need for further examinations and healthcare-related costs. Our research has some limitations. First, all but one of the included studies were retrospective, therefore a subgroup analysis according to study design was not feasible. Second, 6 studies had unclear or high risk of patients’ selection bias. Third, because all the published studies were conducted in tertiary referral centers, it is possible that good results with rEUS-FNA can be replicated only in high-volume centers but not in low-volume centers. Last, temporal bias represents another possible limitation, as the first published study [21] included patients enrolled in 2000, whereas the most recent one [30] closed the enrollment in 2014. Indeed, meta-regression identified temporal bias as a possible heterogeneity factor on rEUS-FNA diagnostic accuracy; this trend might reflect the diagnostic improvement observed in EUS-guided tissue acquisition over decades, due to technological, technical and knowledge innovations. EUS-FNB needles have significantly influenced daily EUS-guided tissue acquisition methods and results. The use of these needles allows to increase the diagnostic yield (up to 95%) and to obtain histologic core samples. To date, use of new-generation FNB needles represents the criterion standard for tissue characterization for all solid pancreatic neoplasms. However, because no data on the role of EUSFNB after nondiagnostic or inconclusive results are still available, we can only hypothesize that these results could be replicated in this setting. We believe that our study has some relevant of
12
implications for future research. First, we think that the evaluation of the diagnostic performance of repeating EUS tissue sampling with FNB is warranted. Second, prospective comparisons of rEUSFNA with versus without ROSE would be appropriate to confirm our findings. In conclusion, this study objectively substantiated the added value of rEUS-FNA for the diagnosis of solid pancreatic masses, in case of previous nondiagnostic or inconclusive results. Moreover, our data suggested that ROSE may be highly beneficial in this setting to increase the amount of definitive diagnoses.
13
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32- Zhang F, Kumbhari V, Tieu AH et al. Endoscopic Ultrasound-Guided Fine Needle Aspiration of Suspected Pancreatic Adenocarcinoma: Yield of the First and Repeat Procedure. JOP. J Pancreas 2016; 17:48-52.
33- Hewitt MJ, McPhail MJ, Possamai L et al. EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis. Gastrointest Endosc. 2012; 75: 319-31.
34- Hébert-Magee S, Bae S, Varadarajulu S et al. The presence of a cytopathologist increases the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration cytology for pancreatic adenocarcinoma: a meta-analysis. Cytopathology. 2013; 24: 159-71.
35- Fuccio L, Hassan C, Laterza L et al. The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a metaanalysis of prospective studies. Gastrointest Endosc. 2013; 78: 596-608.
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Figure legends Figure 1. Forest plots of rEUS-FNA diagnostic performance for solid pancreatic malignancies. A, sensitivity. B, Specificity. C, Positive likelihood ratio. D, Negative likelihood ratio. Figure 2. Summary receiver operating characteristics (SROC) curve of rEUS-FNA sensitivity and specificity for solid pancreatic malignancies. Each circle indicates an individual study; red diamond represents summary sensitivity and specificity; inner and outer ellipses indicate 95% confidence region and prediction region, respectively. Figure 3. Fagan plot depicting the impact of rEUS-FNA on pre-test probabilities (ie, the pooled prevalence of solid pancreatic malignancies, along with 95% CI) to yield post-test probabilities in case of positive or negative result, respectively. For the purpose of the analysis, likelihood ratio is expressed in logarithmic form. A, 75% pre-test probability. B, 63% pre-test probability. C, 81% pretest probability.
Supplementary Figure 1. Flow chart of systematic literature search. Supplementary Figure 2. Risk of bias of included studies according to QUADAS-2 evaluation tool. Supplementary Figure 3. Likelihood ratio scattergram. Summary point of likelihood ratios, obtained as functions of mean sensitivity and specificity is depicted by red diamond. Its placement on the right upper quadrant suggests that rEUS-FNA is useful for confirmation of solid pancreatic malignancy (when positive) and not for its exclusion (when negative). Supplementary Figure 4. Graphical depiction of influence and outlier detection analyses. A, Cook’s distance. B, Scatter plot of standardized level-2 residuals. Supplementary Figure 5. Funnel plot with Deeks’ test. No significant publication bias was shown.
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Table 2. Pooled diagnostic performance of repeated EUS-FNA for solid pancreatic malignancies. 95% CI, 95% confidence interval. Overall pooled estimate (95% CI)
Pooled estimate for ROSE+ (95% CI)
Pooled estimate for ROSE- (95% CI)
Sensitivity
77% (66%-86%)
83% (64%-93%)
65% (57%-73%)
Specificity
98% (78%-100%)
98% (80%-100%)
94% (31%-100%)
Positive likelihood ratio
38.9 (2.8-539.9)
37.6 (3.6-398.4)
10.7 (0.4-292.1)
Negative likelihood ratio
0.23 (0.14-0.39)
0.18 (0.08-0.40)
0.37 (0.27-0.51)
Positive predictive value*
99% (98%-100%)
99% (98%-100%)
97% (93%-100%)
Negative predictive value*
61% (60%-63%)
68 (67%-69%)
50% (48%-53%)
1.3 [1.2 – 2.3]
1.2 (1.1-2.3)
1.7 (1.4-8.3)
Diagnostic performance
Number needed to diagnose
* Based on the observed prevalence of pancreatic solid malignancies (ie, 73%; 95% CI, 62%-81%).
Table 1. Characteristics of the studies included Author (First), year Zhang et al 2016 [32] Tellez-Avila et al 2016 [31] Mitchell et al 2016 [30] Alston et al 2016 [29]
Affiliation, Country Johns Hopkins Hospital, Baltimore, US Instituto Nacional Salvador Zubirán, Mexico University of British Columbia, Canada University of Alabama at Birmingham, US
No. of Center s
Study period
Technique
Diagnostic criteria*
Study population
Age (mean)
Male (%)
Malignant tumor (prevalence)
1
Jan 2006 – Oct 2010
EUS-FNA with ROSE
1,2,3,4,5
43
65.6 ± 12.5
55.2%
83.7%
1
Jan 2006 – Dec 2012
EUS-FNA
1,3,5
34
58.8 ± 16.1
50.0%
61.8%
Retrospective cohort study
1
2007 - 2014
EUS-FNA with ROSE
1,2,5
45
67.3 ± 9.5
62.0%
71.1%
Retrospective cohort study
1
Jul 2000 – Mar 2013
EUS-FNA with ROSE
1,2,3,4,5
40
66 ± 12
58.0%
92.5%
Study design Retrospective evaluation of prospective database Retrospective evaluation of prospective database
Sun et al 2015 [28]
Shanghai Medical College, China
Retrospective evaluation of prospective database
1
Dec 2011 – Dec 2013
EUS-FNA
1,2,3,4,5
38
59.0 ± 9.9
68.4%
81.6%
Suzuki et al 2013 [27]
MD Anderson Cancer Center, US
Retrospective cohort study
2
2005 - 2011
EUS-FNA with ROSE
1,2,3,4,5
80
63.1 ± 12.5
47.6%
90%
A case-controlled matched cohort study A case-controlled matched cohort study
1
Jan 2010 – Jun 2011
EUS-FNA
1,2,3,5
22
57.9
63.6%
45.5%
1
Jul 2011 – Dec 2012
EUS-FNA with ROSE
1,2,3,5
11
65.8
27.3%
81.8%
Prachayacul et al 2013 [25]
Washington University School of Medicine, US Washington University School of Medicine, US Mahidol University, Siriraj Hospital, Thailand
1
Jan 2007 – May 2011
EUS-FNA
1,3,5
15
57.0 ± 11.8
40.0%
73.3%
Nicaud et al 2010 [24]
University of Florida, US
1
2002 - 2008
EUS-FNA with ROSE
1,2,3,5
28
62 [34 – 82]
42.9%
60.7%
1
Jan 2002 – Dec 2006
EUS-FNA
1,2,3,5
71
59 [12 – 81]°
65.7%°
87.3%
Prospective study
1
Jan 2004 – Oct 2006
EUS-FNA with ROSE
1,2,3,5
46
56.3 [21 – 78]
61.0%
52.2%
Retrospective cohort study
1
Jan 2000 – Sep 2006
EUS-FNA with ROSE
1,2,3,4,5
32
59
53.1%
43.8%
Collins et al 2013** [26] Collins et al 2013** [26]
Ainsworth et al 2010 [23] Tadic et al 2008 [22] De Witt et al 2008 [21]
Odense University Hospital, Denmark Dubrava University Hospital, Croatia Indiana University Medical Center (IUMC), US
Retrospective cohort study Retrospective evaluation of prospective database Retrospective evaluation of prospective database
#
Abbreviations: EUS-FNA: endoscopic ultrasound-guided fine-needle aspiration; ROSE: Rapid On-site Evaluation. *Final diagnosis: 1: surgery; 2: histologic/cytologic examinations; 3: imaging techniques; 4: autopsy; 5: follow-up ** Collins et al. included two different cohorts: the first group (no. 22 patients) underwent repeated EUS-FNA without ROSE while the second group (no. 11 patients) underwent repeated EUS-FNA with ROSE. ° Data reported on the entire group of patients who underwent repeated EUS examination (no. 242); of them, only 71 underwent repeated EUS-FNA. #
Patients from different institute were referred to IUMC to perform a second EUS-FNA.
Repeated EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis
Appendix 1 Search strategy and study selection We conducted a comprehensive systematic review of English-language articles up to January 31, 2019 through MEDLINE using PubMed, EMBASE, SCOPUS, the Cochrane Central register and Google Scholar interfaces. Additionally, the bibliography of retrieved articles and reviews was manually analyzed to find other additional eligible studies that eluded the primary search. The search terms were (“Fine needle aspiration”[all fields] OR “Fine needle biopsy”[all fields] OR “EUS-guided tissue acquisition”[all fields] OR “EUS-tissue acquisition”[all fields] OR “EUS-FNA”[all fields] OR “EUS-guided-FNA”[all fields] OR “EUS-FNB”[all fields] OR “EUS-guided FNB”[all fields] OR “EUS-guided fine needle aspiration”[all fields] OR “FNA biopsy”[all fields] AND “pancreas”[all fields] AND English[lang]).
Supplementary Table 1. Impact of a positive or negative result of repeated EUS-FNA on pancreatic solid masses, according to a spectrum of pre-test prevalence of malignancy. Pre-test prevalence of malignancy (%) 40
50
60
70
80
90
Repeated EUS-FNA result
+ + + + + + -
Post-test probability of malignancy (%) 96 13 97 19 98 26 99 35 99 48 100 68
Repeated EUS-FNA of pancreatic masses after non-diagnostic or inconclusive results: systematic review and meta-analysis
Authors: Dr. Andrea Lisotti1, Dr. Leonardo Frazzoni2(first co-authors), Prof. Lorenzo Fuccio2, Dr. Marta Serrani1, Dr. Anna Cominardi1, Prof. Franco Bazzoli2, and Prof. Pietro Fusaroli1 Acronyms and abbreviations: EUS: endoscopic ultrasound; FP: false positive; FN: false negative; NPV: negative predictive value; PC: pancreatic carcinoma; PPV: positive predictive value; rEUS-FNA: repeat EUS-FNA; ROSE: role of rapid on-site evaluation; SROC: summary receiving operating characteristic; TN: true negative; TP: true positive.
1