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Endoscopic ultrasound elastography in the diagnosis of pancreatic masses: A meta-analysis
Accepted Manuscript Endoscopic ultrasound elastography in the diagnosis of pancreatic masses: A metaanalysis Binglan Zhang, Fuping Zhu, Pan Li, Shishi Yu, Yajing Zhao, Minmin Li PII:
S1424-3903(18)30635-5
DOI:
10.1016/j.pan.2018.07.008
Reference:
PAN 900
To appear in:
Pancreatology
Received Date: 21 March 2018 Revised Date:
6 July 2018
Accepted Date: 28 July 2018
Please cite this article as: Zhang B, Zhu F, Li P, Yu S, Zhao Y, Li M, Endoscopic ultrasound elastography in the diagnosis of pancreatic masses: A meta-analysis, Pancreatology (2018), doi: 10.1016/j.pan.2018.07.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT Endoscopic ultrasound elastography in the diagnosis of pancreatic masses: a meta-analysis
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Binglan Zhang1, Fuping Zhu2, Pan Li1, Shishi Yu1, Yajing Zhao3, Minmin Li4*
Department of gastroenterology, the first affiliated hospital of chongqing medical
Department of hepatobiliary surgery, the ninth people's hospital of chongqing, Chongqing 400700,
China 3
Department of sonography, the first affiliated hospital of chongqing medical
university, Chongqing 400016, China
Department of oncology, the first affiliated hospital of chongqing medical university, Chongqing 4000
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2
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university, Chongqing 400016, China
16, China
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Note: *Corresponding author
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Corresponding author: Minmin Li Email: [email protected] Tel.: +86 23 89011613.
ACCEPTED MANUSCRIPT Abstract Background and Aims
Endoscopic ultrasound (EUS) elastography is a novel non-invasive technique
that can be used for distinguishing benign from malignant pancreatic masses. However, the studies
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have reported widely varied sensitivities and specificities. A meta-analysis was performed to assess the performance of EUS elastography for the differentiation of benign and malignant pancreatic masses. Methods
All the eligible studies were searched by PubMed, Medline, Embase, and the Cochrane
Results
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(AUC) were calculated to examine the accuracy.
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Library. Sensitivity, specificity, positive likelihood ratio (LR), negative LR, and area under the curve
A total of nineteen studies which included 1687 patients were analysed. The pooled
sensitivity and specificity for the diagnosis of malignant pancreatic masses were 0.98 (95% confidence interval [CI] 0.96-0.99) and 0.63 (95% CI 0.58-0.69) for qualitative EUS elastography, 0.95 (95% CI
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0.93-0.97) and 0.61 (95% CI 0.56-0.66) for quantitative EUS elastography, respectively. The positive and negative LR were 2.60 (95% CI 1.84-3.66) and 0.05 (95% CI 0.02-0.10) for qualitative EUS elastography, 2.64 (95% CI 1.82-3.82) and 0.10 (95% CI 0.06–0.16) for quantitative EUS elastography,
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respectively. The summary diagnostic odds ratio (DOR) and the AUC were 60.59 (95% CI
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28.12-130.56) and 0.91 (Q*=0.842) for qualitative EUS elastography, 30.09(95% CI 15.40-58.76) and 0.93 (Q*=0.860) for quantitative EUS elastography.Conclusions
Our meta-analysis shows that both
qualitative and quantitative EUS elastography have high accuracy in the detection of malignant pancreatic masses, which could be used as a valuable complementary method to EUS-FNA for the differentiation of pancreatic masses in the future. Key words: Endoscopic ultrasound, Elastography, Pancreatic masses, Diagnosis, Meta-analysis
ACCEPTED MANUSCRIPT Introduction Pancreatic cancer is a highly lethal disease with a poor prognosis, mainly because of its aggressive behavior and the difficulty in early diagnosis(1). Surgical resection offers the only potential cure, but
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small pancreatic cancer has non-specific symptoms, signs or imaging presentations, so that only less than 15% of patients are candidates for pancreatectomy. Therefore, an accurate diagnosis of benign and malignant pancreatic masses is very critical for making clinical decisions.
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Traditionally, several image modalities are used to diagnose pancreatic lesions, including
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transabdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or endoscopic retrograde cholangiopancreatography (ERCP)(2, 3). Taken individually, these methods have limited sensitivity for recognizing early pancreatic tumors. Endoscopic ultrasonography (EUS) is one of the most recent advances in gastrointestinal endoscopy.
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Numerous studies have indicated that EUS is more sensitive for the detection of pancreatic tumors compared with the traditional modalities(4-6). EUS is currently considered to be an important tool for diagnosis of chronic inflammatory, cystic, neoplastic pancreatic lesions and focal pancreatic masses(7,
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8), which also has the ability to provide fine needle aspiration (FNA) and obtain cytology or histology.
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However, EUS often cannot distinguish between chronic pseudotumoral pancreatitis and pancreatic cancer. EUS-guided FNA is an invasive procedure and associated with some inevitable complications(9), which can achieve a robust accuracy and also produce a false-negative result for the patients’ underlying chronic pancreatitis up to 20% to 40%(10, 11). Therefore, the differentiation diagnosis of benign and malignant pancreatic masses remains a challenge. Elastography, a noninvasive method used for the real-time calculation and visualization of tissue elasticity, has shown promising results in the diagnosis of various cancers. To help improve the
ACCEPTED MANUSCRIPT diagnostic yield of EUS, EUS elastography is increasingly being used. Measurements of tissue elasticity would be analyzed either by a qualitative method or a quantitative method. Previous meta-analysis have shown that EUS elastography is a promising non-invasive technique for the
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differentiation of pancreatic masses and can be considered to be a valuable supplemental method to EUS-guided FNA(12-17). Nevertheless, there were many articles published in this field in recent years. The aim of this study is to make a thorough search of the published articles and assess the overall
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performance of real-time EUS elastography for the differentiation of benign and malignant pancreatic
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masses.
Materials and methods Literature search
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We searched PubMed, Medline, Embase, and the Cochrane Library for studies published prior to November 10, 2017. The search terms were elastograms, elastography, elastosonography, elasticity imaging, endoscopic ultrasonography, EUS, elastosonoendoscopy, EUS elastography, pancreas, and
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pancreatic. A full manual search was also performed by using references of eligible articles. Language
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was limited to English.
Study inclusion/exclusion criteria Studies were considered eligible if they met all of the following inclusion criteria, (i) evaluated EUS elastography for the diagnosis of pancreatic masses; (ii) using cytology of EUS-guided FNA samples, histopathology of surgical specimens, or at least 6-month follow-up as reference standard; and (iii) reported data（sensitivity，specificity，negative predictive value，positive predictive value） necessary
ACCEPTED MANUSCRIPT to calculate the true positive (TP), false positive (FP), true negative (TN) and false negative (FN) rates of EUS elastography in the diagnosis of pancreatic masses. Studies were excluded based on any of the following criteria, (i) studies were review articles, case reports, laboratory articles or letters; (ii) studies
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reporting on <10 patients; (iii) studies updated or duplicated.
Study selection and data extraction
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Articles were extracted independently by two investigators (Binglan Zhang and Fuping Zhu), and
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then verified reciprocally, with disagreements in study selection or data extraction being resolved by consensus or in consultation with a third investigator (Minmin Li). For each study, the following information was recorded: first author, publication year, country, number of patients, study design, mean age of patients, male proportion, mean masses size, prevalence of malignant pancreatic masses,
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masses in pancreatic head proportion, reference standard, diagnostic standard, and cut-off value. TP, FP, TN and FN were extracted or calculated according to sensitivity, specificity, positive predictive value
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(PPV), negative predictive value (NPV) in each study.
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Quality assessment
The quality of the studies was assessed independently by Fuping Zhu and Pan Li using a checklist based on the quality assessment of diagnostic accuracy (QUADAS) tool, which contains 14 questions and was designed to evaluate the diagnostic accuracy of the studies and investigations(18).
Statistical analysis
ACCEPTED MANUSCRIPT Overall pooled of sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR) with corresponding 95% CI were used to examine EUS elastography accuracy for the differentiation of benign and malignant pancreatic masses. Summary receiver operating characteristic
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(SROC) curve, constructed as described by Moses et al.(19), was plotted to graphically display the results. The Q* index was used to define the point on the SROC curve where sensitivity equals
and an AUC of 1.0 indicated a perfect diagnostic tool(21).
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specificity(20). The area under the curve (AUC) was calculated, which close to 0.5 indicated a poor test
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The Chi-square and I-square tests were used to assess the heterogeneity. If I2 is greater than 50% or a low P value(＜0.05) of X2 test, it suggests that there is heterogeneity between studies. The fixed-effect model was used for pooled analyses when significant heterogeneity was not present. The random-effect model was applied otherwise.
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All above calculations（TP，FP，TN，FN included）were performed using RevMan5.1 (Cochrane collaboration, Oxford, UK). All statistical analyses shown in all the figures were analyzed by using Meta-Disc version 1.4 (Unit of Clinical Biostatistics, Ramony Cajal Hospital, Madrid, Spain), P value
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＜0.05 was considered to be statistically significant. The Begg’s funnel plot was applied to assess the
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potential publication bias by STATA 11.0 (STATA Corporation, College Station, TX), p > 0.05 was considered that there was no potential publication bias.
Result
Search results and characteristics of studies Based on the described search strategies, a total of 250 studies were retrieved. After screening titles and abstracts, 54 studies were identified for full text review. Of these articles, 22 referred to review
ACCEPTED MANUSCRIPT articles, 5 referred to other detecting methods, 3 were case reports, 3 had no sufficient data for calculation(22-24), 1 was a duplicate publication(25), and 1 was a letter. Finally, 19 potentially relevant studies were identified as eligible studies (shown in Figure 1)(26-44).
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The eligible articles were published from 2006 to 2017. The patients’ clinical characteristics and other useful information were summarized in Table 1. A total of 1687 patients (1703 pancreatic masses) were evaluated in these studies. The overall prevalence of malignant pancreatic masses was 66.01%
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(range, 32.8%–93.0%). The mean age ranged between 55 and 70 years. The mean size of the pancreatic
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masses ranged from 24.7 to 35.6mm.
In current study, colour pattern and elastic score were defined as qualitative EUS elastography, quantitative EUS elastography included hue histogram and strain ratio (SR). Among the included studies, 7 studies used qualitative EUS elastography(26, 27, 29, 30, 33, 37, 42), 9 studies used
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quantitative EUS elastography(28, 32, 34-36, 39-41, 43), and 3 studies used both qualitative and quantitative EUS elastography(31, 38, 44). For those using SR in our meta-analysis, the cut-off valuesvaried from 3.05 to 10. In addition, 4 studies evaluated the diagnostic performance of
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contrast-enhanced ultrasound(CEUS) and EUS elastography(32, 37, 42, 43), 2 studies evaluated the
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elasticity value of pancreatic masses(31, 35), and 1 study also evaluated the result of color pattern and SR(44).
Quality assessment using the QUADAS questionnaire The QUADAS questionnaire was used for quality assessment(Supplementary Table 1). The overall quality of the studies was good, with all the studies having a ‘‘yes’’ rating for over 10 items. Most studies reported that there were three kinds of reference standard, including EUS-FNA, surgery, and
ACCEPTED MANUSCRIPT follow up. Therefore, for item 6, concerning differential verification bias, were rated with ‘‘No’’ for most studies.
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Diagnostic accuracy of qualitative EUS elastography As shown in Figure 2a, the summary sensitivity and specificity for the diagnosis of malignant pancreatic masses by qualitative EUS elastography were 0.98 (95% CI 0.96-0.99) and 0.63 (95% CI
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0.58-0.69), respectively. The positive and negative LR were 2.60 (95% CI 1.84-3.66) and 0.05 (95% CI
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0.02-0.10) for qualitative EUS elastography (Figure 3a). The summary DOR was 60.59 (95% CI 28.12-130.56) (Figure 4a). SROC curves and *Q index of qualitative EUS elastography for pancreatic masses are shown in Figure 5a. The AUC and the estimates of Q* index were 0.91 and 0.842, respectively. In the chi-square and I-square tests, there were statistically significant heterogeneity in the
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sensitivity (heterogeneity X2=20.80, P = 0.0136; I-square 56.7%), specificity (heterogeneity X2= 36.35, P = 0.0000; I-square 75.2%), and positive LR (heterogeneity X2 = 7.514, P = 0.0000; I-square 81.1%), while heterogeneity in negative LR (heterogeneity X2 = 12.91, P = 0.1668; I-square 30.3%) and DOR
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(heterogeneity X2= 12.07, P = 0.2095; I-square 25.4%) were not observed.
Diagnostic accuracy of quantitative EUS elastography The pooled sensitivity and specificity of quantitative EUS elastography for the differentiation of benign and malignant pancreatic masses were 0.95 (95% CI 0.93-0.97) and 0.61 (95% CI 0.56-0.66), respectively (Figure 2b). Both the sensitivity and specificity of quantitative EUS elastography were similar to that of qualitative EUS elastography. As shown in Figure 3b, the positive and negative LR were 2.64 (95% CI 1.82-3.82) and 0.10 (95% CI 0.06–0.16) for quantitative EUS elastography. The
ACCEPTED MANUSCRIPT summary DOR was 30.09 (95% CI 15.40-58.76) (Figure 4b), and the AUC was 0.93 (Q*=0.860) (Figure 5b). In the chi-square and I-square tests, there were statistically significant heterogeneity in the sensitivity (heterogeneity X2 = 29.59, P = 0.0018; I-square 62.8%), specificity (heterogeneity X2 =
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59.13, P = 0.0000; I-square 81.4%), and positive LR (heterogeneity X2 = 86.76, P = 0.0000; I-square 87.3%).The included articles were divided into two groups by the technique approach of quantitative
elastography: strain ratio and hue histogram. The pooled sensitivity and specificity were 0.95 (95% CI
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0.92-0.97) and 0.67 (95% CI 0.59-0.73) for the strain ratio group (Supplementary Figure 1a), 0.96
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(95% CI 0.93-0.98) and 0.55 (95% CI 0.47-0.63) for the hue histogram group (Supplementary Figure 1b), respectively. As shown in Supplementary Figure 2, the positive and negative LR were 2.96 (95% CI 1.55-5.68) and 0.11 (95% CI 0.06-0.20) for the strain ratio group, 2.38 (95% CI 1.63-3.48) and 0.09 (95% CI 0.03–0.22) for the hue histogram group. The summary diagnostic odds ratio (DOR) and the
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AUC were 29.95 (95% CI 10.84-82.72) (Supplementary Figure 3a) and 0.96 (Q*=0.901) (Supplementary Figure 4a) for the strain ratio group, while 37.05 (95% CI 18.32-74.94)
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group.
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(Supplementary Figure 3b) and 0.86 (Q*=0.790) (Supplementary Figure 4b) for the hue histogram
Publication bias
Begg’s test and funnel plot were used to evaluate publication bias. No significant publication bias were found for diagnostic OR of qualitative EUS elastography (P = 0.655) and quantitative EUS elastography (P = 0.217) in the meta-analyses (Figure 6).
Discussion
ACCEPTED MANUSCRIPT Early correct diagnosis of pancreatic masses is essential for making clinical decision and would improve the disease survival. EUS elastography is a new non-invasive technique to complement conventional EUS and has a potential to improve the diagnosis accuracy yet has virtually no potential
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of causing any additional adverse risk. Nowadays, EUS elastography uses a qualitative method or a quantitative method. Color pattern is a qualitative standard that defines the elastographic patterns by use of different colors based on different strains, where hard tissue areas appear as dark blue(26). This
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method is highly operator dependent and cannot provide an objective diagnosis. Recently
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second-generation EUS elastography was developed to evaluate the lesions in a quantitative manner. The hue histogram and strain ratio are two types of quantitative patterns. Hue histogram is a computer-enhanced method for dynamic analysis, which can minimize the operator bias to make an objective evaluation. Strain ratio compares the strain between tumor tissue and the surrounding tissue,
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and a higher ratio indicates a higher probability of malignancy.
We made a meta-analysis of the published articles based on the above two different evaluation methods. Our meta-analysis found that qualitative EUS elastography had a high pooled sensitivity of
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98%, but a poor pooled specificity of 63% in differentiation of benign and malignant solid pancreatic
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masses, with an AUC of 0.91. Similarly, quantitative EUS elastography had a same sensitivity (95%). The specificity was also not satisfactory (61%), and the AUC was 0.93. However, to improve the unsatisfactory specificity will obviously be not possible due to the fact, that stiffness of tissues is not directly related to malignancy, but to various mechanical properties of tissues as desmoplastic tumoral reaction, fibrosis or typical anatomical characteristics of distinct tumors as for example serous microcystic adenoma. The summary DOR of qualitative and quantitative EUS elastography were 60.59 (95% CI 28.12-130.56) and 30.09 (95% CI 15.40-58.76), respectively. The pooled results implied that
ACCEPTED MANUSCRIPT there was no significant difference in the accuracy for the diagnosis of malignant pancreatic masses between qualitative and quantitative EUS elastography. In this respect, EUS elastography may be an appropriate method for screening patients with pancreatic masses, and could be used as a valuable
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complementary method to EUS-FNA. Nevertheless, the limited specificity is still not solved using EUS elastography. In our meta-analysis, there are 4 studies evaluated the diagnostic performance of contrast-enhanced ultrasound(CEUS) and EUS elastography(32, 37, 42, 43). The summary sensitivity
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and specificity for the differentiation of benign and malignant pancreatic masses were 0.89 (95% CI
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0.84-0.93) and 0.76 (95% CI 0.67-0.84), respectively, indicating that the combination of CEUS and EUS elastography help in increasing specificity. However, the sample size was small, and the results should be validated in large prospective multi-center studies. Two studies have reported the elasticity value of pancreatic masses(31, 35). Since the number of articles was too small, we didn't do statistical
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analysis. In addition, Okasha et al. also evaluated the result of color pattern and SR(44). Combining qualitative EUS elastography to quantitative EUS elastography had a sensitivity of 98%, specificity of 77%, PPV of 91%, NPV of 95%, respectively, which increased the accuracy for the differentiation of
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benign from malignant pancreatic masses. For qualitative EUS elastography, heterogeneity was found
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in the sensitivity (heterogeneity X2=20.80, P = 0.0136; I-square 56.7%), specificity (heterogeneity X2= 36.35, P = 0.0000; I-square 75.2%), and positive LR (heterogeneity X2 = 7.514, P = 0.0000; I-square 81.1%) in our meta- analysis. While for quantitative EUS elastography, heterogeneity was found in the sensitivity (heterogeneity X2 = 29.59, P = 0.0018; I-square 62.8%), specificity (heterogeneity X2 = 59.13, P = 0.0000; I-square 81.4%), and positive LR (heterogeneity X2 = 86.76, P = 0.0000; I-square 87.3%). This could be explained by the large variations of patients’ pancreatic lesions between the included studies. The inclusion criteria of different types of focal masses were different in the included
ACCEPTED MANUSCRIPT studies. It is mainly reflected in whether inflammatory diseases, cystic lesions and neuroendocrine tumors are included. Secondly, methodological difference between included studies is also an important source of heterogeneity. Several SR-studies used the "softest" region in peripancreatic regions (the
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sliding are between the gastrointestinal wall and pancreas) as reference, whereas other studies used peritumoral pancreatic tissue. In addition, two studies for example included examinations using a radial scop(33, 42), whereas the other studies were performed using longitudinal scopes. Other important
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explanations could be multiple diagnostic standards, different kinds of ultrasound machine,
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methodology and design of studies.
There are still several limitations in this meta-analysis. The major limitations of EUS elastography are that it has intra- and inter-observer variability owing to endoscopists with different levels of experience, and therefore skill and experience is needed to get reproducible results(45). Secondly, the
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pancreatic cancer detection rate of EUS elastography is depending on tumor size, tumor volume, localization and histological type. Another limitation is articles written in other languages besides English were not included. In addition, one study included was published as an abstract, and some
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details were not available(25).
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In conclusion, our meta-analysis shows that either qualitative or quantitative EUS elastography is a promising noninvasive technique for differentiating pancreatic masses with a high sensitivity, and could be used as a valuable complementary method to differentiate malignant from benign pancreatic lesions, and we believe that it may reduce the unnecessary EUS-FNA required for diagnosis in the future. Nevertheless, a preferable diagnostic standard should be explored and the specificity should be improved.
ACCEPTED MANUSCRIPT Acknowledgements
This work was supported by the National Natural and Scientific Foundation of
China (81703057/H1611).
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index (CEHMI) and low mechanical index (CELMI) endosonography in direct comparison. Z 38. Havre RF, Odegaard S, Gilja OH, Nesje LB. Characterization of solid focal pancreatic lesions using endoscopic ultrasonography with real-time elastography. Scand J Gastroenterol. 2014;49:742-51. 39. Kongkam P, Lakananurak N, Navicharern P, Chantarojanasiri T, Aye K, Ridtitid W, et al. Combination of EUS-FNA and elastography (strain ratio) to exclude malignant solid pancreatic lesions: A prospective single-blinded study. J Gastroenterol Hepatol. 2015;30:1683-9.
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40. Opacic D, Rustemovic N, Kalauz M, Markos P, Ostojic Z, Majerovic M, et al. Endoscopic ultrasound elastography strain histograms in the evaluation of patients with pancreatic masses. World J Gastroenterol. 2015;21:4014-9.
41. Mayerle J, Beyer G, Simon P, Dickson EJ, Carter RC, Duthie F, et al. Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass
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lesions. Pancreatology. 2016;16:110-4.
42. Chantarojanasiri T, Hirooka Y, Kawashima H, Ohno E, Kuwahara T, Yamamura T, et al. Endoscopic ultrasound in diagnosis of solid pancreatic lesions: Elastography or contrast-enhanced
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harmonic alone versus the combination. Endosc Int Open. 2017;5:E1136-E43. 43. Iglesias-Garcia J, Lindkvist B, Larino-Noia J, Abdulkader-Nallib I, Dominguez-Munoz JE. Differential diagnosis of solid pancreatic masses: contrast-enhanced harmonic (CEH-EUS), quantitative-elastography (QE-EUS), or both? United European Gastroenterol J. 2017;5:236-46. 44. Okasha H, Elkholy S, El-Sayed R, Wifi MN, El-Nady M, El-Nabawi W, et al. Real time endoscopic ultrasound elastography and strain ratio in the diagnosis of solid pancreatic lesions. World J Gastroenterol. 2017;23:5962-8. 45. Soares JB, Iglesias-Garcia J, Goncalves B, Lindkvist B, Larino-Noia J, Bastos P, et al. Interobserver agreement of EUS elastography in the evaluation of solid pancreatic lesions. Endosc Ultrasound. 2015;4:244-9.
ACCEPTED MANUSCRIPT Figure legends Figure 1 Literature search and selection schema. Figure 2 Forest plots of sensitivity and specificity for EUS elastography in the diagnosis of malignant
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pancreatic masses. (a) qualitative EUS elastography; (b) quantitative EUS elastography. Figure 3 Forest positive LR and negative LR of EUS elastography for differentiation of pancreatic masses. (a) qualitative EUS elastography; (b) quantitative EUS elastography.
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Figure 4 The summary diagnostic odds ratio (DOR) of qualitative EUS elastography(a) and
benign and malignant pancreatic masses.
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quantitative EUS elastography (b) used to examine the diagnostic accuracy for the differentiation of
Figure 5 Summary receiver operating characteristic (SROC) curve of EUS elastography for differentiation of pancreatic masses. (a) qualitative EUS elastography; (b) quantitative EUS
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elastography.
Figure 6 Funnel plots of publication bias summary for meta-analysis of diagnostic OR. (a) qualitative
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EUS elastography; (b) quantitative EUS elastography.
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Table 1 Main characteristics of the included studies Male No.of Author
No.of EUS
Year Country
Mean age Study design
patients
assessments
mass proportion
(years)
size (%)
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Masses in Mean
Prevalence of
pancreatic
malignant
head
masses (%) (mm)
Reference
Diagnostic
standard
standard
Cut-off
proportion
Prospective, Giovannini et al.
2006
France
24
24
60
NA
Prospective, Janssen et al.
2007 Germany
33
33
67 single-center Prospective,
Saftoiu et al.
2008 Romania
43
43
60.6 single-center
Giovannini et al.
2009
France
121
121
Iglesias-Garcia et al.
2009
Spain
130
130
Multi-center
63 62
75
50
EUS-FNA, surgery
Color pattern
Blue predominant
EUS-FNA, surgery
Color pattern
Blue predominant
Hue histogram
175
Color pattern
Blue predominant
Color pattern
Blue predominant
EUS-FNA, surgery,
Strain ratio or
6.04 or blue
follow up
color pattern
predominant
Hue histogram
175
Color pattern
Blue predominant
Hue histogram
170
Strain ratio
6.04
39.4
30
81.8
69.7
71.7
NA
74
NA
63.6
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Prospective,
24.7
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single-center
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(%)
66.9
EUS-FNA, surgery, follow up
29.5
76
51.2
30.9
67.7
76.2
EUS-FNA, surgery,
single-center
follow up
Prospective, Iglesias-Garcia et al.
2010
Spain
86
86
61
67.4
31.4
67.4
72
single-center 2010 Romania
54
54
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Prospective, Saftoiu et al.
56.9
EUS-FNA, surgery
EUS-FNA, surgery, 79.6
35.6
61.1
87
single-center
follow up
2011
Japan
86
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Retrospective,
Itokawa et al.
86
64.8
64.2
NA
93
NA
64
66.7
NA
81.8
NA
EUS-FNA, surgery
single-center Prospective,
Saftoiu et al.
2011 Romania
258
258
EUS-FNA, surgery,
multi-center
follow up
Prospective, Dawwas et al.
2012
UK
104
111
EUS-FNA, surgery, 67
single-center
54.8
30
83.8
55.8 follow up
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Prospective, Figueiredo et al.
2012
France
47
47
EUS-FNA, surgery, 70
57.4
31
72
51
Hocke et al.
2012 Germany
58
58
NA
60
67.2
NA
Prospective, Havre et al.
2014 Norway
39
48
55
51.3
NA
Prospective, 2015 Thailand
38
38
61
47.4
Prospective, Opacic et al.
2015
Croatia
105
105
63 single-center Prospective,
Mayerle et al.
2016 Mayerle
91
91
68 single-center Retrospective,
2017
Japan
136
136
65.1
49
NA
60.3
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Chantarojanasiri et al.
37.5
34.1
76.3
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single-center
32.8
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single-center
Kongkam et al.
Spain
62
62
31.7
NA
27.6
55.2
74.7
69.9
65.8
64.3
172
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172
55.7
multi-center
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Egypt
EUS-FNA, surgery,
Strain ratio or
3.05 or blue
follow up
color pattern
predominant
Strain ratio
3.17
71
69.8
cytopathology, follow-up EUS-FNA, surgery,
Hue histogram 86
51.5 follow up EUS-FNA, surgery, NA
Strain ratio
10
Color pattern
Blue predominant
Strain ratio
10
EUS-FNA, surgery,
Strain ratio or
7.8 or blue
follow up
color pattern
predominant
follow up EUS-FNA, surgery, 61 biopsy EUS-FNA, surgery,
32
74.2
72.6 follow up
Prospective, 2017
Blue predominant
follow up
Surgery, biopsy,
single-center Okasha et al.
Color pattern
EUS-FNA, surgery,
NA
Prospective, 2017
8
NA
single-center Iglesias-Garcia et al.
Strain ratio follow up
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single-center
NA
71.5
72.7
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S1424-3903(18)30635-5
DOI:
10.1016/j.pan.2018.07.008
Reference:
PAN 900
To appear in:
Pancreatology
Received Date: 21 March 2018 Revised Date:
6 July 2018
Accepted Date: 28 July 2018
Please cite this article as: Zhang B, Zhu F, Li P, Yu S, Zhao Y, Li M, Endoscopic ultrasound elastography in the diagnosis of pancreatic masses: A meta-analysis, Pancreatology (2018), doi: 10.1016/j.pan.2018.07.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT Endoscopic ultrasound elastography in the diagnosis of pancreatic masses: a meta-analysis
1
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Binglan Zhang1, Fuping Zhu2, Pan Li1, Shishi Yu1, Yajing Zhao3, Minmin Li4*
Department of gastroenterology, the first affiliated hospital of chongqing medical
Department of hepatobiliary surgery, the ninth people's hospital of chongqing, Chongqing 400700,
China 3
Department of sonography, the first affiliated hospital of chongqing medical
university, Chongqing 400016, China
Department of oncology, the first affiliated hospital of chongqing medical university, Chongqing 4000
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4
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2
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university, Chongqing 400016, China
16, China
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Note: *Corresponding author
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Corresponding author: Minmin Li Email: [email protected] Tel.: +86 23 89011613.
ACCEPTED MANUSCRIPT Abstract Background and Aims
Endoscopic ultrasound (EUS) elastography is a novel non-invasive technique
that can be used for distinguishing benign from malignant pancreatic masses. However, the studies
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have reported widely varied sensitivities and specificities. A meta-analysis was performed to assess the performance of EUS elastography for the differentiation of benign and malignant pancreatic masses. Methods
All the eligible studies were searched by PubMed, Medline, Embase, and the Cochrane
Results
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(AUC) were calculated to examine the accuracy.
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Library. Sensitivity, specificity, positive likelihood ratio (LR), negative LR, and area under the curve
A total of nineteen studies which included 1687 patients were analysed. The pooled
sensitivity and specificity for the diagnosis of malignant pancreatic masses were 0.98 (95% confidence interval [CI] 0.96-0.99) and 0.63 (95% CI 0.58-0.69) for qualitative EUS elastography, 0.95 (95% CI
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0.93-0.97) and 0.61 (95% CI 0.56-0.66) for quantitative EUS elastography, respectively. The positive and negative LR were 2.60 (95% CI 1.84-3.66) and 0.05 (95% CI 0.02-0.10) for qualitative EUS elastography, 2.64 (95% CI 1.82-3.82) and 0.10 (95% CI 0.06–0.16) for quantitative EUS elastography,
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respectively. The summary diagnostic odds ratio (DOR) and the AUC were 60.59 (95% CI
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28.12-130.56) and 0.91 (Q*=0.842) for qualitative EUS elastography, 30.09(95% CI 15.40-58.76) and 0.93 (Q*=0.860) for quantitative EUS elastography.Conclusions
Our meta-analysis shows that both
qualitative and quantitative EUS elastography have high accuracy in the detection of malignant pancreatic masses, which could be used as a valuable complementary method to EUS-FNA for the differentiation of pancreatic masses in the future. Key words: Endoscopic ultrasound, Elastography, Pancreatic masses, Diagnosis, Meta-analysis
ACCEPTED MANUSCRIPT Introduction Pancreatic cancer is a highly lethal disease with a poor prognosis, mainly because of its aggressive behavior and the difficulty in early diagnosis(1). Surgical resection offers the only potential cure, but
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small pancreatic cancer has non-specific symptoms, signs or imaging presentations, so that only less than 15% of patients are candidates for pancreatectomy. Therefore, an accurate diagnosis of benign and malignant pancreatic masses is very critical for making clinical decisions.
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Traditionally, several image modalities are used to diagnose pancreatic lesions, including
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transabdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or endoscopic retrograde cholangiopancreatography (ERCP)(2, 3). Taken individually, these methods have limited sensitivity for recognizing early pancreatic tumors. Endoscopic ultrasonography (EUS) is one of the most recent advances in gastrointestinal endoscopy.
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Numerous studies have indicated that EUS is more sensitive for the detection of pancreatic tumors compared with the traditional modalities(4-6). EUS is currently considered to be an important tool for diagnosis of chronic inflammatory, cystic, neoplastic pancreatic lesions and focal pancreatic masses(7,
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8), which also has the ability to provide fine needle aspiration (FNA) and obtain cytology or histology.
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However, EUS often cannot distinguish between chronic pseudotumoral pancreatitis and pancreatic cancer. EUS-guided FNA is an invasive procedure and associated with some inevitable complications(9), which can achieve a robust accuracy and also produce a false-negative result for the patients’ underlying chronic pancreatitis up to 20% to 40%(10, 11). Therefore, the differentiation diagnosis of benign and malignant pancreatic masses remains a challenge. Elastography, a noninvasive method used for the real-time calculation and visualization of tissue elasticity, has shown promising results in the diagnosis of various cancers. To help improve the
ACCEPTED MANUSCRIPT diagnostic yield of EUS, EUS elastography is increasingly being used. Measurements of tissue elasticity would be analyzed either by a qualitative method or a quantitative method. Previous meta-analysis have shown that EUS elastography is a promising non-invasive technique for the
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differentiation of pancreatic masses and can be considered to be a valuable supplemental method to EUS-guided FNA(12-17). Nevertheless, there were many articles published in this field in recent years. The aim of this study is to make a thorough search of the published articles and assess the overall
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performance of real-time EUS elastography for the differentiation of benign and malignant pancreatic
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masses.
Materials and methods Literature search
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We searched PubMed, Medline, Embase, and the Cochrane Library for studies published prior to November 10, 2017. The search terms were elastograms, elastography, elastosonography, elasticity imaging, endoscopic ultrasonography, EUS, elastosonoendoscopy, EUS elastography, pancreas, and
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pancreatic. A full manual search was also performed by using references of eligible articles. Language
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was limited to English.
Study inclusion/exclusion criteria Studies were considered eligible if they met all of the following inclusion criteria, (i) evaluated EUS elastography for the diagnosis of pancreatic masses; (ii) using cytology of EUS-guided FNA samples, histopathology of surgical specimens, or at least 6-month follow-up as reference standard; and (iii) reported data（sensitivity，specificity，negative predictive value，positive predictive value） necessary
ACCEPTED MANUSCRIPT to calculate the true positive (TP), false positive (FP), true negative (TN) and false negative (FN) rates of EUS elastography in the diagnosis of pancreatic masses. Studies were excluded based on any of the following criteria, (i) studies were review articles, case reports, laboratory articles or letters; (ii) studies
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reporting on <10 patients; (iii) studies updated or duplicated.
Study selection and data extraction
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Articles were extracted independently by two investigators (Binglan Zhang and Fuping Zhu), and
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then verified reciprocally, with disagreements in study selection or data extraction being resolved by consensus or in consultation with a third investigator (Minmin Li). For each study, the following information was recorded: first author, publication year, country, number of patients, study design, mean age of patients, male proportion, mean masses size, prevalence of malignant pancreatic masses,
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masses in pancreatic head proportion, reference standard, diagnostic standard, and cut-off value. TP, FP, TN and FN were extracted or calculated according to sensitivity, specificity, positive predictive value
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(PPV), negative predictive value (NPV) in each study.
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Quality assessment
The quality of the studies was assessed independently by Fuping Zhu and Pan Li using a checklist based on the quality assessment of diagnostic accuracy (QUADAS) tool, which contains 14 questions and was designed to evaluate the diagnostic accuracy of the studies and investigations(18).
Statistical analysis
ACCEPTED MANUSCRIPT Overall pooled of sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR) with corresponding 95% CI were used to examine EUS elastography accuracy for the differentiation of benign and malignant pancreatic masses. Summary receiver operating characteristic
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(SROC) curve, constructed as described by Moses et al.(19), was plotted to graphically display the results. The Q* index was used to define the point on the SROC curve where sensitivity equals
and an AUC of 1.0 indicated a perfect diagnostic tool(21).
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specificity(20). The area under the curve (AUC) was calculated, which close to 0.5 indicated a poor test
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The Chi-square and I-square tests were used to assess the heterogeneity. If I2 is greater than 50% or a low P value(＜0.05) of X2 test, it suggests that there is heterogeneity between studies. The fixed-effect model was used for pooled analyses when significant heterogeneity was not present. The random-effect model was applied otherwise.
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All above calculations（TP，FP，TN，FN included）were performed using RevMan5.1 (Cochrane collaboration, Oxford, UK). All statistical analyses shown in all the figures were analyzed by using Meta-Disc version 1.4 (Unit of Clinical Biostatistics, Ramony Cajal Hospital, Madrid, Spain), P value
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＜0.05 was considered to be statistically significant. The Begg’s funnel plot was applied to assess the
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potential publication bias by STATA 11.0 (STATA Corporation, College Station, TX), p > 0.05 was considered that there was no potential publication bias.
Result
Search results and characteristics of studies Based on the described search strategies, a total of 250 studies were retrieved. After screening titles and abstracts, 54 studies were identified for full text review. Of these articles, 22 referred to review
ACCEPTED MANUSCRIPT articles, 5 referred to other detecting methods, 3 were case reports, 3 had no sufficient data for calculation(22-24), 1 was a duplicate publication(25), and 1 was a letter. Finally, 19 potentially relevant studies were identified as eligible studies (shown in Figure 1)(26-44).
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The eligible articles were published from 2006 to 2017. The patients’ clinical characteristics and other useful information were summarized in Table 1. A total of 1687 patients (1703 pancreatic masses) were evaluated in these studies. The overall prevalence of malignant pancreatic masses was 66.01%
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(range, 32.8%–93.0%). The mean age ranged between 55 and 70 years. The mean size of the pancreatic
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masses ranged from 24.7 to 35.6mm.
In current study, colour pattern and elastic score were defined as qualitative EUS elastography, quantitative EUS elastography included hue histogram and strain ratio (SR). Among the included studies, 7 studies used qualitative EUS elastography(26, 27, 29, 30, 33, 37, 42), 9 studies used
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quantitative EUS elastography(28, 32, 34-36, 39-41, 43), and 3 studies used both qualitative and quantitative EUS elastography(31, 38, 44). For those using SR in our meta-analysis, the cut-off valuesvaried from 3.05 to 10. In addition, 4 studies evaluated the diagnostic performance of
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contrast-enhanced ultrasound(CEUS) and EUS elastography(32, 37, 42, 43), 2 studies evaluated the
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elasticity value of pancreatic masses(31, 35), and 1 study also evaluated the result of color pattern and SR(44).
Quality assessment using the QUADAS questionnaire The QUADAS questionnaire was used for quality assessment(Supplementary Table 1). The overall quality of the studies was good, with all the studies having a ‘‘yes’’ rating for over 10 items. Most studies reported that there were three kinds of reference standard, including EUS-FNA, surgery, and
ACCEPTED MANUSCRIPT follow up. Therefore, for item 6, concerning differential verification bias, were rated with ‘‘No’’ for most studies.
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Diagnostic accuracy of qualitative EUS elastography As shown in Figure 2a, the summary sensitivity and specificity for the diagnosis of malignant pancreatic masses by qualitative EUS elastography were 0.98 (95% CI 0.96-0.99) and 0.63 (95% CI
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0.58-0.69), respectively. The positive and negative LR were 2.60 (95% CI 1.84-3.66) and 0.05 (95% CI
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0.02-0.10) for qualitative EUS elastography (Figure 3a). The summary DOR was 60.59 (95% CI 28.12-130.56) (Figure 4a). SROC curves and *Q index of qualitative EUS elastography for pancreatic masses are shown in Figure 5a. The AUC and the estimates of Q* index were 0.91 and 0.842, respectively. In the chi-square and I-square tests, there were statistically significant heterogeneity in the
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sensitivity (heterogeneity X2=20.80, P = 0.0136; I-square 56.7%), specificity (heterogeneity X2= 36.35, P = 0.0000; I-square 75.2%), and positive LR (heterogeneity X2 = 7.514, P = 0.0000; I-square 81.1%), while heterogeneity in negative LR (heterogeneity X2 = 12.91, P = 0.1668; I-square 30.3%) and DOR
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(heterogeneity X2= 12.07, P = 0.2095; I-square 25.4%) were not observed.
Diagnostic accuracy of quantitative EUS elastography The pooled sensitivity and specificity of quantitative EUS elastography for the differentiation of benign and malignant pancreatic masses were 0.95 (95% CI 0.93-0.97) and 0.61 (95% CI 0.56-0.66), respectively (Figure 2b). Both the sensitivity and specificity of quantitative EUS elastography were similar to that of qualitative EUS elastography. As shown in Figure 3b, the positive and negative LR were 2.64 (95% CI 1.82-3.82) and 0.10 (95% CI 0.06–0.16) for quantitative EUS elastography. The
ACCEPTED MANUSCRIPT summary DOR was 30.09 (95% CI 15.40-58.76) (Figure 4b), and the AUC was 0.93 (Q*=0.860) (Figure 5b). In the chi-square and I-square tests, there were statistically significant heterogeneity in the sensitivity (heterogeneity X2 = 29.59, P = 0.0018; I-square 62.8%), specificity (heterogeneity X2 =
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59.13, P = 0.0000; I-square 81.4%), and positive LR (heterogeneity X2 = 86.76, P = 0.0000; I-square 87.3%).The included articles were divided into two groups by the technique approach of quantitative
elastography: strain ratio and hue histogram. The pooled sensitivity and specificity were 0.95 (95% CI
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0.92-0.97) and 0.67 (95% CI 0.59-0.73) for the strain ratio group (Supplementary Figure 1a), 0.96
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(95% CI 0.93-0.98) and 0.55 (95% CI 0.47-0.63) for the hue histogram group (Supplementary Figure 1b), respectively. As shown in Supplementary Figure 2, the positive and negative LR were 2.96 (95% CI 1.55-5.68) and 0.11 (95% CI 0.06-0.20) for the strain ratio group, 2.38 (95% CI 1.63-3.48) and 0.09 (95% CI 0.03–0.22) for the hue histogram group. The summary diagnostic odds ratio (DOR) and the
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AUC were 29.95 (95% CI 10.84-82.72) (Supplementary Figure 3a) and 0.96 (Q*=0.901) (Supplementary Figure 4a) for the strain ratio group, while 37.05 (95% CI 18.32-74.94)
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group.
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(Supplementary Figure 3b) and 0.86 (Q*=0.790) (Supplementary Figure 4b) for the hue histogram
Publication bias
Begg’s test and funnel plot were used to evaluate publication bias. No significant publication bias were found for diagnostic OR of qualitative EUS elastography (P = 0.655) and quantitative EUS elastography (P = 0.217) in the meta-analyses (Figure 6).
Discussion
ACCEPTED MANUSCRIPT Early correct diagnosis of pancreatic masses is essential for making clinical decision and would improve the disease survival. EUS elastography is a new non-invasive technique to complement conventional EUS and has a potential to improve the diagnosis accuracy yet has virtually no potential
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of causing any additional adverse risk. Nowadays, EUS elastography uses a qualitative method or a quantitative method. Color pattern is a qualitative standard that defines the elastographic patterns by use of different colors based on different strains, where hard tissue areas appear as dark blue(26). This
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method is highly operator dependent and cannot provide an objective diagnosis. Recently
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second-generation EUS elastography was developed to evaluate the lesions in a quantitative manner. The hue histogram and strain ratio are two types of quantitative patterns. Hue histogram is a computer-enhanced method for dynamic analysis, which can minimize the operator bias to make an objective evaluation. Strain ratio compares the strain between tumor tissue and the surrounding tissue,
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and a higher ratio indicates a higher probability of malignancy.
We made a meta-analysis of the published articles based on the above two different evaluation methods. Our meta-analysis found that qualitative EUS elastography had a high pooled sensitivity of
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98%, but a poor pooled specificity of 63% in differentiation of benign and malignant solid pancreatic
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masses, with an AUC of 0.91. Similarly, quantitative EUS elastography had a same sensitivity (95%). The specificity was also not satisfactory (61%), and the AUC was 0.93. However, to improve the unsatisfactory specificity will obviously be not possible due to the fact, that stiffness of tissues is not directly related to malignancy, but to various mechanical properties of tissues as desmoplastic tumoral reaction, fibrosis or typical anatomical characteristics of distinct tumors as for example serous microcystic adenoma. The summary DOR of qualitative and quantitative EUS elastography were 60.59 (95% CI 28.12-130.56) and 30.09 (95% CI 15.40-58.76), respectively. The pooled results implied that
ACCEPTED MANUSCRIPT there was no significant difference in the accuracy for the diagnosis of malignant pancreatic masses between qualitative and quantitative EUS elastography. In this respect, EUS elastography may be an appropriate method for screening patients with pancreatic masses, and could be used as a valuable
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complementary method to EUS-FNA. Nevertheless, the limited specificity is still not solved using EUS elastography. In our meta-analysis, there are 4 studies evaluated the diagnostic performance of contrast-enhanced ultrasound(CEUS) and EUS elastography(32, 37, 42, 43). The summary sensitivity
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and specificity for the differentiation of benign and malignant pancreatic masses were 0.89 (95% CI
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0.84-0.93) and 0.76 (95% CI 0.67-0.84), respectively, indicating that the combination of CEUS and EUS elastography help in increasing specificity. However, the sample size was small, and the results should be validated in large prospective multi-center studies. Two studies have reported the elasticity value of pancreatic masses(31, 35). Since the number of articles was too small, we didn't do statistical
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analysis. In addition, Okasha et al. also evaluated the result of color pattern and SR(44). Combining qualitative EUS elastography to quantitative EUS elastography had a sensitivity of 98%, specificity of 77%, PPV of 91%, NPV of 95%, respectively, which increased the accuracy for the differentiation of
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benign from malignant pancreatic masses. For qualitative EUS elastography, heterogeneity was found
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in the sensitivity (heterogeneity X2=20.80, P = 0.0136; I-square 56.7%), specificity (heterogeneity X2= 36.35, P = 0.0000; I-square 75.2%), and positive LR (heterogeneity X2 = 7.514, P = 0.0000; I-square 81.1%) in our meta- analysis. While for quantitative EUS elastography, heterogeneity was found in the sensitivity (heterogeneity X2 = 29.59, P = 0.0018; I-square 62.8%), specificity (heterogeneity X2 = 59.13, P = 0.0000; I-square 81.4%), and positive LR (heterogeneity X2 = 86.76, P = 0.0000; I-square 87.3%). This could be explained by the large variations of patients’ pancreatic lesions between the included studies. The inclusion criteria of different types of focal masses were different in the included
ACCEPTED MANUSCRIPT studies. It is mainly reflected in whether inflammatory diseases, cystic lesions and neuroendocrine tumors are included. Secondly, methodological difference between included studies is also an important source of heterogeneity. Several SR-studies used the "softest" region in peripancreatic regions (the
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sliding are between the gastrointestinal wall and pancreas) as reference, whereas other studies used peritumoral pancreatic tissue. In addition, two studies for example included examinations using a radial scop(33, 42), whereas the other studies were performed using longitudinal scopes. Other important
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explanations could be multiple diagnostic standards, different kinds of ultrasound machine,
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methodology and design of studies.
There are still several limitations in this meta-analysis. The major limitations of EUS elastography are that it has intra- and inter-observer variability owing to endoscopists with different levels of experience, and therefore skill and experience is needed to get reproducible results(45). Secondly, the
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pancreatic cancer detection rate of EUS elastography is depending on tumor size, tumor volume, localization and histological type. Another limitation is articles written in other languages besides English were not included. In addition, one study included was published as an abstract, and some
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details were not available(25).
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In conclusion, our meta-analysis shows that either qualitative or quantitative EUS elastography is a promising noninvasive technique for differentiating pancreatic masses with a high sensitivity, and could be used as a valuable complementary method to differentiate malignant from benign pancreatic lesions, and we believe that it may reduce the unnecessary EUS-FNA required for diagnosis in the future. Nevertheless, a preferable diagnostic standard should be explored and the specificity should be improved.
ACCEPTED MANUSCRIPT Acknowledgements
This work was supported by the National Natural and Scientific Foundation of
China (81703057/H1611).
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012.
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ACCEPTED MANUSCRIPT Figure legends Figure 1 Literature search and selection schema. Figure 2 Forest plots of sensitivity and specificity for EUS elastography in the diagnosis of malignant
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pancreatic masses. (a) qualitative EUS elastography; (b) quantitative EUS elastography. Figure 3 Forest positive LR and negative LR of EUS elastography for differentiation of pancreatic masses. (a) qualitative EUS elastography; (b) quantitative EUS elastography.
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Figure 4 The summary diagnostic odds ratio (DOR) of qualitative EUS elastography(a) and
benign and malignant pancreatic masses.
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quantitative EUS elastography (b) used to examine the diagnostic accuracy for the differentiation of
Figure 5 Summary receiver operating characteristic (SROC) curve of EUS elastography for differentiation of pancreatic masses. (a) qualitative EUS elastography; (b) quantitative EUS
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elastography.
Figure 6 Funnel plots of publication bias summary for meta-analysis of diagnostic OR. (a) qualitative
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EUS elastography; (b) quantitative EUS elastography.
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Table 1 Main characteristics of the included studies Male No.of Author
No.of EUS
Year Country
Mean age Study design
patients
assessments
mass proportion
(years)
size (%)
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Masses in Mean
Prevalence of
pancreatic
malignant
head
masses (%) (mm)
Reference
Diagnostic
standard
standard
Cut-off
proportion
Prospective, Giovannini et al.
2006
France
24
24
60
NA
Prospective, Janssen et al.
2007 Germany
33
33
67 single-center Prospective,
Saftoiu et al.
2008 Romania
43
43
60.6 single-center
Giovannini et al.
2009
France
121
121
Iglesias-Garcia et al.
2009
Spain
130
130
Multi-center
63 62
75
50
EUS-FNA, surgery
Color pattern
Blue predominant
EUS-FNA, surgery
Color pattern
Blue predominant
Hue histogram
175
Color pattern
Blue predominant
Color pattern
Blue predominant
EUS-FNA, surgery,
Strain ratio or
6.04 or blue
follow up
color pattern
predominant
Hue histogram
175
Color pattern
Blue predominant
Hue histogram
170
Strain ratio
6.04
39.4
30
81.8
69.7
71.7
NA
74
NA
63.6
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Prospective,
24.7
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single-center
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(%)
66.9
EUS-FNA, surgery, follow up
29.5
76
51.2
30.9
67.7
76.2
EUS-FNA, surgery,
single-center
follow up
Prospective, Iglesias-Garcia et al.
2010
Spain
86
86
61
67.4
31.4
67.4
72
single-center 2010 Romania
54
54
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Prospective, Saftoiu et al.
56.9
EUS-FNA, surgery
EUS-FNA, surgery, 79.6
35.6
61.1
87
single-center
follow up
2011
Japan
86
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Retrospective,
Itokawa et al.
86
64.8
64.2
NA
93
NA
64
66.7
NA
81.8
NA
EUS-FNA, surgery
single-center Prospective,
Saftoiu et al.
2011 Romania
258
258
EUS-FNA, surgery,
multi-center
follow up
Prospective, Dawwas et al.
2012
UK
104
111
EUS-FNA, surgery, 67
single-center
54.8
30
83.8
55.8 follow up
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Prospective, Figueiredo et al.
2012
France
47
47
EUS-FNA, surgery, 70
57.4
31
72
51
Hocke et al.
2012 Germany
58
58
NA
60
67.2
NA
Prospective, Havre et al.
2014 Norway
39
48
55
51.3
NA
Prospective, 2015 Thailand
38
38
61
47.4
Prospective, Opacic et al.
2015
Croatia
105
105
63 single-center Prospective,
Mayerle et al.
2016 Mayerle
91
91
68 single-center Retrospective,
2017
Japan
136
136
65.1
49
NA
60.3
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Chantarojanasiri et al.
37.5
34.1
76.3
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single-center
32.8
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single-center
Kongkam et al.
Spain
62
62
31.7
NA
27.6
55.2
74.7
69.9
65.8
64.3
172
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172
55.7
multi-center
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Egypt
EUS-FNA, surgery,
Strain ratio or
3.05 or blue
follow up
color pattern
predominant
Strain ratio
3.17
71
69.8
cytopathology, follow-up EUS-FNA, surgery,
Hue histogram 86
51.5 follow up EUS-FNA, surgery, NA
Strain ratio
10
Color pattern
Blue predominant
Strain ratio
10
EUS-FNA, surgery,
Strain ratio or
7.8 or blue
follow up
color pattern
predominant
follow up EUS-FNA, surgery, 61 biopsy EUS-FNA, surgery,
32
74.2
72.6 follow up
Prospective, 2017
Blue predominant
follow up
Surgery, biopsy,
single-center Okasha et al.
Color pattern
EUS-FNA, surgery,
NA
Prospective, 2017
8
NA
single-center Iglesias-Garcia et al.
Strain ratio follow up
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single-center
NA
71.5
72.7
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