The decision for EUS in patients with BD and negative other imaging modalities usually represents a dilemma for clinicians. Thus, we conducted this prospective diagnostic study to evaluate the role of linear EUS in this category of patients after non-diagnostic MRCP and help in the decision-making through identifying predictors of PB neoplasm on EUS.
In the present study, most patients were symptomatic with a minority of incidental asymptomatic patients. Jaundice (70.5%) was the most common presentation in our cohort of patients, and specifically in group A (89.7%) in contrast to the study by Carriere et al., in which 75% of patients had abdominal pain and only 23% had hyperbilirubinemia, but similarly, 56% of their cases had EUS explanation of CBD dilatation [14]. Chen et al. conducted a similar study on patients with suspected OJ and negative US and also detected pathology in 67.5% of cases [1]. Definitely, many studies revealed a higher incidence of pathological findings in symptomatic patients [1, 2, 14,15,16] and those with abnormal liver chemistry [17,18,19,20] compared to asymptomatic patients [21,22,23]. This could explain the high rate of positive EUS findings in our study.
EUS has greatly added beneficial steps reaching the definitive diagnosis in the current study. Out of 61 included patients, 59 had a positive finding on EUS examination with diagnostic accuracy as 98.3%. One patient showed negative findings by EUS, but the patient had persistent abdominal pain for which she was further diagnosed as acalcular cholecystitis in another facility and underwent surgical cholecystectomy with biliary exploration revealing a benign distal biliary stenosis. Nonetheless, benign distal stenosis is often difficult to diagnose and actually could be missed during EUS [2]. In the study by Chen and his colleagues, EUS showed 95.9% overall accuracy in detection cause of BD and 100% for no pathological finding [1]. These data demonstrate the vital role of EUS particularly in symptomatic patients even with unrecognizable etiology on other abdominal imaging.
Likewise, the neoplasm detection rate in our cases was 47.5% (29/61) with a diagnostic accuracy of 96.7% and overall sensitivity, specificity, PPV, and NPV as 100%, 93.8%, 93.5%, and 100%, respectively. Similar to our results, malignancy was detected in the study by Chen et al., in 33% of cases with an overall accuracy of 97.6% [1]. One patient in our study had distal CBD inflammatory stenosis which was falsely diagnosed as malignant stricture and another patient with mass-forming AIP was initially diagnosed as malignant pancreatic head mass by EUS and a definite diagnosis for both was achieved after EUS-guided biopsy. Definitely, biliary strictures remain challenging for different diagnostic tools including EUS. A meta-analysis of 36 studies (3532 patients) by Garrow et al. showed a high overall pooled sensitivity (78%) and specificity (84%) for malignancy detection by EUS; however, in case of suspected strictures, studies were associated with lower test performance [10].
The most common neoplasm detected by EUS in the current study was PHC 41.3% (12/29) followed by AC 37.9% (11/29) with a median size of 2.3 cm at the largest diameter. Chen and his colleagues found that EUS has accurately detected PHC and AC, 30.9% (13/42) and 54.7% (23/42) respectively with 100% accuracy for each type. Indeed, EUS is well-designed to evaluate the periampullary region due to the close proximity of the transducer to the duodenum. On the other side, in a study by Müller et al., EUS sensitivity for the detection of pancreatic neoplasms < 3 cm in diameter was 93% compared to 53% for CT and 67% for MR imaging [24]. Such small-sized tumors are still amenable to surgical resection [25] while can be easily missed on other abdominal imaging tools.
Contrariwise, missed choledocholithiasis was the most common etiology in group B, 37.5% (12/32). Garrow et al., in their meta-analysis, showed a high overall pooled sensitivity (89%) and specificity (94%) for choledocholithiasis detection by EUS [10]. In addition, a recent meta-analysis showed that EUS had a significantly higher diagnostic accuracy and sensitivity for the detection of CBD stones compared to MRCP, most likely due to a higher detection rate of small choledocholithiasis [26]. The median size of missed CBD stones detected by EUS was 6.6 mm in our cohort. ERCP was performed in the same EUS session after real-time detection of choledocholithiasis. According to an abstract by JS Leeds, EUS and ERCP can be performed safely in the same session with no increase in adverse events [27], and a study by Vila et al. showed that anesthesia dose was significantly reduced when EUS and ERCP are combined versus in two sessions [28]. Cost-effectiveness analyses have shown that EUS is a cost-effective option compared with MRCP, especially if ERCP can be performed during the same session [29, 30]. Interestingly, in the study by Chu and his colleagues, ERCP was canceled in four patients depending on EUS findings [31]. Analogous to their data, ERCP was canceled in two patients in our study with previous suspicion for CBD stones on MRCP and negative EUS (picture of passed stones). Decisively, EUS may be considered as an alternative for MRCP particularly when the therapeutic decision is warranted.
Indication of EUS examination in symptomatic patients may be logical and easy to decide; however, in asymptomatic subjects with isolated biliary dilatation, this semi-invasive maneuver often needs justification. Many studies [21,22,23] were conducted to answer this question with a recent meta-analysis [21] which declared that EUS for asymptomatic biliary dilations has a low detection rate of benign findings (9.2%) (including CBD stones, stricture, and PAD) and much lower (0.5%) for biliary neoplasms (mainly ampullary lesions). Although a minority of our patients were asymptomatic, however, EUS succeeded to delineate similar positive findings including P-NET, PAD, and benign biliary stenosis (Table 4). The median CBD diameter in this group of patients was 13.5mm (8–20.8mm). On the other hand, there is an increased concern about risks of the endoscopic procedure in this category of patients including infection risk and other rare events like perforation, hemorrhage, and sedation-related complications. All these points of costs and expected benefits should be shared with the patient before taking this decision [21].
Regarding post-cholecystectomy state, there has been much debate on its effect on BD, with a suggestion that the upper limit of biliary diameter may be increased to 10 mm after cholecystectomy [4]. In our study, 6 patients had prior cholecystectomy, with a median CBD diameter of 11.25mm (8–13mm), 5 of them were symptomatic. Positive EUS findings were obtained in symptomatic patients including 3 with missed choledocholithiasis, 1 with ampullary adenoma, and 1 with papillary stenosis while the other asymptomatic patient had PAD. This indicates EUS role even in post-cholecystectomy state particularly when symptoms are present.
Factors predicting EUS-positive findings were the main concern of many studies [1, 2, 11, 14, 15, 22, 32]. Our data supported Chen et al. study which showed that abdominal pain, significant weight loss, increased CA19-9, increased ALP, and CBD dilatation were all associated with malignancy and that CBD dilatation was the only independent predictor of malignancy (P < 0.05). The optimal cut-off level of CBD diameter in their study was 12.3 mm resulting in 46.3% sensitivity and 76.8% specificity for the presence of malignant obstruction with AUC as 0.702. Similarly, in our data, CA 19-9 to >37.1 U/ML, CBD diameter to > 12.9mm, total bilirubin to >2.6 mg/dl, and ALP to >165 mg/dl, all were significant predictors for the presence of neoplastic lesions at univariate analysis. In addition, both CA 19-9 > 37.1 u/ML and CBD diameter > 12.9mm were independent predictors at multivariate regression analysis with AUC as 0.788 and 0.706, respectively. Although there is published data that nullify the role of CBD diameter in the prediction of malignancy [2, 33], in contrast, our data confirms the vitality of EUS examination once these parameters are present even with non-diagnostic MRCP to exclude any missed lesions.
Limitations
The gold standard test in our study for choledocholithiasis was ERCP which sometimes has fallacies. Owing to resectability terms, surgery could not be performed for all neoplastic lesions in our cohort of patients.