Diagnostic performance of imaging modalities in chronic pancreatitis: a systematic review and meta-analysis

Objectives Obtain summary estimates of sensitivity and specificity for imaging modalities for chronic pancreatitis (CP) assessment. Methods A systematic search was performed in Cochrane Library, MEDLINE, Embase and CINAHL databases for studies evaluating imaging modalities for the diagnosis of CP up to September 2016. A bivariate random-effects modeling was used to obtain summary estimates of sensitivity and specificity. Results We included 43 studies evaluating 3460 patients. Sensitivity of endoscopic retrograde cholangiopancreatography (ERCP) (82%; 95%CI: 76%-87%) was significant higher than that of abdominal ultrasonography (US) (67%; 95%CI: 53%-78%; P=0.018). The sensitivity estimates of endoscopic ultrasonography (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) were 81% (95%CI: 70%-89%), 78% (95%CI: 69%-85%), and 75% (95%CI: 66%-83%), respectively, and did not differ significantly from each other. Estimates of specificity were comparable for EUS (90%; 95%CI: 82%-95%), ERCP (94%; 95%CI: 87%-98%), CT (91%; 95% CI: 81%-96%), MRI (96%; 95%CI: 90%-98%), and US (98%; 95%CI: 89%-100%). Conclusions EUS, ERCP, MRI and CT all have comparable high diagnostic accuracy in the initial diagnosis of CP. EUS and ERCP are outperformers and US has the lowest accuracy. The choice of imaging modality can therefore be made based on invasiveness, local availability, experience and costs. Key Points • EUS, ERCP, MRI and CT have high diagnostic sensitivity for chronic pancreatitis • Diagnostic specificity is comparable for all imaging modalities • EUS and ERCP are outperformers and US has the lowest accuracy • The choice of imaging can be made based on clinical considerations


Introduction
Chronic pancreatitis (CP) is a disabling inflammatory disease of the pancreas characterized by severe recurrent or continuous abdominal pain and considerable impact on the quality of life [1][2][3][4]. Patients with CP usually develop endocrine and exocrine insufficiency during the course of the disease as a result of the progressive loss of pancreatic parenchyma.
There is lack of international consensus regarding the initial diagnosis of CP, particularly at its early stages. The diagnosis is often made by a combination of clinical symptoms (e.g. abdominal pain, malabsorption, diabetes mellitus), pancreatic function tests (e.g. fecal elastase-1) and morphological abnormalities seen on imaging (e.g. calcifications, ductal lesions, pseudocysts) [5,6]. Imaging plays a key role in the diagnosis and therapeutic management of patients with CP. The most frequently used imaging modalities for CP are endoscopic ultrasonography (EUS), endoscopic retrograde

Overall diagnostic accuracy
For each included study we constructed a 2 × 2 contingency table for each imaging modality. If diagnostic accuracy was compared between different observers, mean values were calculated. Sensitivity and specificity estimates, the positive predictive value and negative predictive values, and the accuracy were calculated from the reconstructed contingency tables. We used the I 2 test with 95% confidence interval (95% CI) to quantify heterogeneity [11]. Mean logit sensitivity and specificity were acquired, and the anti-logit transformation was then obtained to calculate summary estimates of P prospective, R retrospective, OE observer experience reported, PTC percutaneous transhepatic cholangiogram, ePFT endoscopic pancreatic function test, FU follow-up, NA not available sensitivity and specificity with 95% CIs. Forest plots were made to visualize the sensitivity and specificity with the 95% CIs. Summary estimates of sensitivity and specificity, including 95% CI, were obtained by using a random-effects model [12]. In cases where a negative covariance between the logit sensitivity and logit specificity was obtained, summary receiver operating characteristic curve (sROC) were generated for each separate imaging modality. We used the z test to NA not available *Mean **Median evaluate differences in sensitivity and specificity between the five imaging modalities. A p value of less than 0.05 indicated a statistically significant difference.

Heterogeneity exploration
The following factors were incorporated in the bivariate model and we evaluated the effect on the sensitivity and specificity, and cause of heterogeneity for all imaging modalities according to the QUADAS-2 tool: clear description of criteria for bias (low bias versus high bias or unclear) for (a) patient selection, (b) criteria for the index test used, (c) sufficient description and verification with the reference standard, and (d) the flow and timing.

Head to head comparison
A head to head comparison was performed in studies that compared the diagnostic accuracy of two or more imaging modalities. Heterogeneity was quantified by I 2 test, with 95% CI. The random-effects (I 2 > 25%) and fixed effects (I 2 ≤ 25%) models were used to obtain summary estimates of sensitivity and specificity, and compared with one another by a paired z test. For data analysis, Review Manager (RevMan, version 5.3. Copenhagen: The Cochrane Collaboration, 2014) and SAS (version 9.3; SAS Institute, Cary, NC) were used. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13].

Study selection
The initial search resulted in 11,111 hits, of which 2988 duplicates were removed, resulting in a total of 8123 titles and abstracts that were screened for eligibility. The full text of 277 articles was retrieved; 43 of these articles fulfilled the inclusion criteria. See Appendix Table 6 for the excluded articles. Figure 1 shows the flow chart of the search.

Study and patient characteristics
Study characteristics, including the reference standard for the diagnosis of CP for each included study, are listed in Table 1. The 43 included studies were published between 1975 and 2016; 26 studies were prospective and 23 studies were published after the year 2000. A total of 3460 patients were evaluated, of which 1242 patients were diagnosed with CP . The age of the patients ranged from 36 to 65 years, with a median of 50% male. Criteria for selection of patients were those with suspected pancreatic disease or patients with suspected CP. Patient characteristics are depicted in Table 2.

Overall diagnostic accuracy
Analyses for summary estimates of sensitivity and specificity were done for EUS, ERCP, MRI, CT and US (Table 3). Figures 3 and 4 show sensitivity and specificity of individual studies in forest plots and in receiver operator curves (ROC), respectively. A negative covariance between the logit sensitivity and logit specificity was not obtained; therefore, no sROC for MRI and US could be drawn. The summary estimate of sensitivity for EUS, ERCP, MRCP, CT and US was 81%, 82%, 78%, 75% and 67%, respectively. The summary estimate of specificity for EUS, ERCP, MRCP, CT and US was 90%, 94%, 96%, 91% and 98%, respectively. Sensitivity of ERCP was significant higher than sensitivity of US (p = 0.018). Other pairwise comparisons of sensitivity between imaging modalities revealed no significant difference. Specificity did not differ significantly among all modalities (Table 3). Sensitivity and specificity values for each study are listed in Appendix Table 10.

Heterogeneity exploration
The bivariate model for heterogeneity exploration showed that the factor 'flow and timing' was significantly associated with a higher sensitivity of US (p = 0.01). 'Description and verification with the reference standard' was significantly associated with a higher specificity for MRCP (p = 0.0002).

Head to head comparison
Six head to head comparisons were performed ( Table 4). The specificity of ERCP and EUS, and the sensitivity of ERCP, EUS and CT in the summary estimates of the head to head studies were significantly higher as compared with US.

Discussion
EUS, ERCP, MRI and CT all have comparable high diagnostic accuracy in the initial diagnosis of chronic pancreatitis. EUS and ERCP are outperformers and US has the lowest accuracy. The choice of imaging modality can therefore be made on the basis of invasiveness, local availability, experience and costs.
Several recent guidelines [57][58][59] advocate the use of EUS, MRCP or CT for the diagnosis of CP, although summary estimates of their accuracy, thus far, were lacking. There is one guideline from Germany on CP that has reported sensitivity and specificity regarding EUS, ERCP, MRCP and US, although not for CT [60]. In this guideline 14 studies were selected, reporting ranges rather than pooling the data on sensitivity and specificity estimates. This method resulted in results slightly different from those in the present meta-analyses. For example the guideline reports a sensitivity of 70-80% for ERCP and 88% for MRI versus summary estimates of 82% and 78%, respectively, in the present meta-analyses. The European Society of Radiology (ESR) is developing the ESR iGuide, a clinical decision support system for European imaging referral guidelines, covering various clinical scenarios, indications and recommendations (www.esriguide.org) [61][62][63]. The results from the present systematic review may be useful to incorporate in that system.
We excluded three studies where sensitivity and specificity data were provided, but it was not possible to extract sufficient data to produce 2 × 2 tables and calculate the diagnostic accuracy values, because only the sensitivity and specificity estimates were given [64][65][66]. In the study by Wang et al., estimates of sensitivity and specificity for EUS, ERCP and US were in line with the present results; the sensitivity of MR imaging and CT, however, were much lower (66% and 61%) [66]. The studies by Clave et al. and Orti et al. showed a lower sensitivity of ERCP (62% and 70%, respectively) compared to present results (82%) [64,65].
The risk of missing important studies was minimized by performing a search in four major databases by two reviewers independently, without setting any restrictions for language and publication date. However, this systematic review has some limitations. The heterogeneity of the pooled studies was moderate to high in all analyses (between 39% and 93%). However, in the head to head comparison analyses, the heterogeneity was low in most comparisons (<25%). Furthermore, the heterogeneity of the reference standards used in the studies could have influenced individual study results. Surgery, histology and long-term follow-up of patients are reliable methods. Some reference standards, such as the use of endoscopic pancreatic function test (ePFT) for establishing the diagnosis of CP, could have resulted in under-or overestimation of the sensitivity and specificity. In addition, the diagnosis of CP and the criteria used are different in different stages of the disease (e.g. absence of calcifications in the early phase of the disease). Another limitation was that our analyses included imaging studies and imaging protocols performed over the last 40 years in different centres with inherent variations in techniques and equipment. Especially in the last decade the quality of some imaging modalities (e.g. MRCP and CT) has improved considerably. Also there were concerns about the quality of the available evidence, as assessed by QUADAS-2 and the GRADE scoring system. The highest scores for accuracy in the diagnosis of CP were found for EUS and ERCP, but these are invasive techniques. ERCP has a relatively high risk of complications, such as post-ERCP pancreatitis (1.6-15.7%, mean complication rate of 4%) and is nowadays only used for therapeutic purposes (e.g. stenting of pancreatic duct) [67][68][69]. To date, diagnostic ERCP is largely replaced by EUS and the cross-sectional imaging modalities CT and MRCP.
It has been suggested that CT is better in detecting parenchymal calcifications and intraductal calcifications compared to MRCP [70][71][72][73]. On the other hand, MRCP is more often able to detect significant abnormalities of the pancreatic duct (e.g. PD dilatation and strictures) and slight changes of the pancreatic parenchyma and side branches, which can be attributed to early signs CP (i.e. atrophy, side branch ectasia) compared to CT [74]. Early diagnosis can also lead to a timely start of treatment, which has been associated with improved long-term outcome [75]. Nevertheless, for very early CP this association needs to be established in further research, such as the ESCAPE trial, evaluating the effect of early intervention in patients with CP [76]. As diagnostic sensitivity of CT and MRCP is not significantly lower than that of ERCP and EUS, and specificity is comparable, non-invasive modalities except for US are a likely first choice in patients with suspected pancreatic disease including chronic pancreatitis.
Acknowledgements The scientific guarantor of this publication is M.A. Boermeester. The authors of this manuscript declare relationships with the following companies: Baxter, Acelity/KCI, Ipsen, Mylan, Johnson & Johnson, Bard. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. The authors state that this work has not received any funding. Two of the authors have significant statistical expertise (SB, MAB). Institutional review board approval was not required because of the nature of the study (a systematic review).